bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical methods of nucleic acid transfer: general concepts and applications
Authors: Villemejane Julien , Mir Lluis M.
Published: January 2009

Physical methods of gene (and/or drug) transfer need to combine two effects to deliver the therapeutic material into cells. The physical methods must induce reversible alterations in the plasma membrane to allow the direct passage of the molecules of interest into the cell cytosol. They must also bring the nucleic acids in contact with the permeabilized plasma membrane or facilitate access to the inside of the cell. These two effects can be achieved in one or more steps, depending upon the methods employed. In this review, we describe and compare several physical methods: biolistics, jet injection, hydrodynamic injection, ultrasound, magnetic field and electric pulse mediated gene transfer. We describe the physical mechanisms underlying these approaches and discuss the advantages and limitations of each approach as well as its potential application in research or in preclinical and clinical trials. We also provide conclusions, comparisons, and projections for future developments. While some of these methods are already in use in man, some are still under development or are used only within clinical trials for gene transfer. The possibilities offered by these methods are, however, not restricted to the transfer of genes and the complementary uses of these technologies are also discussed. As these methods of gene transfer may bypass some of the side effects linked to viral or biochemical approaches, they may find their place in specific clinical applications in the future.

This article is part of a themed section on Vector Design and Drug Delivery. For a list of all articles in this section see the end of this paper, or visit: http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009
Optimizing the treatment of chronic hepatitis due to hepatitis C virus genotypes 2 and 3: a review
Authors: Tarantino Giuseppe , Craxì Antonio
Published: January 2009

Recently several randomized trials involving exclusively HCV 2 and 3 patients have explored the possibility of reducing the duration of therapy with PEG IFNs and ribavirin to 12–16 weeks. Among these, the largest studies (ACCELERATE, NORTH‐C and NORDynamIC) have failed to demonstrate, by intention‐to‐treat analysis, that short treatment is non‐inferior to the standard duration of 24 weeks originated by phase 3 trials. Even though obtaining univocal conclusions from these studies are difficult to obtain due to some critical differences (trial design, genotypes 2/3 ratio, rate of cirrhosis at baseline, ribavirin dose, assays to detect HCV‐RNA etc), all have proved that a rapid virological response (HCV‐RNA negative at 4 weeks) is the strongest predictor of SVR. Therefore, excluding risk factors for virological relapse at baseline, and identifying in the early phase of treatment, features related to a sustained response, the decision to reduce the duration of treatment to less than 24 weeks in HCV‐2 and 3 patients can be response‐guided appropriately.

Ongoing studies will assess whether extended 48 week regimens can benefit non‐RVR patients with HCV 2 or 3, especially those with more severe fibrosis.
The history of the “natural history” of hepatitis C (1968–2009)
Authors: Seeff Leonard B.
Published: January 2009

In the late 1960's, only types A and B hepatitis were believed to exist, distinguished by circumstances of exposure and incubation periods. In the early 1970's, studies of transfusion recipients were begun with the belief that hepatitis B would be responsible should transfusion‐associated hepatitis develop. After discovery of the viruses of hepatitis A and B, neither agent was found responsible, hence non‐A, non‐B (NANB) hepatitis. Initial follow‐up of these cases showed that ∼ 50% developed chronic hepatitis based on persistence of serum enzymes for at least 6 months. Approximately 15 years later, after the hepatitis C virus had been identified as the cause for NANB hepatitis, chronic hepatitis was found to develop more frequently as indicated by persistent viral infection in over 80% of infected adults but in only about 50% of infected children or young women. Follow‐up over 2 to 4 decades indicated that many infected persons developed progressive hepatic fibrosis, sometimes culminating in cirrhosis and/or liver cancer. Long‐term natural history studies have proved to be challenging because disease onset is often silent and progression extremely slow. Differing strategies have been used to determine the natural history, the descriptions and results of which are presented in this review.
Protease and polymerase inhibitors for the treatment of hepatitis C
Authors: Asselah Tarik , Benhamou Yves , Marcellin Patrick
Published: January 2009

Chronic hepatitis C is among the leading causes of chronicliver disease worldwide, with approximately 170 million people infected. The severity of disease varies from asymptomaticchronic infection to cirrhosis and hepatocellular carcinoma.

Recently,advances have been made, with the combination of pegylated interferon (PEG‐IFN) and ribavirin leading to a sustained virological response (SVR) in approximately 55% of cases. In genotypes 2 or 3, SVR rates reach 80%; in genotype 1 SVR rates is 50%. Furthermore, SVR appears to be long lasting, associated probably with a reduction in the risk of cirrhosis and hepatocellular carcinoma. Despite this progress, treatment failure still occurs in about halfof the patients. Furthermore, therapy results in several side effects and high costs. These limitations have led to important development of novel compounds under the name of specifically targeted antiviral therapy for HCV (STAT‐C). Also, considering side effects and treatment cost, prediction of virologicalnon‐response is mandatory. The management of chronic hepatitis C must include better knowledge of viral cycle and mechanisms of non response. The development of new molecules such as HCV enzyme inhibitors is ongoing. The aim of this review is to summarize results obtained with STATC: protease and polymerase inhibitors.
New drugs for the treatment of hepatocellular carcinoma
Authors: Boucher Eveline , Forner Alejandro , Reig Maria , Bruix Jordi
Published: January 2009

