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Aims This paper reviews the published literature regarding outcomes following maternal treatment with buprenorphine in five areas: maternal efficacy, fetal effects, neonatal effects, effects on breast milk and longer-term developmental effects. Methods Within each outcome area, findings are summarized first for the three randomized clinical trials and then for the 44 non-randomized studies (i.e. prospective studies, case reports and series and retrospective chart reviews), only 28 of which involve independent samples. Results Results indicate that maternal treatment with buprenorphine has comparable efficacy to methadone, although difficulties may exist with current buprenorphine induction methods. The available fetal data suggest buprenorphine results in less physiological suppression of fetal heart rate and movements than methadone. Regarding neonatal effects, perhaps the single definitive conclusion is that prenatal buprenorphine treatment results in a clinically significant less severe neonatal abstinence syndrome (NAS) than treatment with methadone. The limited research suggests that, like methadone, buprenorphine is compatible with breastfeeding. Data available thus far suggest that there are no deleterious effects of in utero buprenorphine exposure on infant development. Conclusions While buprenorphine produces a less severe neonatal abstinence syndrome than methadone, both methadone and buprenorphine are important parts of a complete comprehensive treatment approach for opioid-dependent pregnant women.

Aim To determine pre- and post-dosing effects of prenatal methadone compared to buprenorphine on fetal wellbeing. Design A secondary analysis of data derived from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study, a double-blind, double-dummy, randomized clinical trial. Setting Six United States sites and one European site that provided comprehensive opioid-dependence treatment to pregnant women. Participants Eighty-one of the 131 opioid-dependent pregnant women completing the MOTHER clinical trial, assessed between 31 and 33 weeks of gestation. Measurements Two fetal assessments were conducted, once before and once after study medication dosing. Measures included mean fetal heart rate (FHR), number of FHR accelerations, FHR reactivity in the fetal non-stress test (NST) and biophysical profile (BPP) score. Findings Significant group differences were found for number of FHR accelerations, non-reactive NST and BPP scores (all Ps

Aims To examine the relationship of anxiety and depression symptoms with treatment outcomes (treatment discontinuation, rates of ongoing use of illicit drugs and likelihood of preterm delivery) in opioid-dependent pregnant women and describe their use of psychotropic medications. Design and setting Secondary data analysis from a randomized clinical trial of treatment for opioid dependence during pregnancy. Participants A total of 175 opioid-dependent pregnant women, of whom 131 completed treatment. Measurements Symptoms of anxiety and depression were captured with the 15-item Mini International Neuropsychiatric Interview (MINI) screen. Use of illicit drugs was measured by urine drug screening. Preterm delivery was defined as delivery prior to 37 weeks' gestation. Self-reported use of concomitant psychotropic medication at any point during the study was recorded. Findings Women reporting only anxiety symptoms at study entry were more likely to discontinue treatment [adjusted odds ratio (OR) = 4.56, 95% confidence interval (CI): 1.91–13.26, P = 0.012], while those reporting only depression symptoms were less likely to discontinue treatment (adjusted OR = 0.14, 95% CI: 0.20–0.88, P = 0.036) compared to women who reported neither depression nor anxiety symptoms. No statistically significant between-group differences were observed for ongoing illicit drug use or preterm delivery. A majority (61.4%) of women reported use of concomitant psychotropic medication at some point during study participation. Conclusions Opioid agonist-treated pregnant patients with co-occurring symptoms of anxiety require additional clinical resources to prevent premature discontinuation.

