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The U.S. deployed a missile defense system, Terminal High Altitude Area Defense (THAAD) in South Korea in April 2017, citing North Korea's nuclear and missile "threats" as justification. Its deployment, however, needs to be seen in the wider strategic context. Not only does the measure raise the arms race with North Korea, it also facilitates Japan's "proactive contribution to peace" and exacerbates the security dilemma between the U.S. and its allies on one side and China and Russia on the other. [ABSTRACT FROM AUTHOR]

Positive allometry of signalling traits has often been taken as evidence for sexual selection. However, few studies have explored interspecific differences in allometric scaling relationships among closely related species that vary in their degree of ecological similarity. Anolis lizards possess an elaborate retractable throat fan called a dewlap that is used for visual communication and differs greatly in size and colour among species. We observed that Anolis dewlaps demonstrate positive allometry: relative dewlap size increases with body size. We also observed that coexisting species are divergent in signal size allometries, while convergent species-similar in other aspects of ecology, morphology and behaviour-typically share similar dewlap allometric scaling relationships. These patterns suggest that dewlap scaling relationships may follow the same pattern as other traits in the anole radiation, where ecologically different sympatric species have evolved a suite of divergent traits.

Excessive gingival display (EGD) is a common esthetic concern. Lip repositioning surgery (LRS) was introduced as one of the treatment options to manage EGD. LRS can be used for skeletally and/or muscularly induced EGD. The present case series applied LRS using an Er,Cr:YSGG laser to treat 24 patients with minor vertical maxillary overgrowth or a hypermobile lip. At 6 months, the gingival display had decreased by 3.79 ± 1.59 mm (mean ± standard deviation), and the visible lip body when smiling had increased by 1.23 ± 0.74 mm. A questionnaire revealed that the level of satisfaction with the smile increased among the patients and that they had a positive attitude toward Er,Cr:YSGG laser-assisted LRS.

Adherence is a major factor in the effectiveness of the injectable extended-release naltrexone as a relapse prevention treatment in opioid use disorder. We examined the value of a variant of the Go/No-go paradigm in predicting extended-release naltrexone adherence in 27 detoxified opioid use disorder patients who were offered up to 3 monthly extended-release naltrexone injections. Before extended-release naltrexone, participants performed a Go/No-go task that comprised positively valenced Go trials and negatively valenced No-go trials during a functional magnetic resonance imaging scan. Errors of commission and neural responses to the No-go vs Go trials were independent variables. Adherence, operationalized as the completion of all 3 extended-release naltrexone injections, was the outcome variable. Fewer errors of commission and greater left accumbal response during the No-go vs Go trials predicted better adherence. These findings support the clinical potential of the behavioral and neurophysiological correlates of response inhibition in the prediction of extended-release naltrexone treatment outcomes in opioid use disorder., (© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.)

Background: Substance use disorder (SUD) patients with a history of trauma exhibit poorer treatment outcome, greater functional impairment and higher risk for relapse. Endorsement of prior trauma has, in several SUD populations, been linked to abnormal functional connectivity (FC) during task-based studies. We examined amygdala FC in the resting state (RS), testing for differences between cocaine patients with and without prior trauma., Methods: Patients with cocaine use disorder (CUD; n=34) were stabilized in an inpatient setting prior to a BOLD fMRI scan. Responses to Addiction Severity Index and the Mini-International Neuropsychiatric Interview were used to characterize the No-Trauma (n=16) and Trauma (n=18) groups. Seed-based RSFC was conducted using the right and left amygdala as regions of interest. Examination of amygdala RSFC was restricted to an a priori anatomical mask that incorporated nodes of the limbic-striatal motivational network., Results: RSFC was compared for the Trauma versus No-Trauma groups. The Trauma group evidenced greater connectivity between the amygdala and the a priori limbic-striatal mask. Peaks within the statistically significant limbic-striatal mask included the amygdala, putamen, pallidum, caudate, thalamus, insula, hippocampus/parahippocampus, and brain stem., Conclusions: Results suggest that cocaine patients with prior trauma (versus without) have heightened communication within nodes of the motivational network, even at rest. To our knowledge, this is the first fMRI study to examine amygdala RSFC among those with CUD and trauma history. Heightened RSFC intralimbic connectivity for the Trauma group may reflect a relapse-relevant brain vulnerability and a novel treatment target for this clinically-challenging population., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Drug-reward cues trigger motivational circuitry, a response linked to drug-seeking in animals and in humans. Adverse life events have been reported to increase sensitivity to drug rewards and to bolster drug reward signaling. Therefore, we hypothesized that cocaine-dependent individuals with prior emotional, physical and sexual abuse might have a heightened mesolimbic brain response to cues for drug reward in a new brief-cue probe. Cocaine-dependent human individuals (N = 68) were stabilized in an inpatient setting and then completed an event-related blood-oxygen-level dependent functional magnetic resonance imaging task featuring 500-ms evocative (cocaine, sexual, aversive) and comparator (neutral) cues. Responses to three questions about emotional, physical and sexual abuse from the Addiction Severity Index were used to divide the patients into subgroups (history of Abuse [n = 40] versus No Abuse [n = 28]). When subjects were grouped by the historical presence or absence of emotional, physical or sexual abuse, the Abuse group showed a heightened midbrain, thalamic, caudate, and caudal orbitofrontal cortex response to cocaine cues; a similar result was found in other evocative cues, as well. These findings are the first reported for a 500-ms cocaine-cue probe, and they highlight the ability of very brief evocative cues to activate the brain's motivational circuitry. Although all participants had severe cocaine use disorders, individuals reporting prior abuse had a heightened mesolimbic response to evocative cues. To our knowledge, this is the first study in humans linking a history of abuse to a brain vulnerability (heightened mesolimbic response to drug cues) previously shown to contribute to drug-seeking., (© 2016 Society for the Study of Addiction.)