Treatment of hepatocellular carcinoma has dramatically changed in the last years. The better knowledge of the molecular mechanisms responsible of tumor initiation and progression has allowed the development of molecular targeted therapies that specifically block the disrupted pathways. Among all these new agents, Sorafenib is the only one that has shown efficacy in terms of survival in advanced stage in two randomized, double‐blind, controlled trials. The positive result of these two trials are the proof of the efficacy of molecular targeted therapies in hepatocellular carcinoma and opens the door to multipathway blockade and the use of these targeted therapies in the adjuvant setting. Other agents have shown promising results in phase 1‐2 trials but further studies are needed to demonstrate their efficacy. In the next years, efforts should be directed to identifying genomic and proteomic profiling that will help us to assess the prognosis and to define what treatment benefits whom, ultimately giving way to personalized medicine.
Hepatitis C genotype 4 therapy: increasing options and improving outcomes
Authors: Kamal Sanaa M.
Published: January 2009

Hepatitis C virus genotype 4 (HCV‐G4) is prevalent in the Middle East and Africa and has spread to several regions in Europe. HCV‐G4 represents a major health problem in Egypt, with a prevalence rate of 13%. Recently, HCV‐G4 has been spreading in Europe particularly among intravenous drug users (IDU) populations, who represent the main reservoir for HCV in Europe. This article reviews the current therapeutic strategies for HCV‐G4 infections in different populations. HCV‐G4 has been considered a difficult‐to‐treat genotype because of the poor sustained virological response (SVR) rates reported with a conventional interferon (IFN)‐based regimen. Pegylated IFN and ribavirin combination therapy was associated with significant improvements in SVR rates that currently exceed 60%, particularly with individualized therapy. Lower response rates have been reported in specific situations, namely chronic HCV‐G4 infection in IDUs and patients co‐infected with human immunodeficiency virus (HIV). Rapid and early virological responses have been useful tools for determination of the duration of therapy. In conclusion: therapy of HCV‐G4 has shown significant improvements, with higher sustained response rates and possibilities for a shorter duration. More research is required to optimize therapy in special populations such as IDUs and HIV‐co‐infected patients.
Retreatment of chronic hepatitis C: who and how?
Authors: Heathcote Jenny
Published: January 2009

All but about 10% of patients with chronic hepatitis C (CHC) (predominantly those infected with genotype 1) can respond to some degree to ‘combination’ therapy with interferon (IFN) and ribavirin. The slower the virological response to treatment, the less likely sustained viral clearance will take place. Many factors influence response to antiviral therapy; most cannot be reversed (e.g. sex, age, cirrhosis, genotype and viral load). A sustained viral clearance is considerably facilitated by compliance with full‐dose therapy for the prescribed time. The potential cause(s) for non‐response need(s) to be ascertained before attempting retreatment. The 10% of patients who are true ‘null’ responders may respond to the new specifically targeted antiviral therapies but whether the response can be sustained off‐therapy is unclear. Adjunctive therapies may facilitate response to retreatment if intolerance to treatment leading to diminished or absent doses was problematic in the past. Retreatment with a long‐acting IFN and an adequate ribavirin dose (15 mg/kg), but given for 72 weeks in prior relapsers following 48 weeks of treatment, will enhance sustained virological response (SVR) rates. No benefit is gained from changing one pegylated IFNα (PEG IFNα) to another unless the treatment duration is extended. Only α‐interferons are effective. For those individuals who still fail to achieve SVR, recruitment to trials of new treatments should be encouraged particularly for those with advanced liver disease. Lifestyle modification may be appropriate in attempt to reduce the chance of complications of liver disease, namely hepatocellular carcinoma, by smoking cessation, eliminating obesity and increasing coffee consumption.
Assessment of hepatitis C: non‐invasive fibrosis markers and/or liver biopsy
Authors: Bedossa Pierre
Published: January 2009

Chronic viral hepatitis is a prolonged inflammatory disease of the liver that may lead to the development of fibrosis, necro‐inflammation and other associated pathological features. Because fibrosis and its end‐point cirrhosis are the main causes of morbidity and mortality, fibrosis assessment is considered as the most relevant information for the evaluation of the severity of the disease and as a useful indicator for prognosis and treatment decision. Because fibrosis implies morphological damage, liver biopsy has come to be the natural gold standard for staging the disease. However, the high prevalence of chronic hepatitis C in addition to the cost and constraints generated by this procedure have triggered an intensive search for alternative methods for fibrosis evaluation. In this article, the strengths and weaknesses of liver biopsy and of non‐invasive markers will be reviewed and their respective roles in management of patients with chronic hepatitis C will be discussed.
Natural history of chronic hepatitis B virus infection and long‐term outcome under treatment
Authors: Liaw Yun‐Fan
Published: January 2009