Aims To compare the profile of signs of neonatal abstinence syndrome (NAS) in methadone- versus buprenorphine- exposed infants. Design, setting and participants Secondary analysis of NAS data from a multi-site, double-blind, double-dummy, flexible-dosing, randomized clinical trial. Data from a total of 129 neonates born to opioid-dependent women who had been assigned to receive methadone or buprenorphine treatment during pregnancy were examined. Measurements For 10 days after delivery, neonates (methadone = 72, buprenorphine = 57) were assessed regularly using a 19-item modified Finnegan scale. Data from neonates who required pharmacological treatment (metha- done = 41, buprenorphine = 27) were included up to the time treatment was initiated. The incidence and mean severity of the total NAS score and each individual sign of NAS were calculated and compared between medication conditions, as was the median time until morphine treatment initiation among treated infants in each condition. Findings Two NAS signs (undisturbed tremors and hyperactive Moro reflex) were observed significantly more frequently in methadone-exposed neonates and three (nasal stuffiness, sneezing, loose stools) were observed more frequently in buprenorphine-exposed neonates. Mean severity scores on the total NAS score and five individual signs (disturbed and undisturbed tremors, hyperactive Moro reflex, excessive irritability, failure to thrive) were significantly higher among methadone-exposed neonates, while sneezing was higher among buprenorphine-exposed neonates. Among treated neonates, methadone-exposed infants required treatment significantly earlier than buprenorphine- exposedinfants(36versus59hourspostnatal,respectively).Conclusions Theprofileof neonatalabstinencesyndrome differs in methadone- versus buprenorphine-exposed neonates, with significant differences in incidence, severity and treatment initiation time. Overall, methadone-exposed neonates have a more severe neonatal abstinence syndrome.

Aims To characterize infections and compare obstetric outcomes in opioid-dependent pregnant women who participated in a randomized clinical trial comparing agonist medications, methadone and buprenorphine. Design Incidence of infections was identified as part of the screening medical assessment. As part of a planned secondary analysis, analysis of variance and polytomous logistic regressions were conducted on obstetric outcome variables using treatment randomization condition (maternal maintenance with either methadone or buprenorphine) as the predictor variable, controlling for differences between study sites. Setting Six United States sites and one European site that provided comprehensive treatment to opioid-dependent pregnant women. Participants Pregnant opioid-dependent women (n = 131) who delivered while participating in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study. Measurements Obstetric, infectious and other maternal medical complications captured by medical records, physical examination, blood tests and self-report. Neonatal medical complications captured by medical records. Findings Hepatitis C was the most common infection (32.3%), followed by hepatitis B (7.6%) and chlamydia (6.1%) among participants at study enrollment. Maternal methadone versus buprenorphine maintenance was associated with a higher incidence of preterm labor (P = 0.04) and a significantly higher percentage of signs of respiratory distress in neonates at delivery (P = 0.05). Other medical and obstetric complications were infrequent in the total sample, as well as in both methadone and buprenorphine conditions. Conclusions Buprenorphine appears to have an acceptable safety profile for use during pregnancy.

Aims The Maternal Opioid Treatment: Human Experimental Research (MOTHER) project, an eight-site randomized, double-blind, double-dummy, flexible-dosing, parallel-group clinical trial is described. This study is the most current—and single most comprehensive—research effort to investigate the safety and efficacy of maternal and prenatal exposure to methadone and buprenorphine. Methods The MOTHER study design is outlined, and its basic features are presented. Conclusions At least seven important lessons have been learned from the MOTHER study: (i) an interdisciplinary focus improves the design and methods of a randomized clinical trial; (ii) multiple sites in a clinical trial present continuing challenges to the investigative team due to variations in recruitment, patient populations and hospital practices that, in turn, differentially impact recruitment rates, treatment compliance and attrition; (iii) study design and protocols must be flexible in order to meet the unforeseen demands of both research and clinical management; (iv) staff turnover needs to be addressed with a proactive focus on both hiring and training; (v) the implementation of a protocol for the treatment of a particular disorder may identify important ancillary clinical issues worthy of investigation; (vi) timely tracking of data in a multi-site trial is both demanding and unforgiving; and (vii) complex multi-site trials pose unanticipated challenges that complicate the choice of statistical methods, thereby placing added demands on investigators to effectively communicate their results.

Aim To identify factors that predict the expression of neonatal abstinence syndrome (NAS) in infants exposed to methadone or buprenorphine in utero. Design and Setting Multi-site randomized clinical trial in which infants were observed for a minimum of 10 days following birth, and assessed for NAS symptoms by trained raters. Participants A total of 131 infants born to opioid dependent mothers, 129 of whom were available for NAS assessment. Measurements Generalized linear modeling was performed using maternal and infant characteristics to predict: peak NAS score prior to treatment, whether an infant required NAS treatment, length of NAS treatment and total dose of morphine required for treatment of NAS symptoms. Findings Of the sample, 53% (68 infants) required treatment for NAS. Lower maternal weight at delivery, later estimated gestational age (EGA), maternal use of selective serotonin re-uptake inhibitors (SSRIs), vaginal delivery and higher infant birthweight predicted higher peak NAS scores. Higher infant birthweight and greater maternal nicotine use at delivery predicted receipt of NAS treatment for infants. Maternal use of SSRIs, higher nicotine use and fewer days of study medication received also predicted total dose of medication required to treat NAS symptoms. No variables predicted length of treatment for NAS. Conclusions Maternal weight at delivery, estimated gestational age, infant birthweight, delivery type, maternal nicotine use and days of maternal study medication received and the use of psychotropic medications in pregnancy may play a role in the expression of neonatal abstinence syndrome severity in infants exposed to either methadone or buprenorphine.