Relapse is a widely recognized and difficult to treat feature of the addictions. Substantial evidence implicates cue-triggered activation of the mesolimbic dopamine system as an important contributing factor. Even drug cues presented outside of conscious awareness (i.e., subliminally) produce robust activation within this circuitry, indicating the sensitivity and vulnerability of the brain to potentially problematic reward signals. Because pharmacological agents that prevent these early cue-induced responses could play an important role in relapse prevention, we examined whether baclofen-a GABAB receptor agonist that reduces mesolimbic dopamine release and conditioned drug responses in laboratory animals-could inhibit mesolimbic activation elicited by subliminal cocaine cues in cocaine-dependent individuals. Twenty cocaine-dependent participants were randomized to receive baclofen (60 mg/d; 20 mg t.i.d.) or placebo. Event-related BOLD fMRI and a backward-masking paradigm were used to examine the effects of baclofen on subliminal cocaine (vs neutral) cues. Sexual and aversive cues were included to examine specificity. We observed that baclofen-treated participants displayed significantly less activation in response to subliminal cocaine (vs neutral) cues, but not sexual or aversive (vs neutral) cues, than placebo-treated participants in a large interconnected bilateral cluster spanning the ventral striatum, ventral pallidum, amygdala, midbrain, and orbitofrontal cortex (voxel threshold p < 0.005; cluster corrected at p < 0.05). These results suggest that baclofen may inhibit the earliest type of drug cue-induced motivational processing-that which occurs outside of awareness-before it evolves into a less manageable state.

Rationale: Addiction theories posit that drug-related cues maintain and contribute to drug use and relapse. Indeed, our recent study in cocaine-dependent patients demonstrated that subliminally presented cocaine-related stimuli activate reward neurocircuitry without being consciously perceived. Activation of reward neurocircuitry may provoke craving and perhaps prime an individual for subsequent drug-seeking behaviors., Objectives: Using an equivalent paradigm, we tested whether cannabis cues activate reward neurocircuitry in treatment-seeking, cannabis-dependent individuals and whether activation was associated with relevant behavioral anchors: baseline cannabis craving (drug-seeking behavior) and duration of use (degree of conditioning)., Methods: Twenty treatment-seeking, cannabis-dependent individuals (12 males) underwent event-related blood oxygen level-dependent functional magnetic resonance imaging during exposure to 33-ms cannabis, sexual, and aversive cues presented in a backward-masking paradigm. Drug use history and cannabis craving were assessed prior to imaging., Results: Participants showed increased activity to backward-masked cannabis cues in regions supporting reward detection and interoception, including the left anterior insula, left ventral striatum/amygdala, and right ventral striatum. Cannabis cue-related activity in the bilateral insula and perigenual anterior cingulate cortex was positively associated with baseline cannabis craving, and cannabis cue-related activity in the medial orbitofrontal cortex was positively correlated with years of cannabis use. Neural responses to backward-masked sexual cues were similar to those observed during cannabis cue exposure, while activation to aversive cues was observed only in the left anterior insula and perigenual anterior cingulate cortex., Conclusions: These data highlight the sensitivity of the brain to subliminal reward signals and support hypotheses promoting a common pathway of appetitive motivation.

Introduction: The aim of this study was to characterize clinicopathological features of acute panmyelosis with myelofibrosis (APMF), acute megakaryoblastic leukemia with myelofibrosis (AMKL-MF), primary myelofibrosis (PMF) and myelodysplastic syndrome with myelofibrosis (MDS-MF) in order to provide the keys to the differential diagnosis of bone marrow (BM) fibrosis., Methods: We compared age, gender, splenomegaly, serum lactate dehydrogenase level, blood cell counts, blast counts in peripheral blood (PB) and BM, megakaryocyte counts, BM cellularity, dysplasia, and the karyotypes of patients with APMF (n = 6), AMKL-MF (n = 7), PMF (n = 44), and MDS-MF (n = 44)., Results: APMF showed hyperplasia of all three lineages, increase in megakaryocyte count with dysplasia and frequent abnormal karyotypes. AMKL-MF was associated with elevated BM blast counts, decreased BM megakaryocyte count with rare megakaryocytic dysplasia and chromosome 21 abnormality. PMF patients displayed splenomegaly, rare blasts in PB/BM, and JAK2 V617F mutation. MDS-MF patients showed pancytopenia, dysplasia in all three lineages and recurrent chromosomal abnormalities involving chromosome 5,7,12, and 17., Conclusions: Although differential diagnosis among APMF, AMKL-MF, PMF, and MDS-MF is very challenging due to the overlapping clinical and morphological features, meticulous investigation of the patient with respect to splenomegaly, blood cell count, PB and BM findings, and karyotype will serve as a guide to correct diagnosis., (© 2013 John Wiley & Sons Ltd.)