Chronic hepatitis B virus (HBV) infection is a dynamic state of interactions among HBV, the hepatocytes and the immune system of the patient. Perinatally or early childhood‐acquired chronic HBV infection has a long ‘immune tolerant phase’, when patients are young, and HBeAg seropositive with a high viral load but with no significant liver disease. Persistent or episodic liver injuries during the ‘immune clearance phase’ may lead to decompensation, fibrosis progression or cirrhosis development in some patients, but may eventually lead to HBV‐DNA seroclearance with HBeAg seroconversion and entry into the ‘inactive phase’ with remission. Hepatitis may relapse, because of reactivation of HBV with precore or basal core promptor mutations, and develop ‘HBeAg‐negative chronic hepatitis’, in some patients. In contrast, HBsAg seroclearance may occur in those with sustained remission. During the course, HBV replication is the key driver of disease progression including development of cirrhosis and hepatocellular carcinoma (HCC). Among the currently available anti‐HBV drugs, the most extensive and longest experience has been gained with conventional interferon (IFN)‐α and lamivudine. A finite course of IFN therapy has long‐term benefit in achieving a cumulative response, increasing HBsAg seroclearance and reducing cirrhosis and/or HCC. Maintained virological response to lamivudine therapy has a similar long‐term benefit in reducing disease progression. Pegylated IFN and newer nucleos(t)ide analogues may have even better long‐term outcomes because of better therapeutic efficacy and/or a low risk of drug resistances. The treatment outcomes are still far from satisfactory. The development of safe and affordable anti‐HBV agents/strategies is needed to further improve outcomes.
HBeAg‐positive chronic hepatitis B: why do I treat my patients with pegylated interferon
Authors: Lau George K. K.
Published: January 2009

Worldwide, chronic hepatitis B virus infection is a major cause of end‐stage liver disease and hepatocellular carcinoma. While the past two decades have brought major advances in the availability of treatments to help delay or prevent these outcomes, treatment of chronic hepatitis B remains a serious challenge. With the recent availability of potent new nucleot(s)ide such as entecavir, tenofovir and telbuvidine, I still use pegylated interferon (PEG‐IFN)‐α for the treatment of chronic HBeAg‐positive patients. This is based on its relatively higher effectiveness in restoring the host immune control on viral replication, resulting in sustained diseases remission in a proportion of patients, a finite course of therapy and the absence of viral resistance. The two major hindrances to its wide application are its lack of effectiveness in a large proportion of patients and its side‐effect profile. The former shortcoming can be circumvented to a certain extent with the use of response predictor models. Recently, based on long‐term follow‐up study, the better durability of sustained response further enhances the confidence in the use of PEG‐IFN‐α in chronic HBeAg‐positive patients.
Optimal therapy in genotype 1 patients
Authors: Farnik Harald , Mihm Ulrike , Zeuzem Stefan
Published: January 2009

Most infections with hepatitis C virus (HCV) fail to resolve spontaneously and progress to chronic hepatitis C. Genotype 1 HCV accounts for most hepatitis C infections in North America, Western Europe, and Japan. Patients infected with HCV genotype 1 are the most resistant to treatment, which results in poor treatment outcomes. Although sustained virologic response (SVR) rates have significantly improved with introduction of combination therapy with pegylated interferon alfa and ribavirin, the rates are still lower than those in genotype 2 or 3 infections. This review discusses how treatment outcomes in patients with HCV genotype 1 infection can be optimized by using the drugs currently licensed for treatment of hepatitis C: pegylated interferon alfa‐2a/b and ribavirin. Dose modifications and variations of treatment duration are the two strategies that have been investigated best, so far. Treatment – naïve patients and non‐responders and relapsers to prior antiviral therapy are discussed separately.
Flora, vegetation and climate at Sokli, northeastern Fennoscandia, during the Weichselian Middle Pleniglacial
Authors: BOS JOHANNA A. A. , HELMENS KARIN F. , BOHNCKE SJOERD J. P. , SEPPÄ HEIKKI , BIRKS H. JOHN B.
Published: January 2009

A 2 m thick laminated lacustrine deposit of silt and clay recovered from the high‐latitudinal site at Sokli (northern Finland) provides a unique mid‐Weichselian fossil record for Fennoscandia. High‐resolution botanical and zoological analyses of the lacustrine deposit allow detailed reconstruction of the regional vegetational development and of the history of the lake and the wetland ecosystem within the Sokli basin during the early part of the Weichselian Middle Pleniglacial (=equivalent to Marine Isotope Stage (MIS) 3). The inferred terrestrial vegetation represented by the Sokli MIS 3 sequence (so‐called Tulppio Interstadial) was probably low‐arctic tundra, treeless but with shrub elements including juniper, willow, dwarf birch, ericoids, lycopods and a rich herb flora with a variety of arctic–alpine taxa and heliophilous, pioneer elements. The presence of herbs such as Rubus chamaemorus, Epilobium palustre, Potentilla palustris and Sphagnum, Drepanocladus and other mosses suggests that the lake was fringed by wet meadows and peatlands or peaty telmatic communities. The distributional ranges of pine and tree birch were probably only a few hundred kilometres south or southeast of Sokli. This is concordant with evidence for the presence of boreal tree taxa during the MIS 3 in the Baltic countries and further east in Europe, but contradicts with the commonly inferred treeless tundra or grass‐dominated steppe conditions in central Europe.
Genesis of hummocks in glaciofluvial corridors near the Keewatin Ice Divide, Canada
Authors: UTTING DANIEL J. , WARD BRENT C. , LITTLE EDWARD C.
Published: January 2009