Aim To examine hepatic enzyme test results throughout the course of pregnancy in women maintained on metha- done or buprenorphine. Design Participants were randomized to either methadone or buprenorphine maintenance. Bloodchemistrytests,includinglivertransaminasesandhepatitisCvirus(HCV)status,weredeterminedevery4weeks and once postpartum. As part of a planned secondary analysis, generalized mixed linear models were conducted with aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) as the dependent variables. Setting Six US sites and one European site that provided comprehensive treatment to pregnant opioid-dependent women. Participants A total of 175 opioid-dependent pregnant women enrolled in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study.Findings ALT, AST and GGT levels decreased for all subjects across pregnancy trimesters, rising slightly postpartum. HCV-positive subjects exhibited higher transami- nases at all time-points compared to HCV-negative subjects, regardless of medication (all Ps < 0.05) condition. Both HCV-positive and negative buprenorphine-maintained participants exhibited lower GGT levels than those who were methadone-maintained (P < 0.05). Conclusions Neither methadone nor buprenorphine appear to have adverse hepatic effects in the treatment of pregnant opioid-dependent women.

Objective: Intrathecal (IT) drug delivery systems for patients with chronic non-malignant pain are intended to improve pain and quality of life and reduce side effects of systemic use. A subset of patients may have escalating pain, functional decline, and/or intolerable side effects even as IT opioid doses are increased. Discontinuation of IT medications may represent a viable treatment option but strategies to accomplish this are needed. Subjects and Interventions: Three patients with intrathecal drug delivery systems (IDDS), inadequate pain control, and declining functionality underwent abrupt IT opioid cessation. This was accomplished through a standardized protocol with symptom-triggered administration of clonidine and buprenorphine, monitored using the clinical opiate withdrawal scale. Results: Symptoms of IT withdrawal were similar in all patients and included diuresis, agitation, hyperalgesia, mild diarrhea, yawning, and taste and smell aversion. Hypertension and tachycardia were effectively controlled by clonidine administration. Classic symptoms of withdrawal, such as piloerection, chills, severe diarrhea, nausea, vomiting, diaphoresis, myoclonus, and mydriasis, were not noted. At 2 to 3 months follow-up, patients reported decreased, but ongoing pain, with improvements in functional capacity and quality of life. Conclusions: This preliminary work demonstrates the safety of abrupt IT opioid cessation utilizing standardized inpatient withdrawal protocols. To our knowledge, these are among the first reported cases of intentional, controlled IT opioid cessation without initiation of an opioid bridge: self-reported pain scores, functional capacity, and quality of life improved. The IT opioid withdrawal syndrome is characterized based upon our observations and a review of the literature.