Objective: : Determining the brain substrates underlying the motivation to abuse addictive drugs is critical for understanding and treating addictive disorders. Laboratory neuroimaging studies have demonstrated differential activation of limbic and motivational circuitry (eg, amygdala, hippocampus, ventral striatum, insula, and orbitofrontal cortex) triggered by cocaine, heroin, nicotine, and alcohol cues. The literature on neural responses to marijuana cues is sparse. Thus, the goals of this study were to characterize the brain's response to marijuana cues, a major motivator underlying drug use and relapse, and determine whether these responses are linked to self-reported craving in a clinically relevant population of treatment-seeking marijuana-dependent subjects., Methods: : Marijuana craving was assessed in 12 marijuana-dependent subjects using the Marijuana Craving Questionnaire-Short Form. Subsequently, blood oxygen level dependent functional magnetic resonance imaging data were acquired during exposure to alternating 20-second blocks of marijuana-related versus matched nondrug visual cues., Results: : Brain activation during marijuana cue exposure was significantly greater in the bilateral amygdala and the hippocampus. Significant positive correlations between craving scores and brain activation were found in the ventral striatum and the medial and lateral orbitofrontal cortex (P < 0.0001)., Conclusions: : This study presents direct evidence for a link between reward-relevant brain responses to marijuana cues and craving and extends the current literature on marijuana cue reactivity. Furthermore, the correlative relationship between craving and brain activity in reward-related regions was observed in a clinically relevant sample (treatment-seeking marijuana-dependent subjects). Results are consistent with prior findings in cocaine, heroin, nicotine, and alcohol cue studies, indicating that the brain substrates of cue-triggered drug motivation are shared across abused substances.

Voxel-based morphometry (VBM) studies have interpreted longitudinal medication- or behaviorally induced changes observed on T1-weighted magnetic resonance images (MRIs) as changes in neuronal structure. Although neurogenesis or atrophy certainly occurs, the use of T1-weighted scans to identify change in brain structure in vivo in humans has vulnerability: the T1 relaxation time for arterial blood and gray matter are not clearly distinguishable and therefore, apparent reported structural findings might be at least partially related to changes in blood flow or other physiological signals. To examine the hypothesis that apparent structural modifications may reflect changes introduced by additional mechanisms irrespective of potential neuronal growth/atrophy, we acquired a high-resolution T1-weighted structural scan and a 5-min perfusion fMRI scan (a measurement of blood flow), before and after administration of an acute pharmacological manipulation. In a within-subject design, 15 subjects were either un-medicated or were administered a 20 mg dose of baclofen (an FDA-approved anti-spastic) approximately 110 min before acquiring a T1-weighted scan and a pseudo continuous arterial spin labeled perfusion fMRI scan. Using diffeomorphic anatomical registration through exponentiated lie algebra within SPM7, we observed macroscopic, and therefore implausible, baclofen-induced decreases in VBM 'gray matter' signal in the dorsal rostral anterior cingulate (family wise error corrected at p<0.04, T = 6.54, extent: 1,460 voxels) that overlapped with changes in blood flow. Given that gray matter reductions are unlikely following a single dose of medication these findings suggest that changes in blood flow are masquerading as reductions in gray matter on the T1-weighted scan irrespective of the temporal interval between baseline measures and longitudinal manipulations. These results underscore the crucial and immediate need to develop in vivo neuroimaging biomarkers for humans that can uniquely capture changes in neuronal structure dissociable from those related to blood flow or other physiological signals.

Background: Preclinical and clinical evidence show that the GABA B agonist, baclofen is a promising treatment for addictive disorders; however, until recently its mechanism of action in the human brain was unknown. In previous work we utilized a laboratory model that included a medication versus placebo regimen to examine baclofen's actions on brain circuitry. Perfusion fMRI [measure of cerebral blood flow (CBF)] data acquired 'at rest' before and on the last day of the 21-day medication regimen showed that baclofen diminished CBF bilaterally in the VS, insula and medial orbitofrontal cortex (mOFC). In the present study, we hypothesized that a single dose of baclofen would have effects similar to repeated dosing., Methods: To test our hypothesis, in a crossover design, CBF data were acquired using pseudo continuous arterial spin labeled (pCASL) perfusion fMRI. Subjects were either un-medicated or were administered a 20mg dose of baclofen approximately 110 min prior to scanning., Results: Acute baclofen diminished mOFC, amygdala, and ventral anterior insula CBF without causing sedation (family-wise error corrected at p=0.001)., Conclusions: Results demonstrate that similar to repeated dosing, an acute dose of baclofen blunts the 'limbic' substrate that is hyper-responsive to drugs and drug cues. Smokers often manage their craving and can remain abstinent for extended periods after quitting, however the risk of eventual relapse approaches 90%. Given that chronic medication may not be a practical solution to the long-term risk of relapse, acute baclofen may be useful on an 'as-needed' basis to block craving during 'at risk' situations., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Stepping over obstacles requires vision to guide the leading leg, but direct visual information is not available to guide the trailing leg. The neural mechanisms for establishing a stored obstacle representation and thus facilitating the trail leg trajectory in humans are unknown. Twenty-four subjects participated in one of three experiments, which were designed to investigate the contribution of visual, proprioceptive, and efference copy signals. Subjects stepped over an obstacle with their lead leg, stopped, and straddled the obstacle for a delay period before stepping over it with their trail leg while toe elevation was recorded. Subsequently, we calculated maximum toe elevation and toe clearance. First, we found that subjects could accurately scale trail leg toe elevation and clearance, despite straddling an obstacle for up to 2 min, similar to quadrupeds. Second, we found that when the lead leg was passively moved over an obstacle (eliminating an efference copy signal and altering proprioception) without vision, trail leg toe elevation and clearance were reduced, and variability increased compared with when subjects actively moved their lead leg. Trail leg toe measures returned to normal when vision was provided during the passive manipulation. Finally, we found that altering lead leg proprioceptive feedback by adding mass to the ankle had no effect on trail leg toe measures. Taken together, our results suggest that humans can store a neural representation of obstacle properties for extended periods of time and that vision appears to be sufficient in this process to guide trail leg trajectory.