Glaciofluvial corridor hummocks (GCHs) within the Walker Lake map area, Canada, were examined in order to determine the character and genesis of these geomorphic features and their associated deposits. Located south of the Chantrey Moraine and north of the Keewatin Ice Divide, these corridors occur within a belt extending approximately 120 km east–west and approximately 60 km north–south. They are spaced 5–10 km apart and are hundreds of metres to several kilometres in width. They have undulating longitudinal profiles, abrupt material boundaries with the surrounding till and occur in valleys and over interfluves. Hummocks were investigated using longitudinal and perpendicular ground‐penetrating radar (GPR) surveys in conjunction with pit excavations. From these analyses, the hummocks comprise a single lithofacies consisting of coarsely stratified, matrix‐supported gravely sand to a depth of approximately 10 m. This sediment is similar to that of a ‘sliding bed facies’ observed in esker sediments and hyperconcentrated flow deposits, both of which are attributed to high meltwater discharges. Therefore, we hypothesize that the Walker Lake GCHs formed from sedimentation in cavities at the base of the ice sheet by a rapid influx of meltwater.
Migraine in the Triptan Era: Lessons From Epidemiology, Pathophysiology, and Clinical Science
Authors: Bigal Marcelo E. , Ferrari Michel , Silberstein Stephen D. , Lipton Richard B. , Goadsby Peter J.
Published: January 2009

The triptan era has been a time of remarkable progress for migraine diagnosis and treatment. In this paper, we review some of the advances achieved in migraine science during this era focusing on 3 themes: lessons from clinical practice, lessons from epidemiology and lessons from pathophysiology. Science has shown that migraine is a disorder of the brain, and that the key events happen in the the trigeminal neuronal pathways, not on blood vessels. Clinical science has led to the observation that migraine sometimes progresses or remits. This in turn led to longitudinal epidemiologic studies focusing on factors that determine migraine prognosis. In addition, these studies raised questions about the mechanisms of migraine progression, including the role of allodynia, obesity, inflammation, and medications as determinants of progression. This in turn opens a new set of scientific questions about the neurobiologic determinants of migraine, as well as of its clinical course, and exciting opportunities to develop new therapies for this highly disabling brain disorder.
Acute Migraine Treatment With Rizatriptan in Real World Settings – Focusing on Treatment Strategy, Effectiveness, and Behavior
Authors: Hu Henry , Kurth Tobias , Cady Roger , Santanello Nancy , Bigal Marcelo E.
Published: January 2009

Although randomized controlled trials (RCTs) are the gold standard for assessing efficacy of a drug intervention, because they are conducted in a highly selected group of patients, they do not necessarily reflect normal customary or optimized patient care. Accordingly, information from RCTs must be supplemented by outcomes research and by nonexperimental or quasi‐experimental study designs. Herein, we discuss information that supplements the rigorous but sometimes rigid nature of RCTs in an effort to better understand the clinical utility of drug treatment for migraine with patient‐centered outcomes in mind. We start by discussing several lessons we learned from RCTs on comparative triptan studies, followed by presenting data on outcomes studies for rizatriptan. We then briefly discuss migraine treatment behavior issues, including early treatment and adherence to treatment.
The Prevalence of Headache and Its Association With Socioeconomic Status Among Schoolchildren in Istanbul, Turkey
Authors: Işık Uğur , Topuzoğlu Ahmet , Ay Pınar , Ersu Refika Hamutçu , Arman Ayşe Rodopman , Önsüz M. Fatih , Karavuş Melda , Dağlı Elif
Published: January 2009

Objective.— The etiology and pathogenesis of migraine and other types of headache are still under discussion. An interaction of organic, psychological, and psychosocial factors is operative. In this study, we aimed to determine the prevalence of headache and its association with socioeconomic status among schoolchildren.

Study Design.— A cross‐sectional study was performed on 2669 schoolchildren via a parental questionnaire. Socioeconomic status was determined according to the Turkish socioeconomic status scale.

Results.— The mean age of the students was 8.2 ± 2.4 years. The headache prevalence was 46.2% (95% CI: 44.3‐48.1). The prevalence of migraine was 3.4% (95% CI: 2.8‐4.1), the prevalence of probable migraine was 8.7% (95% CI: 7.6‐9.8), and that of non‐migraine headache was 34.1% (95% CI: 32.3‐35.9). Multivariate analysis revealed that older age, being a girl, having a family history of headache, and exposure to passive smoking at home were independently associated with headache. There was an inverse association between socioeconomic status and all 3 types of headaches after adjusting for age, sex, family history of headache, and presence of passive smoking. When the group with the lowest socioeconomic status was taken as the reference category, the odds ratios for the highest socioeconomic group were 0.33 (95% CI: 0.16‐0.69, P = .003) for the migraine, 0.30 (95% CI: 0.11‐0.89, P = .029) for the probable migraine, and 0.34 (95% CI: 0.16‐0.72, P = 0.005) for the non‐migraine headache.

Conclusion.— Headache is more common among children with lower socioeconomic groups. Social causation can play a role in the pathogenesis of headache.
Population pharmacokinetics of levetiracetam and dosing recommendation in children with epilepsy
Authors: Chhun Stephanie , Jullien Vincent , Rey Elisabeth , Dulac Olivier , Chiron Catherine , Pons Gérard
Published: January 2009

Purpose:  To develop a population pharmacokinetic model to evaluate the demographic and physiologic determinants of levetiracetam (LEV) pharmacokinetics (PK) and to suggest recommended doses of LEV in children.

Methods:  LEV PK were investigated in a prospective open trial of LEV as adjunctive therapy using a population approach performed with NONMEM (Nonlinear Mixed Effects Model) on 170 LEV concentration–time records and covariate information from 44 children between 4 and 16 years of age. Possible associations between pharmacokinetic parameters and age, gender, body weight, creatinine clearance, and concomitant antiepileptic drugs (AEDs) were assessed. The final model was used to perform Monte Carlo simulations in order to identify the dosing regimens that should achieve the same nominal target concentration range as in adults.