Opioid alkaloids have been used medicinally for centuries as analgesics, for their antidiarrheal and antitussive properties, and as hypnotics. Opioids were initially derived from the poppy plant (Papaver somniferum) by the ancients of the Mediterranean Basin. Written records of the medicinal uses of opioids date to before the time of Hippocrates (460–377 BC). Paracelsus prescribed opium in a medicinal drink of wine and spices in the 16th century. Sir William Osler, the renowned Canadian physician of the late 1800’s remarked that opium was “God’s own Medicine”. Opioids are considered superb medications by modern physicians, who widely prescribed them still and for the most part without significant adverse consequences. Yet there is a “dark side” to opioids for those who develop dependence on these drugs (1). Opioids have significant dependence liability because of compelling biphasic central effects, behavioral activation at low doses and sedation at higher doses, accompanied by allostatic neuroadaptation of the CNS, leading to use of rapidly escalating doses. These dynamics may be amplified in persons having altered dopamine receptors in the limbic system, suggesting a possible genetic association (2). Dependent individuals may be unable to stop compulsive self-administration of opioids, in part because of these plastic changes in the brain akin to learning and memory that are highly resistant to modification. Synaptic alterations in neurons of the reward and limbic circuits may irreversibly modify emotions and responses to the environment, thereby permeating the behavioral repertoire of the addict. Accordingly, it may be impossible for most actively dependent individuals to live a fulfilling life simply because so much of their effort becomes devoted to activities necessary to obtain illicit opioids, use them, and recover from their use. Indeed, some individuals who have been dependent on opioids may never be able to return to a normal emotional life without intensive ongoing therapeutic support that allows the acquisition of new learning and more effective coping. The goal of the psychiatrist is to assist the opioid dependent patient to achieve recovery from an opioid-focused life, to help the individual to live a full and balanced life that is no longer fixated on drugs. Those who addictively use opioids often develop complications, less from opioid use per se than from a life outside the law, a direct consequence of their involvement with illicit drugs. The life and exceptional achievements of Dr. William Halsted, first chief of Surgery at Johns Hopkins Hospital, suggests that chronic opioid use may not necessarily be incompatible with a productive life. (Halsted turned to daily morphine use in a futile attempt to “cure” his cocaine dependence, contracted via self-administration of cocaine during research studies to develop a surgical anesthetic. Halstead had ready, unrestricted access to inexpensive, high-grade morphine, so he

An intrauterine abstinence syndrome (IAS) is a potentially fatal consequence of maternal opiate withdrawal. This study reviews the evidence for this syndrome. Withdrawal also creates an adverse environment for the developing fetal brain that can have long-term health effects. Effective methadone treatment eliminates risks of fetal withdrawal. However, concerns about neonatal abstinence syndrome (NAS) in methadone-exposed neonates have resulted in efforts to withdraw women from methadone during pregnancy or to use buprenorphine, a mixed agonist/antagonist opiate in place of methadone. Both approaches necessarily expose the fetus to either acute or chronic withdrawal. Routine fetal monitoring is not able to detect such symptoms, unless they are life-threatening. Therefore, the safety of the fetus during buprenorphine inductions or methadone tapers cannot be assured and the fetus should be protected from such procedures. Further research into methods of diagnosing IAS and its developmental consequences is ne...

Background: Alcohol dependence is associated with neurocognitive deficits related to neuropathological changes in structure, metabolism, and function of the brain. Impairments of motor functioning in alcoholics have been attributed to well-characterized neuropathological brain abnormalities in cerebellum. Methods: Using functional magnetic resonance imaging (fMRI), we studied in vivo the functional connectivity between cerebellar and cortical brain regions. Participants were 10 uncomplicated chronic alcoholic patients studied after 5 to 7 days of abstinence when signs of withdrawal had abated and 10 matched healthy controls. We focused on regions of prefrontal, frontal, temporal, and parietal cortex that exhibited an fMRI response associated with nondominant hand finger tapping in the patients but not in the controls. We predicted that fronto-cerebellar functional connectivity would be diminished in alcoholics compared with controls. Results: Functional connectivity in a circuit involving premotor areas (Brodmann Area 6) and Lobule VI of the superior cerebellum was reduced in the patients compared with the controls. Functional connectivity was also reduced in a circuit involving prefrontal cortex (Brodmann Area 9) and Lobule VIII of the inferior cerebellum. Reductions in connectivity were specific to fronto-cerebellar circuits and were not found in other regions examined. Conclusions: Our findings show a pattern in recently abstinent alcoholic patients of specific deficits in functional connectivity and recruitment of additional brain regions for the performance of a simple finger-tapping task. A small sample, differences in smoking, and a brief abstinence period preclude definitive conclusions, but this pattern of diminished fronto-cerebellar functional connectivity is highly compatible with the characteristic neuropathological lesions documented in alcoholics and may reflect brain dysfunction associated with alcoholism.