This paper offers a proposed program of research using single-case time-series methods that can be used by practicing clinicians. The paper is written for psychodynamically oriented clinicians who want to get involved in psychotherapy research and make contributions to the scientific literature. How to measure treatment outcomes and psychodynamic constructs are discussed. With few exceptions, conducting single-case time-series research using psychodynamic psychotherapy has far more advantages than disadvantages.

Context: Varenicline, an effective smoking cessation medication, functions as an α4β2 nicotinic acetylcholine receptor partial agonist. It indirectly affects the dopaminergic reward system by reducing withdrawal symptoms during abstinence and by decreasing the reinforcement received from nicotine while smoking. We hypothesize that varenicline would have a third mechanism to blunt responses to smoking cues in the reward-related ventral striatum and medial orbitofrontal cortex and would be associated with a reduction in smoking cue–elicited craving., Design: A laboratory model of conditioned responding and arterial spin-labeled perfusion functional magnetic resonance imaging, a biomarker of regional brain activity, was used to test our hypothesis. Perfusion functional magnetic resonance imaging is quantitative and stable across time, facilitating the measurement of medication-induced neural modifications in the brain in response to a challenge (smoking cue exposure) and in the brain in the resting condition (without provocation). Smokers were imaged during rest and during smoking cue exposure before and after a 3-week randomized placebo-controlled medication regimen. Subjects were nonabstinent to explicitly examine the effects of varenicline on cue reactivity independent of withdrawal., Setting: Center for the Study of Addictions, University of Pennsylvania, Philadelphia. Subjects Subjects were nicotine-dependent smokers who responded to advertisements placed on local radio and Listservs to participate in a medication-related research study that specifically stated "this is not a Quit Smoking Study" and "smokers may be contemplating but not currently considering quitting.", Results: Prerandomization smoking cues vs nonsmoking cues activated the ventral striatum and medial orbitofrontal cortex (t = 3.77) and elicited subjective reports of craving (P = .006). Craving reports correlated with increased activity in the posterior cingulate (t = 4.11). Administration of varenicline diminished smoking cue–elicited ventral striatum and medial orbitofrontal cortex responses (t values from –3.75 to –5.63) and reduced self-reported smoking cue–elicited craving, whereas placebo-treated subjects exhibited responses similar to those observed prior to randomization. Varenicline-induced activation of lateral orbitofrontal cortex in the brain at rest (t = 5.63) predicted blunting of smoking cue responses in the medial orbitofrontal cortex (r = –0.74)., Conclusions: Varenicline's reciprocal actions in the reward-activated medial orbitofrontal cortex and in the reward-evaluating lateral orbitofrontal cortex underlie a diminished smoking cue response, revealing a distinctive new action that likely contributes to its clinical efficacy.

Previously we demonstrated profound effects of dopamine transporter (DAT) SLC6A3 genotype on limbic responses to smoking cues (SCs). Probands carrying at least one copy of the 9-repeat allele (9-repeat carriers) had greater neural responses to SCs in the anatomically interconnected rostral ventral striatum/medial orbitofrontal cortex (VS/mOFC), compared with homozygotes for the 10-repeat allele (10/10-repeats). To test the reliability of the initial findings, we examined perfusion functional magnetic resonance images acquired during SC exposure in a new cohort of smokers (N=26) who were genotyped for the SLC6A3 polymorphism. In smokers overall, activity was enhanced in the VS/mOFC (t=3.77). Contrasts between allelic groups revealed that 9-repeat carriers had a greater response to SCs in the VS (t=3.12) and mOFC (t=3.19). In separate groups, 9-repeat carriers showed increased activity in the VS (t=5.47) and mOFC (T=4.96), while no increases were observed in 10-repeats. Subjective reports of craving correlated with increased activity in reward-related structures including the extended amygdala, insula and post-central gyrus, and decreased activity in the dorsolateral prefrontal cortex, and were DAT-genotype dependent (r=0.63-0.96). In secondary analyses, we found that The Fagerström Test for Nicotine Dependence scores correlated with enhanced SC-induced perfusion in 10/10-repeats in the insula, mOFC, medial temporal and superior frontal gyri (r=0.50-0.82), while correlations were absent in 9-repeat carriers. Despite heterogeneity introduced by a host of factors, including variance in other genes involved in smoking behavior, we confirm that DAT genotype predicts the direction and location of neural responses to SCs., (© 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.)