Results:  LEV PK were well described by a one‐compartment model with first‐order absorption and elimination. Both LEV apparent clearance and distribution volume were related to body weight, and no pharmacokinetic interaction was observed. Monte Carlo simulations showed that a 10mg/kg twice daily (b.i.d.) regimen provides a plasma concentration similar to that obtained in adults for the recommended 500 mg b.i.d. starting dose, and that a 20 mg/kg b.i.d. regimen would achieve the previously described 6–20 mg/L target range for the trough concentration.

Discussion:  Our results support the use of a weight‐based LEV dosing regimen and provide a basis for a recommended pediatric dosage regimen. The relationship between LEV plasma concentrations and clinical effect has not been evaluated fully and could differ between adults and children. Clinical studies should be able to validate these dosing recommendations.
The effects of right and left amygdala kindling on the female reproductive system in rats
Authors: Hum Kathryn M. , Megna Sofia , McIntyre Burnham W.
Published: January 2009

Purpose:  Women with epilepsy often have comorbid reproductive dysfunction. Using the amygdala kindling model in rats, the present study examined the effects of seizures of limbic origin on the reproductive system.

Methods:  Female Wistar rats were kindled from the left or right basolateral amygdala to a criterion of 40 stage V seizures. Sham‐kindled subjects were handled but not stimulated. Vaginal cytology was assessed daily for the duration of the study. Twenty‐four hours following the last kindled seizure, kindled subjects and their yoked controls were sacrificed and their brains and serum were extracted.

Results:  Kindled subjects displayed significantly more abnormal estrous cycle days and significantly elevated levels of estradiol as compared to controls. There was, however, no total suppression of cycling. No laterality effects were seen for estrous cycle abnormalities.

Discussion:  Seizures of limbic origin cause changes in estrous cycling. Right and left kindling seem to have a similar effect. These findings highlight the need for clinicians to monitor reproductive issues among individuals with epilepsy.
Surgery for pharmacoresistant epilepsy in the developing world: A pilot study
Authors: Boling Warren , Palade Adriana , Wabulya Angela , Longoni Nicoletta , Warf Benjamin , Nestor Scott , Alpitsis Rubina , Bittar Richard , Howard Charles , Andermann Frederick
Published: January 2009

Epilepsy prevalence in the developing world is many fold that found in developed countries. For individuals whose conditions failed to respond to pharmacotherapy, surgery is the only opportunity for cure. In Uganda, we developed a center for treatment of intractable temporal lobe epilepsy (iTLE) that functions within the technologic and expertise constraints of a severely low resource area. Our model relies on partnership with epilepsy professionals and training of local staff. Patients were prescreened at regional clinics for iTLE. Individuals meeting inclusion criteria were referred to the treating Ugandan hospital (CURE Children’s’ Hospital of Uganda, CCHU) for video‐EEG (electroencephalography), computed tomography (CT) imaging, and neuropsychological evaluation. Data were transferred to epilepsy experts for analysis and treatment recommendations. Ten patients were diagnosed with iTLE and surgically treated at CCHU. Six (60%) were seizure free, and there was no neurologic morbidity or mortality. Our model for surgical treatment of pharmacoresistant TLE has functioned successfully in a true developing world low resource setting.
Searching for Responders to Acamprosate and Naltrexone in Alcoholism Treatment: Rationale and Design of thePredict Study
Authors: Mann Karl , Kiefer Falk , Smolka Michael , Gann Horst , Wellek Stefan , Heinz Andreas ,   and the PREDICT Study research team
Published: January 2009

Background: Alcoholism represents a major public health issue and treating alcohol dependent patients remains an imminent challenge. Evidence based psychotherapies and pharmacotherapies are available. However, when administered to heterogeneous populations of patients effect sizes are only modest. We present the rationale and design of a double‐blind randomized trial comparing acamprosate, naltrexone, and placebo. Additionally we subtype patients on the basis of biological and psychometric measures and explore their treatment response to both acamprosate and naltrexone. According to our initial hypothesis, the “relief drinker/craver” is an endophenotype associated with glutamatergic dysfunction who responds to acamprosate. The “reward drinker/craver” is mainly associated with alterations in the dopaminergic and opioidergic system and responds to naltrexone.

Methods: The study is planned for 430 patients (2:2:1 for both drugs and placebo) over 12 weeks of medication. All receive manualized counselling to improve compliance (Medical Management) which is extended to 6 months. Subtyping is primarily done using the acoustic startle reflex, functional magnetic resonance imaging, positron emission tomography (in a subset of patients), and the Inventory of Drinking Situations. Relapsers will be re‐randomized into a second study where additional psychotherapy (Cognitive Behavioral Intervention) is used in a stepped care approach. Genotyping and additional analyses such as health economy are being done as well. The study follows the assessment methods, treatments, and medications used in the U.S. based COMBINE study, which will allow for a direct comparison between this U.S. study trial and a study performed in Europe.
Chronic Ethanol Feeding Alters Hepatocyte Memory Which is not Altered by Acute Feeding
Authors: Bardag‐Gorce F. , Oliva Joan , Dedes Jennifer , Li Jun , French Barbara A. , French Samuel W.
Published: January 2009

Background:  Gene expression changes in the liver after acute binge drinking may differ from the changes seen in chronic ethanol feeding in the rat. The changes in gene expression after chronic ethanol feeding may sensitize the liver to alcohol‐induced liver damage, which is not seen after acute binge drinking.