Gamma-aminobutyric acid (GABA) and glutamate (Glu) levels, normalized to total creatine (tCr), were measured in the anterior cingulate and cerebellar vermis in healthy adults (n=19, age=24.6±6.4 years) using ¹H MRS at 3 T, and metabolite correlations across regions and subjects were determined. Mean anterior cingulate and cerebellar GABA/tCr ratios were 0.31 (0.08) and 0.23 (0.06), respectively, while corresponding Glu levels were 1.16 (0.10) and 0.70 (0.07), respectively. Anterior cingulate and cerebellar glutamate levels were correlated (r=0.6103, P=.0140), although it is noted that when adjusted for multiple comparisons, all correlations reported here cluster to a P value of .0583. It is unlikely that this correlation is driven by correlations in tCr, since interregional correlations were not observed for other metabolites referenced to tCr. Correlations were also observed among metabolites in both the anterior cingulate and cerebellar vermis. In the former, N-acetylasparate was linearly dependent on glutamate (r=0.6577, P=.0063) and, at or below this significance threshold, four metabolites were correlated in the cerebellar vermis (Ins/tCh: r=0.6261, P=.0109. NAA/tCh: r=0.6426, P=.0082. NAA/Glu: r=0.6412, P=.0085. tCh/Glu: r=0.6193, P=0.0122).

Pridopidine (ACR16) belongs to a new pharmacological class of agents affecting the central nervous system called dopaminergic stabilizers. Dopaminergic stabilizers act primarily at dopamine type 2 (D(2)) receptors and display state-dependent behavioural effects. This article aims to give an overview of the preclinical neurochemical and behavioural in vivo pharmacological properties of pridopidine. Pridopidine was given s.c. to male Sprague-Dawley rats (locomotor, microdialysis and tissue neurochemistry) and i.p. to Swiss male mice (tail suspension test). Pridopidine dose-dependently increased striatal tissue levels of the dopamine metabolite 3,4-dihydroxyphenylalanin (ED(50)=81 micromol/kg), and prefrontal cortex dialysate levels of dopamine and noradrenaline as measured by high performance liquid chromatography. The agent reduced hyperlocomotion (d-amphetamine: ED(50)=54 micromol/kg; MK-801: ED(50)=40 micromol/kg), but preserved spontaneous locomotor activity, confirming state-dependent behavioural effects. In addition, pridopidine significantly reduced immobility time in the tail suspension test. We conclude that pridopidine state-dependently stabilizes psychomotor activity by the dual actions of functional dopamine D(2) receptor antagonism and strengthening of cortical glutamate functions in various settings of perturbed neurotransmission. The putative restoration of function in cortico-subcortical circuitry by pridopidine is likely to make it useful for ameliorating several neurological and psychiatric disorders, including Huntington's disease.

Background: Chronic alcohol-dependent patients (ALC) exhibit neurocognitive impairments attributed to alcohol-induced fronto-cerebellar damage. Deficits are typically found in complex task performance, whereas simple tasks may not be significantly compromised, perhaps because of little understood compensatory changes. Methods: We compared finger tapping with either hand at externally paced (EP) or maximal self-paced (SP) rates and concomitant brain activation in ten pairs of right-hand dominant, age-, and gender-matched, severe, uncomplicated ALC and normal controls (NC) using functional magnetic resonance imaging (fMRI). Results: Mean tapping rates were not significantly different in ALC and NC for either task, but SP tapping variances were greater in ALC for both hands. SP tapping was more rapid with dominant hand (DH) than non-dominant hand (NDH) for both groups. EP and SP tapping with the non-dominant hand demonstrated significantly more activation in ALC than NC in the pre and postcentral gyri, inferior frontal gyrus, inferior parietal lobule, and the middle temporal gyrus. Areas activated only by ALC (not at all by NC) during NDH tapping included the inferior frontal gyrus, middle temporal gyrus, and postcentral gyrus. There were no significant group activation differences with DH tapping. No brain regions activated more in NC than ALC. SP tapping in contrast to EP activated fronto-cerebellar networks in NC, including postcentral gyrus, anterior cingulate, and the anterior lobe and vermis of the cerebellum, but only parietal precuneus in ALC. Conclusions: These findings with NDH finger tapping support previous reports of neurocognitive inefficiencies in ALC. Inferior frontal activation with EP in ALC, but not in NC, suggests engagement of regions needed for planning, organization, and impulse regulation; greater contralateral parietal lobe activation with SP in ALC may reflect right hemispheric impairments in visuospatial performance. Contrasting brain activation during SP and EP suggests that ALC may not have enlisted a fronto-cerebellar network as did NC but rather employed a higher order planning mode by recruiting parietal lobe functions to attain normal mean finger tapping rates. Elucidation of the compensatory neural mechanisms that allow near normal performance by ALC on simple tasks can inform functional rehabilitation of patients in recovery.