Purpose: Fatigue is one of the most common symptoms experienced by patients with cancer. This trial was developed to evaluate the efficacy of long-acting methylphenidate for improving cancer-related fatigue and to assess its toxicities., Patients and Methods: Adults with cancer were randomly assigned in a double-blinded manner to receive methylphenidate (target dose, 54 mg/d) or placebo for 4 weeks. The Brief Fatigue Inventory was the primary outcome measure, while secondary outcome measures included a Symptom Experience Diary (SED), the Short Form-36 (SF-36) Vitality Subscale, a linear analog self-assessment, the Pittsburgh Sleep Quality Index, and the Subject Global Impression of Change., Results: In total, 148 patients were enrolled. Using an area under the serum concentration-time curve analysis, there was no evidence that methylphenidate, as compared with placebo, improved the primary end point of cancer-related fatigue in this patient population (P = .35). Comparisons of secondary end points, including clinically significant changes in quality-of-life variables and cancer-related fatigue change from baseline, were similarly negative. However, a subset analysis suggested that patients with more severe fatigue and/or with more advanced disease did have some fatigue improvement with methylphenidate (eg, in patients with stage III or IV disease, the mean improvement in usual fatigue was 19.7 with methylphenidate v 2.1 with placebo; P = .02). There was a significant difference in self-reported toxicities (SED), with increased levels of nervousness and appetite loss in the methylphenidate arm., Conclusion: This clinical trial was unable to support the primary prestudy hypothesis that the chosen long-acting methylphenidate product would decrease cancer-related fatigue.

Objectives: Cannabis is the most widely used drug in the United States, and its use carries negative health consequences; however, universal screening for cannabis use is cumbersome. If data commonly collected in the primary care setting (eg, use of alcohol, smoking status, and depression symptoms) could predict cannabis use, then providers can implement targeted marijuana screening in high-risk groups., Methods: We reviewed Behavioral Health Laboratory data collected between 2003 and 2006 from 5512 patients referred by Veterans Affairs primary care clinics for potential mental health needs. Logistic regression was used to determine the predictors of past year marijuana use., Results: A total of 11.5% of the sample reported using marijuana in the past year. Age, gender, other drug use, presence of alcohol use disorders, smoking status, depressive disorders, posttraumatic stress disorder, anxiety disorders, and psychotic symptoms, individually, were associated with the patients' use of marijuana during the past year. When controlling for age, race, and gender in a logistic regression analyses, only other drug use, alcohol use disorder, and smoking status were linked to past year marijuana use. Patients were 5.4 (95% confidence interval [CI] 4.3-6.7) times more likely to have used marijuana during the past year if they used another illicit drug during the past year. Those with alcohol use disorder diagnosis or current smokers were 2.3 (95% CI 1.9-2.8) and 1.5 times (95% CI 1.3-1.7), respectively, more likely to have used marijuana during the past year. Receiver operating characteristic curve (area under curve = 0.79) represents good sensitivity and specificity of the model, correctly classifying 88.4% of the past year marijuana users., Conclusion: Identifying patients at high risk for cannabis use may facilitate targeted screening and provision of interventions in primary care. Patients who screen positive for cigarette use, alcohol abuse or dependence, or have evidence of other illicit drug use could be considered for cannabis screening.

Background: Clinically depressed patients without substance use disorders, compared to controls, exhibit significantly lower resting regional cerebral blood flow (rCBF) in the prefrontal cortex (PFC). In this study, we examined the link between resting rCBF in the PFC and current depressive symptoms in methadone-maintained opiate-dependent (MM) patients with or without major depression., Methods: Arterial spin labeled perfusion fMRI at 3 Tesla was used to measure resting rCBF in 21 MM patients. Perfusion data were analyzed using SPM2. The relationship between Beck Depression Inventory (BDI) score and resting rCBF was examined in a single regression analysis., Results: The BDI scores ranged between 0 and 18 (m=7.0, S.D.=4.8), and 30% of the sample had mild to moderate depression symptoms according to BDI scores. A negative correlation was observed between BDI scores and relative rCBF in the bilateral ventrolateral prefrontal cortex, and middle frontal gyri., Conclusions: The inverse relationship between prefrontal paralimbic rCBF and depression scores suggests a link between reduced fronto-limbic activity and depressive symptoms in MM patients. A significant subgroup of opiate-dependent patients has clinical or sub-clinical depression that is often undetected; our data identify brain substrates of depression symptoms that may also be a potential marker of relapse in this population. Treatment strategies targeting these brain regions may improve outcomes in depressed substance abusers.

Recently, we reported that naltrexone at 150 mg/day significantly decreased cocaine and alcohol use for men but not women with co-occurring cocaine and alcohol dependence. The present study is an exploratory investigation of predictors that explain the different gender responses to naltrexone, with a particular focus on differential predictors of treatment attrition. No significant predictors were associated with treatment discontinuation in men. Women, however, were more likely to discontinue treatment when reporting severe pre-treatment psychiatric problems or nausea while in treatment. Further research on the impact of pre-treatment and in-treatment gender differences with naltrexone is warranted.