Methods:  To test this hypothesis, gene microarray analysis was performed on the livers of rats (n = 3) fed an acute binge dose of ethanol (6 g/kg body wt) and killed at 3 and 12 hours after ethanol by gavage. The gene microarrays were compared with those made on the liver of rats from a previous study, in which the rats were fed ethanol by intragastric tube for 1 month (36% of calories derived from ethanol).

Results:  Microarray analysis data varied between the acute and chronic models in several important respects. Growth factors increased mainly in the chronic alcohol fed rat. Changes in enzymes involved in oxidative stress were noted only with chronic ethanol feeding. Gene expression of fat metabolism was increased only with chronic ethanol feeding. Most importantly, epigenetic related enzymes and acetylation and methylation of histones changed only after chronic ethanol feeding.

Conclusions:  The results support the concept that chronic ethanol ingestion induces altered gene expression as a result of changes in epigenetic mechanisms, where acetylation and methylation of histones were altered.
Association Between Val66Met Brain‐Derived Neurotrophic Factor (BDNF) Gene Polymorphism and Post‐Treatment Relapse in Alcohol Dependence
Authors: Wojnar Marcin , Brower Kirk J. , Strobbe Stephen , Ilgen Mark , Matsumoto Halina , Nowosad Izabela , Sliwerska Elzbieta , Burmeister Margit
Published: January 2009

Background:  The purpose of this study was to examine relationships between genetic markers of central serotonin (5‐HT) and dopamine function, and risk for post‐treatment relapse, in a sample of alcohol‐dependent patients.

Methods:  The study included 154 patients from addiction treatment programs in Poland, who met DSM‐IV criteria for alcohol dependence. After assessing demographics, severity of alcohol use, suicidality, impulsivity, depression, hopelessness, and severity of alcohol use at baseline, patients were followed for approximately 1 year to evaluate treatment outcomes. Genetic polymorphisms in several genes (TPH2, SLC6A4, HTR1A, HTR2A, COMT, and BDNF) were tested as predictors of relapse (defined as any drinking during follow‐up) while controlling for baseline measures.

Results:  Of 154 eligible patients, 123 (80%) completed follow‐up and 48% (n = 59) of these individuals relapsed. Patients with the Val allele in the Val66Met BDNF polymorphism and the Met allele in the Val158Met COMT polymorphism were more likely to relapse. Only the BDNF Val/Val genotype predicted post‐treatment relapse [odds ratio (OR) = 2.62; p = 0.019], and time to relapse (OR = 2.57; p = 0.002), after adjusting for baseline measures and other significant genetic markers. When the analysis was restricted to patients with a family history of alcohol dependence (n = 73), the associations between the BDNF Val/Val genotype and relapse (OR = 5.76, p = 0.0045) and time to relapse (hazard ratio = 4.93, p = 0.001) were even stronger.

Conclusions:  The Val66Met BDNF gene polymorphism was associated with a higher risk and earlier occurrence of relapse among patients treated for alcohol dependence. The study suggests a relationship between genetic markers and treatment outcomes in alcohol dependence. Because a large number of statistical tests were conducted for this study and the literature on genetics and relapse is so novel, the results should be considered as hypothesis generating and need to be replicated in independent studies.
Field and Laboratory Alcohol Detection With 2 Types of Transdermal Devices
Authors: Marques Paul R. , McKnight A. Scott
Published: January 2009

Background:  Two types of transdermal electrochemical sensors that detect alcohol at the skin surface were evaluated. One, the AMS SCRAM™ device, is locked onto the ankle and is based on a fuel cell sensor; the other, a Giner WrisTAS™ device, worn on the wrist, is based on a proton exchange membrane. SCRAM is used by several court systems in the United States to monitor alcohol offenders, WrisTAS, a research prototype, is not commercially available.

Methods:  The 2 devices were worn concurrently by 22 paid research subjects (15 men, 7 women), for a combined total of 96 weeks. Subjects participated in both laboratory‐dosed drinking to a target of 0.08 g/dl blood alcohol concentration (BAC), and normal drinking on their own; all subjects were trained to use and carry a portable fuel‐cell breath tester for BAC determinations. Overall 271 drinking episodes with BAC ≥ 0.02 g/dl formed the signal for detection—60 from laboratory dosing, and 211 from self‐dosed drinking, with BAC ranging from 0.02 to 0.230 g/dl (mean 0.077 g/dl).

Results:  False negatives were defined as a transdermal alcohol concentration response equivalent <0.02 g/dl when BAC ≥ 0.02 g/dl. The overall true‐positive hit rate detected by WrisTAS was 24%. The low detection rate was due to erratic output and not recording during nearly 67% of all episodes; reportedly a chipset, not a sensor problem. SCRAM correctly detected 57% across all BAC events, with another 22% (total 79%) detected, but as <0.02 g/dl. When subjects dosed themselves to BAC ≥ 0.08 g/dl, SCRAM correctly detected 88% of these events. SCRAM devices lost accuracy over time likely due to water accumulation in the sensor housing. Neither unit had false‐positive problems when true BAC was <0.02 g/dl.