Background: Alcoholics Anonymous (AA) members represent an important and relatively understudied population for improving our understanding of alcohol dependence recovery as over 1 million Americans participate in the program. Further insight into coffee and cigarette use by these individuals is necessary given AA members’ apparent widespread consumption and the recognized health consequences and psychopharmacological actions of these substances. Methods: Volunteers were sought from all open-AA meetings in Nashville, TN during the summer of 2007 to complete a questionnaire (n = 289, completion rate = 94.1%) including timeline followback for coffee, cigarette, and alcohol consumption; the Alcoholics Anonymous Affiliation Scale; coffee consumption and effects questions; the Fagerstrom Test for Nicotine Dependence (FTND); and the Smoking Effects Questionnaire. Results: Mean (±SD) age of onset of alcohol consumption was 15.4 ± 4.2 years and mean lifetime alcohol consumption was 1026.0 ± 772.8 kg ethanol. Median declared alcohol abstinence was 2.1 years (range: 0 days to 41.1 years) and median lifetime AA attendance was 1000.0 meetings (range: 4 to 44,209 meetings); average AA affiliation score was 7.6 ± 1.5. Most (88.5%) individuals consumed coffee and approximately 33% of coffee consumers drank more than 4 cups per day (M = 3.9 ± 3.9). The most common self-reported reasons for coffee consumption and coffee-associated behavioral changes were related to stimulatory effects. More than half (56.9%) of individuals in AA smoked cigarettes. Of those who smoked, 78.7% consumed at least half a pack of cigarettes per day (M = 21.8 ± 12.3). Smokers’ FTND scores were 5.8 ± 2.4; over 60% of smokers were highly or very highly dependent. Reduced negative affect was the most important subjective effect of smoking. Conclusions: A greater proportion of AA participants drink coffee and smoke cigarettes in larger per capita amounts than observed in general U.S. populations. The effects of these products as described by AA participants suggest significant stimulation and negative affect reduction. Fundamental knowledge of the quantitative and qualitative aspects of coffee and cigarette consumption among AA members will enable future research to discern their impact on alcohol abstinence and recovery.

Objective: To report 2 cases that examine the use of oxcarbazepine as treatment for individuals with posttraumatic stress disorder (PTSD) and comorbid alcohol dependence. Case Summaries: A 59-year-old male with a past psychiatric history significant for PTSD and alcohol dependence underwent alcohol detoxification and was subsequently prescribed oxcarbazepine 300 mg twice daily, which was titrated to 600 mg twice daily prior to discharge. He experienced significant reduction in PTSD symptoms including anxiety, nightmares, flashbacks, racing thoughts, and avoidance behaviors. Over time, he also experienced a reduction in alcohol cravings and decreased daily alcohol intake. A 62-year-old male with a past psychiatric history of PTSD and alcohol dependence was treated in the outpatient clinic. He experienced almost complete resolution of PTSD symptoms and any craving for alcohol within 4 months of starting oxcarbazepine treatment, which was initiated at 150 mg twice daily and increased to 600 mg/day during that time. Discussion: Both patients appeared to receive excellent symptomatic relief from their PTSD symptoms. Recurring symptoms, including nightmares and flashbacks, seemed to be particularly responsive to the treatment. Additionally, in both cases, it is possible that oxcarbazepine had a secondary beneficial effect by decreasing alcohol cravings, although this was not formally measured. Conclusions: Our experience with these patients suggests that oxcarbazepine could be an effective treatment for the symptoms of PTSD and may decrease alcohol cravings and consumption in patients with co-occurring alcohol dependence. Controlled studies examining the effectiveness of oxcarbazepine for treatment of patients with PTSD, including those with complicating alcohol dependence, are warranted.