This is a randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy of a higher-than-typical daily dose of naltrexone (150 mg/day), taken for 12 weeks, in 164 patients (n = 116 men and n = 48 women) with co-occurring cocaine and alcohol dependence. Patients were stratified by gender and then randomly assigned to either naltrexone or placebo, and to either cognitive-behavioral therapy or a type of medical management. The two primary outcomes were cocaine use and alcohol use. Significant Gender x Medication interactions were found for cocaine use via urine drug screens (three way, with time) and self-reports (two way) for drug severity (two way) and alcohol use (two way). The type of psychosocial treatment did not affect outcomes. Thus, 150 mg/day naltrexone added to a psychosocial treatment resulted in reductions in cocaine and alcohol use and drug severity in men, compared to higher rates of cocaine and alcohol use and drug severity in women.

Background: The clinical outcomes and costs of implantable cardioverter-defibrillators (ICDs) used for primary prevention of sudden cardiac death in nonexperimental settings are uncertain., Objective: The purpose of this study was to measure the health outcomes and costs among a nationally representative cohort of elderly, primary-prevention ICD recipients., Methods: We collected health-care cost and utilization data from all Medicare beneficiaries hospitalized for congestive heart failure (CHF) who had received primary-prevention ICDs between October 2003 and September 2005 as well as propensity-score-matched control Medicare beneficiaries hospitalized for CHF during the same period. A multivariable Cox proportional hazards model was fitted to the cohort, which comprised 7125 ICD recipients and 7125 controls and which was followed through December 2005. Medicare claims in the first year inclusive of the index hospitalization were used to assess differences in health-care costs., Results: ICD receipt was associated with a significant reduction in mortality (adjusted hazard ratio = 0.62, 95% confidence interval 0.58-0.67). ICD patients had higher median hospital costs in the first 30 days after initial hospitalization (median difference = $41,542, P <.001) and at 1 year (median difference = $41,503, P <.001) as well as higher outpatient and physician costs at 6 months (median difference = $1828, P <.001)., Conclusions: ICD implantation was associated with reduced mortality in a nonexperimental, elderly, primary-prevention patient population hospitalized for CHF. The additional health-care costs of ICD implantation were substantial but comparable to published cost-effectiveness models that have projected ICDs to be cost-effective.

Background: Although patients receiving implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden cardiac death are the fastest growing segment of the ICD recipient population, the quality-of-life (QOL) effects of the ICD among primary prevention patients are not well understood. The purpose of this study was to measure and compare the health-related QOL among primary and secondary prevention ICD recipients, and to determine predictive factors for high or low QOL in each group., Methods: Forty-five primary prevention and 75 secondary prevention ICD recipients receiving routine care in electrophysiology clinics within the University of Pennsylvania Health System were assessed using several well-validated general and ICD-specific QOL instruments., Results: Between primary and secondary prevention patients, there were no significant differences in EuroQol 5D (medians: 0.84 vs 0.84, P = 0.71), Health Utilities Index (medians: 0.88 vs 0.85, P = 0.95), Short Form-12 aggregate physical summary (means: 45 vs 46, P = 0.64), and Short Form-12 aggregate mental summary (means: 46 vs 47, P = 0.93) scores. Both primary and secondary prevention patients viewed their devices favorably according to the Florida Patient Acceptance Survey scale, with no significant differences between group means (80 vs 83, P = 0.71). However, substantial fractions of both primary and secondary prevention recipients had particular concerns about lifting (40%), sexual activity (19%), and driving (14%)., Conclusions: QOL does not significantly differ between primary prevention and secondary prevention ICD recipients. Device recipients had comparable QOL to published, nationwide QOL estimates among non-ICD patients of similar age. The ICD was highly acceptable to most primary and secondary prevention patients.

Objectives: While the efficacy of drug-eluting coronary stents (DES) has been demonstrated by several clinical trials, the impact of DES on health-care costs and recipient quality of life (QOL) is controversial. We performed a systematic review of the published literature on DES costs and the QOL effects of restenosis and target vessel revascularization (TVR)., Methods: Among 536 potential articles initially identified by a broad search, 12 publications ultimately met inclusion criteria. Data were independently abstracted, evaluated for quality and relevance, and summarized by two reviewers. Excessive heterogeneity among these studies prevented formal meta-analysis, thus a narrative synthesis of the literature was performed., Results: In four economic studies, DES recipients had 1,600 dollars-3,200 dollars higher up-front costs than recipients of bare metal stents, but the differences in total costs after 1 year were less pronounced (200 dollars-1,200 dollars), and estimates of the average cost of an avoided revascularization ranged widely (1,800 dollars-36,900 dollars). All eight QOL studies indicated that restenosis was associated with lower QOL, but only two studies quantified this in terms of quality-adjusted life years (QALYs), with estimates ranging from 0.06 to 0.08. An additional study estimated that the median willingness to pay to prevent restenosis was 2,400 dollars-3,600 dollars., Conclusions: There is a lack of convergence in the literature on the cost of DES in avoiding TVR. There is more agreement that the average QALY benefit of an avoided revascularization is 0.04-0.08. This implies that use of DES in patients where the average cost per avoided revascularization exceeds 8,000 dollars may be less likely to be cost-effective.