Conclusions:  Each device had peculiarities that reduced performance, but both types are able to detect alcohol at the skin surface. With product improvements, transdermal sensing may become a valuable way to monitor the alcohol consumption of those who should be abstaining.
Quantitative Lipid Metabolomic Changes in Alcoholic Micropigs With Fatty Liver Disease
Authors: Zivkovic Angela M. , Bruce German J. , Esfandiari Farah , Halsted Charles H.
Published: January 2009

Background:  Chronic ethanol consumption coupled with folate deficiency leads to rapid liver fat accumulation and progression to alcoholic steatohepatitis (ASH). However, the specific effects of alcohol on key liver lipid metabolic pathways involved in fat accumulation are unknown. It is unclear whether lipid synthesis, lipid export, or a combination of both is contributing to hepatic steatosis in ASH.

Methods:  In this study we estimated the flux of fatty acids (FA) through the stearoyl‐CoA desaturase (SCD), phosphatidylethanolamine‐N‐methyltransferase (PEMT), and FA elongation pathways in relation to liver triacylglycerol (TG) content in Yucatan micropigs fed a 40% ethanol folate‐deficient diet with or without supplementation with S‐adenosyl methionine (SAM) compared with controls. Flux through the SCD and PEMT pathways was used to assess the contribution of lipid synthesis and lipid export respectively on the accumulation of fat in the liver. Liver FA composition within TG, cholesterol ester (CE), phosphatidylethanolamine, and phosphatidylcholine classes was quantified by gas chromatography.

Results:  Alcoholic pigs had increased liver TG content relative to controls, accompanied by increased flux through the SCD pathway as indicated by increases in the ratios of 16:1n7 to 16:0 and 18:1n9 to 18:0. Conversely, flux through the elongation and PEMT pathways was suppressed by alcohol, as indicated by multiple metabolite ratios. SAM supplementation attenuated the TG accumulation associated with alcohol.

Conclusions:  These data provide an in vivo examination of liver lipid metabolic pathways confirming that both increased de novo lipogenesis (e.g., lipid synthesis) and altered phospholipid metabolism (e.g., lipid export) contribute to the excessive accumulation of lipids in liver affected by ASH.
Improvements in Life Cycle Energy Efficiency and Greenhouse Gas Emissions of Corn‐Ethanol
Authors: Liska Adam J. , Yang Haishun S. , Bremer Virgil R. , Klopfenstein Terry J. , Walters Daniel T. , Erickson Galen E. , Cassman Kenneth G.
Published: January 2009

Corn‐ethanol production is expanding rapidly with the adoption of improved technologies to increase energy efficiency and profitability in crop production, ethanol conversion, and coproduct use. Life cycle assessment can evaluate the impact of these changes on environmental performance metrics. To this end, we analyzed the life cycles of corn‐ethanol systems accounting for the majority of U.S. capacity to estimate greenhouse gas (GHG) emissions and energy efficiencies on the basis of updated values for crop management and yields, biorefinery operation, and coproduct utilization. Direct‐effect GHG emissions were estimated to be equivalent to a 48% to 59% reduction compared to gasoline, a twofold to threefold greater reduction than reported in previous studies. Ethanol‐to‐petroleum output/input ratios ranged from 10:1 to 13:1 but could be increased to 19:1 if farmers adopted high‐yield progressive crop and soil management practices. An advanced closed‐loop biorefinery with anaerobic digestion reduced GHG emissions by 67% and increased the net energy ratio to 2.2, from 1.5 to 1.8 for the most common systems. Such improved technologies have the potential to move corn‐ethanol closer to the hypothetical performance of cellulosic biofuels. Likewise, the larger GHG reductions estimated in this study allow a greater buffer for inclusion of indirect‐effect land‐use change emissions while still meeting regulatory GHG reduction targets. These results suggest that corn‐ethanol systems have substantially greater potential to mitigate GHG emissions and reduce dependence on imported petroleum for transportation fuels than reported previously.
Persistent Racial and Ethnic Disparities in Up‐to‐Date Colorectal Cancer Testing in Medicare Enrollees
Authors: Fenton Joshua J. , Tancredi Daniel J. , Green Pamela , Franks Peter , Baldwin Laura‐Mae
Published: January 2009

OBJECTIVES: To assess whether greater colonoscopy use among white as compared with nonwhite Medicare enrollees since Medicare established coverage for colorectal cancer (CRC) screening has been associated with a widening in white versus nonwhite disparities in up‐to‐date CRC testing status.

DESIGN: Serial cross‐sectional analysis of Medicare claims.

SETTING: Surveillance, Epidemiology, and End Results (SEER) regions in nine states, representing 14% of the U.S. population.

PARTICIPANTS: A 5% random sample of fee‐for‐service Medicare enrollees aged 70 to 79 within each 6‐month period from mid‐1995 through 2003.

MEASUREMENTS: Trends in up‐to‐date status (having a fecal occult blood test (FOBT) claim in the prior year or a sigmoidoscopy or colonoscopy claim in the prior 5 years) according to race or ethnicity, estimated using repeated‐measures logistic regression adjusting for age, sex, rural versus urban residence, income, comorbidity, and SEER region.