Coffee is the most consumed beverage in the world and a significant source of phenolic compounds, particularly chlorogenic acids (CGA). During coffee roasting, some CGA are partially transformed into chlorogenic acid lactones (CGL). Both CGA and CGL are important compounds for flavor and potentially beneficial to human health. In the present study, using LC–MS and synthetic standards, we investigated major and minor CGA and CGL isomers in green and roasted samples of economically relevant Brazilian Coffea arabica and Coffea canephora coffee cultivars. For the first time, in addition to nineteen previously identified CGA and CGL, 1-feruloylquinic acid, 1-feruloylquinic lactone and 3,4-diferuloylquinic acid were quantified in C. arabica and C. canephora, the contents of 3- and 4-p-coumaroylquinic lactones were reported in C. canephora and 3,4-di-p-coumaroylquinic acid was identified in C. arabica. Despite their low concentrations, the implications of these findings for flavor, cup quality and the biological properties of coffee merit further investigation.

Magnetic resonance imaging (MRI)-targeted, 3D transrectal ultrasound (TRUS)-guided “fusion” prostate biopsy aims to reduce the 21–47% false negative rate of clinical 2D TRUS-guided sextant biopsy. Although it has been reported to double the positive yield, MRI-targeted biopsy still has a substantial false negative rate. Therefore, we propose optimization of biopsy targeting to meet the clinician’s desired tumor sampling probability, optimizing needle targets within each tumor and accounting for uncertainties due to guidance system errors, image registration errors, and irregular tumor shapes. As a step toward this optimization, we obtained multiparametric MRI (mpMRI) and 3D TRUS images from 49 patients. A radiologist and radiology resident contoured 81 suspicious regions, yielding 3D surfaces that were registered to 3D TRUS. We estimated the probability, P , of obtaining a tumor sample with a single biopsy, and investigated the effects of systematic errors and anisotropy on P . Our experiments indicated that a biopsy system’s lateral and elevational errors have a much greater effect on sampling probabilities, relative to its axial error. We have also determined that for a system with RMS error of 3.5 mm, tumors of volume 1.9 cm 3 and smaller may require more than one biopsy core to ensure 95% probability of a sample with 50% core involvement, and tumors 1.0 cm 3 and smaller may require more than two cores.

The current opioid epidemic in the United States is changing our perceptions of the face of addiction. Opioid Use Disorder (OUD) has become pervasive and is affecting all ethnicities, races, socioeconomic classes, the young and the old. In 2015, 46 people will lose their life each day to a chronic brain disease that is going unnoticed and undertreated. Over the last five decades, numerous scientific and clinical breakthroughs have allowed for a better understanding of the mechanisms underlying addiction, and the development of medications that can help support a patient’s long-term recovery. All of those that have contributed to these advancements have aided in redefining addiction as a primary, chronic disease of the brain reward, motivation, memory and related circuitry; however, our treatment strategies have not necessarily advanced to the same extent as our current understanding of the disease. This commentary will explore how personal philosophies can bias treatments strategies and definitions of treatment success, and prevent adoption of chronic disease treatment models that would significantly improve the quality of life of those suffering with OUD. This is a challenge to consider how our views and stigma can impact a patient’s recovery. We are currently losing a battle with a disease that is taking the lives of 46 individuals daily; it is time to fully embrace a chronic disease model which comprises an integrated pharmacopsychosocial approach for treating the biopsychosocial disorder that is addiction to reverse these trends.

Objective: To report the novel finding of a significant improvement in essential tremor symptoms with oxcarbazepine in a patient with a suboptimal response to propranolol. Case Summary: A 40-year-old woman with a history of substance abuse complicated by essential tremor and neuropathic pain was admitted to our addictions unit with altered mental state due to escalating use of alprazolam. Alprazolam had been prescribed several months prior to admission for treatment of anxiety. The doses had risen to 5–10 mg/day during that period. Apparently, her essential tremor had responded inadequately to propranolol, but had responded well to alprazolam. She was started on a sedative/hypnotic withdrawal protocol, but did not require treatment with phenobarbital. She subsequently rated her tremor as “moderately severe.” On discontinuation of the withdrawal protocol, oxcarbazepine 450 mg twice daily was initiated to treat her neuropathic pain, and the tremor improved, with a clinically significant reduction in tremor and a decreased pain score. Discussion: Essential tremor is a common neurologic disorder with uncertain pathophysiology. Practice guidelines advocate the use of propranolol or primidone as first-line agents to treat essential tremor. Unfortunately, primidone has abuse potential and propranolol has variable pharmacokinetics; these characteristics limit their effectiveness in treating tremor. Our patient experienced a significant and sustained improvement in her tremor following the initiation of oxcarbazepine. To our knowledge, as of September 2, 2006, this is the first report of the use of oxcarbazepine in essential tremor. While the exact therapeutic action remains unclear, oxcarbazepine offers significant advantages compared with current first-line agents, including its good tolerability profile, the extended half-life of its metabolite, and lack of abuse potential. Conclusions: We report a case of essential tremor responding to oxcarbazepine. This drug offers several potential advantages over current first-line agents. Further research is warranted to test the robustness of this preliminary finding.