Although the clinical efficacy of implantable cardioverter-defibrillators (ICDs) has been convincingly demonstrated in clinical trials, the impact of ICDs on health care costs and recipients' quality of life (QOL) is less certain. The existing medical research on the health care costs and QOL effects of ICDs was reviewed and summarized. Medline and the Institute for Scientific Information's Web of Knowledge were searched for publications reporting costs of care and QOL assessments of ICD recipients. Unpublished and non-peer-reviewed "gray" publications were excluded. Reports were included if they reported primary, original patient data that were collected after 1993, when nonthoracotomy defibrillators entered clinical practice. Two reviewers independently evaluated publications for relevance and quality, abstracted study data, and summarized the findings. Excessive heterogeneity among studies prevented formal meta-analysis, so a narrative synthesis was performed, and key themes were identified from the published research. There were limited published data on the costs of ICD care, especially for the primary prevention of sudden cardiac death. The published research on ICD QOL lacked large, multicenter, longitudinal studies. Many ICD QOL studies were performed in small numbers of patients at single centers. Initial ICD implantation costs ranged (in 2006 United States dollars) from $28,500 to $55,200, with annual follow-up costs ranging from $4,800 to $17,000. QOL was higher for ICD recipients than for patients treated with antiarrhythmic drugs, but there was a substantial prevalence of anxiety, depression, and "loss of control" in ICD recipients, particularly in those who had received ICD shocks. In conclusion, ICD implantation remains costly but may be becoming less expensive over time, and ICD recipients' QOL is significantly affected by their devices.

For more than 55 years, disulfiram has been approved by the Food and Drug Administration for the treatment of alcohol dependence. It is a unique medication that relies on "psychological threat" to avoid disulfiram-ethanol reactions. This paper reviews the history of disulfiram treatment, the current status of disulfiram treatment, the ensuing developments in disulfiram use in treating various addictions, and future directions. Clinical trials using disulfiram for the treatment of alcohol, cocaine, or co-occurring alcohol + cocaine dependence were included in this review. Disulfiram efficacy studies focusing on supervised, implant, and combination pharmacotherapies were also examined. In clinical trials, disulfiram has demonstrated inconsistent results in helping patients to abstain from alcohol, and patients poorly adhere to a disulfiram-treatment regimen. This has raised questions about disulfiram's practicality in the treatment of alcohol dependence. Recently, however, disulfiram has gained attention as a complementary agent to newer pharmacological medications, such as an opiate antagonist that specifically reduces alcohol craving. One hypothesis is that disulfiram would assist patients in gaining psychological control over drinking when given in conjunction with an opiate antagonist that would act directly on reducing alcohol craving. Preliminary evidence also suggests that disulfiram treatment could be a viable treatment for cocaine dependence because it was shown to reduce cocaine use among nonalcoholic, cocaine-dependent patients.

Narrow dentoalveolar ridges remain a serious challenge for the successful placement of endosseous implants. This case series describes a modification of previous ridge-splitting techniques using a microsaw blade. The approach enables treatment of ridges as thin as 2.5 mm at the alveolar crest and simultaneous placement of dental implants. In one extreme case reported here, where the crest width was less than 2.5 mm, a two-stage approach was used; implants were placed about 1 month after ridge expansion. In the 10 patients treated in this series, 27 dental implants were placed and achieved successful integration.

Neuronal migration disorders (NMDs) constitute the main pathologic substrate of medically intractable epilepsy in human. This study is designed to investigate the changes in expression of glutamate receptor subtypes on radiation-induced NMD in rats. The lesion was produced by intrauterine irradiation (240 cGy) on E17 rats, and then 10 weeks old rats were used for the study. The pathologic and immuno-histochemical findings for glutamate receptor subunit proteins on NMD cortex were correlated with development of behavioral seizures and EEG abnormality. Spontaneous seizures uncommonly occurred in NMD rats (5%); however, clinical stages of seizures were significantly increased in NMD rats by an administration of kainic acid. Brains taken from irradiated rats revealed gross and histopathologic features of NMD. Focal cortical dysplasia was identified by histopathology and immunohistochemistry with neurofilament protein (NF-M/H). Significantly strong NR1 and NR2A/B immunoreactivities were demonstrated in cytomegalic and heterotopic neurons of NMD rats. The results of the present study indicate that epileptogenesis of NMD might be caused by upregulation of glutamate receptor expression in dysplastic neurons of the rat cerebral cortex with NMDs.

In this study, we evaluated the effect of platelet-rich plasma (PRP) on bone regeneration in an autogenous bone graft in a canine model. The mandibular premolar teeth had been bilaterally extracted previously, and the ridges had been allowed to heal for 3 months. After this period, continuity resection was performed on both sides of the mandible. One defect (the PRP group) was reconstructed with the original particulate bone mixed with PRP. As a control, the contralateral defect (non-PRP group) was reconstructed with the original particulate bone alone. Biopsies after 6 weeks showed lower levels of bone formation in the PRP group than in the non-PRP group, and fluorescence microscopy revealed a delay in the remodelling of grafts loaded with PRP. These findings suggest that the addition of PRP does not appear to enhance new bone formation in autogenous bone grafts.