RESULTS: From mid‐1995 through 2003, the adjusted percentage of enrollees that were up‐to‐date increased by a similar magnitude in whites (from 39.4% to 47.3%), blacks (from 29.0% to 38.1%), Asians and Pacific Islanders (from 33.1% to 41.8%), and Hispanics (from 23.7% to 33.2%). Although white versus nonwhite disparities in up‐to‐date status via colonoscopy widened, this was counterbalanced by narrowing white versus nonwhite disparities in up‐to‐date status via FOBT and sigmoidoscopy.

CONCLUSION: White versus nonwhite disparities in up‐to‐date CRC testing status in Medicare enrollees largely persisted through 2003.
Factors Associated with Place of Death for Elderly Japanese‐American Men: The Honolulu Heart Program and Honolulu‐Asia Aging Study
Authors: Bell Christina L. , Davis James , Harrigan Rosanne C. , Somogyi‐Zalud Emese , Tanabe Marianne K. G. , Masaki Kamal H.
Published: January 2009

Place of death is an indicator of health service utilization at the end of life and differs according to cause of death. Asian Americans may have a higher percentage of hospital deaths than Caucasian Americans, yet reasons for this finding are unclear. This study examined distribution of place of death and the associations between place and cause of death in elderly Japanese‐American men in a longitudinal cohort: the Honolulu Heart Program and Honolulu‐Asia Aging Study. Data collected between 1991 and 1999 on 1,352 men aged 73 to 99 at death were analyzed for associations between cause‐of‐death characteristics and hospital, home, or nursing home location of death. Fifty‐nine percent of men died in hospitals, 23% died at home, and 18% died in nursing homes. Of the dementia‐related deaths, 43% occurred in hospitals (vs 16% in a national study), 37% occurred in nursing homes (vs 67% in a national study), and 20% occurred at home. Of the stroke deaths, 53% occurred in hospitals, 40% were in nursing homes, and 7% occurred at home. Of the cancer deaths, 53% occurred in hospitals, 34% occurred at home, and 13% were in nursing homes. Traditional family obligation to care for elderly people at home and inability to access care for dementia may account for the greater rate of hospital death and lower rate of nursing home deaths in this cohort. Attitudes of elderly Japanese Americans and their families regarding place of care at the end of life, particularly in the setting of dementia, merit future study.
Low‐avidity HPA‐1a alloantibodies in severe neonatal alloimmune thrombocytopenia are detectable with surface plasmon resonance technology
Authors: Socher Ines , Andrei‐Selmer Cornelia , Bein Gregor , Kroll Hartmut , Santoso Sentot
Published: January 2009

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is mostly caused by maternal alloantibodies directed against the human platelet alloantigen (HPA)‐1a. Currently, the serologic diagnosis of FNAIT is based on the characterization of the HPA alloantibodies in monoclonal antibody–based antigen‐capture assays (e.g., MAIPA assay). Accumulated current evidence indicated that such assays may overlook some HPA‐1a antibodies.

STUDY DESIGN AND METHODS: This study employed surface plasmon resonance (SPR) technology using immunoaffinity‐purified glycoprotein IIb/IIIa isoforms immobilized on biosensor chips to study the binding kinetics of HPA‐1a alloantibodies from different FNAIT cases in real time.

RESULTS: Analysis of HPA‐1a alloantibodies from FNAIT cases (n = 9) in SPR showed a moderate relative response (22.2‐69.7 resonance units [RU]) and slow antibody dissociation. After the dissociation phase, varying amounts of bound antibodies (41%‐79%) remained on the chip. In contrast in HPA‐1a alloantibodies from a patient suffering from posttransfusion purpura, a high relative response (∼490 RU) was observed at the end of the association phase and no dissociation of antibody binding was detectable. Of particular relevance, by the use of this SPR technique, HPA‐1a alloantibodies were detected in two severe FNAIT cases that had determined as false negative by MAIPA assay. In SPR, these HPA‐1a alloantibodies showed low‐avidity nature characterized by gradual dissociation of antibody during the association phase and complete detachment of antibody binding after the dissociation phase. This high “off‐rate” character of low‐avidity HPA‐1a alloantibodies indicates that such antibody binding is easily detachable by the extensive washing procedure of the MAIPA.

CONCLUSIONS: Our results demonstrated that the SPR method can facilitate the diagnosis of clinically relevant low‐avidity HPA‐1a antibodies.
Effects of applied muscle tension on the likelihood of blood donor return
Authors: Ditto Blaine , France Christopher R. , Albert Michael , Byrne Nelson , Smyth‐Laporte Julie
Published: January 2009

BACKGROUND: Blood donation–related symptoms such as dizziness and fainting are unpleasant for the donor and a significant disincentive for repeat donation. The muscle tensing technique of applied muscle tension reduced symptoms in several studies.

STUDY DESIGN AND METHODS: Follow‐up data from a randomized controlled trial of different components of applied tension were obtained. The number of subsequent blood donations in a 2‐year period was determined for 1059 of 1209 donors originally assigned to one of six conditions involving tension of different muscle groups or donation as usual.

RESULTS: In general, women who were assigned to one of the applied tension conditions were significantly more likely to return than women assigned to the donation as usual condition (67% vs. 55%, χ2(1) = 4.71, p = 0.03). There was no significant enhancement of return among male donors. Also, there was no association between the actual reduction of symptoms in different applied tension conditions and higher levels of return.

CONCLUSION: Participation in a condition that involved learning repeated muscle tension with the expectation that this might help reduce blood donation–related symptoms was associated with a greater likelihood of return for women.