A variety of treatment modalities have been proposed for the management of peri-implantitis. These are mostly based on empiric experience and use the systemic administration of an antibiotic in conjunction with surgical intervention. To ensure decontamination of the affected implant surface(s), chemical and/or mechanical debridement is used. For textured implant surfaces, detoxification using implantoplasty could also give favorable results when used as part of the procedure. Two cases are reported in which implants developed localized peri-implantitis lesions. Implantoplasty followed by topical tetracycline decontamination was used in conjunction with guided bone regeneration. In both cases, the procedures were effective in arresting disease and regenerating lost bone. These results suggest that the technique holds promise and should be investigated further.

Following kainate (KA)-induced epilepsy, rat hippocampal neurons strongly express immediate early gene (IEG) products, i.e., c-FOS and c-JUN, and neural stress protein, HSP72. Prolonged expression of c-JUN and c-FOS 48 hr after cerebral ischemia has been underwent delayed neuronal death. However, it is not yet clear whether IEGs actually assume the essential roles in the cell death process or simply as a by-product due to external stimuli because of the prolonged expression of c-FOS, more than one week, on intact CA2 neurons of the hippocampus in a KA-induced epilepsy model. This study investigated the relationships between prolonged expression of c-JUN and hippocampal neuronal apoptosis in a KA-induced epilepsy model. Epileptic seizure was induced in rats by a single microinjection of KA (1 microgram/microL) into the left amygdala. Characteristic seizures and hippocampal neuronal injury were developed. The expression of c-JUN was evaluated by immunohistochemistry, and neuronal apoptosis by in situ end labeling. The seizures were associated with c-JUN expression in the hippocampal neurons, of which the level showed a positive correlation with that of apoptosis. Losses of hippocampal neurons, especially in the CA3 region, were partly caused by apoptotic cell death via a c-JUN-mediated signaling pathway. This is thought to be an important component in the pathogenesis of hippocampal neuronal injury via KA-induced epilepsy.

Background: The various methods for regeneration of periodontal tissue that have been developed can be classified into guided tissue regeneration and bone implantation. Since the implantation materials have shown both deficiencies and merits, dentists have begun exploring the bioactive glass first used in plastic surgery. This paper examines the effectiveness of this new material on periodontal intrabony defects., Methods: Clinical effects of bioactive glass implantation in intrabony periodontal defects were evaluated 6 months after surgery in 38 intrabony defects from 38 patients with chronic periodontitis. Twenty-one experimental defects received bioactive glass implantation (test group), while 17 control defects were treated with a flap procedure only (control group). The criteria for comparative observation were preoperative and postoperative probing depth (PD), clinical attachment level (CAL), bone probing depth (BPD), and gingival recession., Results: Reductions in PD were observed in both groups (P<0.01). The reduction in PD was significantly greater in the test group when preoperative PD exceeded 7 mm (P<0.01). Improvements in CAL were also observed in both groups (P<0.01), with the test group showing significantly greater gains (P<0.05). In those cases where preoperative CAL was less than 7 mm, there was no statistically significant difference between the two groups. Reduction in BPD was observed in both groups, with the test group showing significantly greater reduction (P <0.01). There was no significant difference in BPD change, however, when preoperative BPD was < or =7 mm. Significantly greater reduction of BPD in the test group was observed when intrabony defect depth was >4 mm (P <0.05). Significant improvements in PD, CAL, and BPD were noted in the test group when the crestal involvement exceeded 100 degrees. Correlation test between various clinical parameters indicated that greater changes in PD and CAL in the test group were observed when preoperative CAL was large (P<0.001), and greater changes in PD (P<0.05), CAL (P<0.01), and BPD (P<0.05) were noted when preoperative BPD was large. Correlation between crestal involvement and CAL change was noted only in the control group (P<0.01). High correlations were observed between PD changes and CAL changes and between CAL changes and BPD changes in both groups., Conclusions: Use of a bone substitute in a flap operation resulted in significantly greater improvements in CAL and BPD over flap operation alone and seemed to have positive effects in postoperative PD, CAL, and BPD in those cases with more severe preoperative CAL and BPD.

To assess the epileptogenic lesions, a series of 202 cases with temporal lobectomy were analyzed histopathologically. The severity of hippocampal neuronal loss in patients with temporal lobe epilepsy was quantitatively analyzed and compared against autopsy controls of patients who died of nonneurologic disorders. For the histopathologic diagnosis of neuronal migration disorder (NMD), immunohistochemical stains for neurofilament protein (NF-M/H) and microtubule-associated protein 2 (MAP2) and Bielschowsky silver stains were routinely performed. Histopathology of NMD was classified by the 4-grade system. MAP2 immunoreactivity was useful in the identification of loss of normal polarization of dendrites in the abnormal neurons. NF-M/H immunohistochemistry and silver stains effectively labeled microscopic or occult lesions of NMD (grade II and III). Ammon hom sclerosis (AHS) was identified in 73.3% and NMD in 57.9%. There was more than 50% neuronal cell loss in 82.8% of AHS, and variable degrees of cell loss were observed in the dual-pathology groups. The frequency of dual pathology (both AHS and NMD) was 65.0% and showed relatively equal distributions in grades I, II, III, whereas the pure NMD group were classified predominantly as grades II and III. NMD might be a basic pathogenic substrate causing temporal lobe epilepsy. The dual pathology may indicate the presence of epileptogenic lesions in the neocortical and temporolimbic areas., (Copyright 2001 by W.B. Saunders Company.)