The market for decaffeinated coffees has been increasingly expanding over the years. Caffeine extraction may result in losses of other compounds such as chlorogenic acids (CGA) and, consequently, their 1,5-gamma-quinolactones (CGL) in roasted coffee. These phenolic compounds are important for flavor formation as well as the health effects of coffee; therefore, losses due to decaffeination need to be investigated. The present study evaluates the impact of decaffeination processing on CGA and CGL levels of green and roasted arabica coffees. Decaffeination produced a 16% average increase in the levels of total CGA in green coffee (dry matter), along with a 237% increase in CGL direct precursors. Different degrees of roasting showed average increments of 5.5-18% in CGL levels of decaffeinated coffee, compared to regular, a change more consistent with observed levels of total CGA than with those of CGL direct precursors in green samples. On the other hand, CGA levels in roasted coffee were 3-9% lower in decaffeinated coffee compared to regular coffee. Although differences in CGA and CGL contents of regular and decaffeinated roasted coffees appear to be relatively small, they may be enough to affect flavor characteristics as well as the biopharmacological properties of the final beverage, suggesting the need for further study.

Of all plant constituents, coffee has one of the highest concentrations of chlorogenic acids. When roasting coffee, some of these are transformed into chlorogenic acid lactones (CGL). We have studied the formation of CGL during the roasting of coffee beans in Coffea arabica cv. Bourbon; C. arabicacv. Longberry; and C. canephora cv. Robusta. Individual CGL levels were determined by comparison of HPLC peaks with those of synthetic CGL standards. Seven CGL were identified: 3-caffeoylquinic-1,5-lactone (3-CQL), 4- caffeoylquinic-1,5-lactone (4-CQL), 3-coumaroylquinic-1,5-lactone (3-pCoQL), 4-coumaroylquinic-1,5-lactone (4-pCoQL), 3-feruloylquinic-1,5-lactone (3-FQL), 4-feruloylquinic-1,5-lactone (4-FQL), and 3,4-dicaffeoylquinic-1,5-lactone (3,4-diCQL). 3-CQL was the most abundant lactone in C. arabica and C. canephora, reaching peak values of 230 +/- 9 and 254 +/- 4 mg/100 g (dry weight), respectively, at light medium roast ( approximately 14% weight loss). 4-CQL was the second most abundant lactone (116 +/- 3 and 139 +/- 2 mg/100 g, respectively. The maximum amount of CGL represents approximately 30% of the available precursors. The relative levels of 3-CQL and 4-CQL in roasted coffee were reverse to those of their precursors in green coffee. This suggests that roasting causes isomerization of chlorogenic acids prior to the formation of lactones and that the levels of lactones in roasted coffee do not reflect the levels of precursors in green coffee.

Since the symptoms of intoxication with non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists closely mimic symptoms in patients with schizophrenia, [+]-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene-5,10-iminehydrogenmaleate (MK-801)-treated rodents are often used as a model for schizophrenia. In most studies, acute injections of MK-801 to rats have been used, but in some studies, longer periods of treatment have been performed. In our previous work, alterations in mRNA/protein expression were screened in the cerebral cortex of MK-801 treated rats. Different proteins were altered in different treatment courses of MK-801. The main objective of the present study was to evaluate different treatment periods of treatment with MK-801 in rats as a model for schizophrenia. Thalamus proteins from treated (acute, six and 12 days) and control rats were analyzed with two-dimensional gel electrophoresis and mass spectrometry. Our results show that different treatment times of MK-801 to rats give different biochemical results. Therefore, it is important to use the same treatment time in studies that will be compared.

Purpose: MRI-targeted, 3D transrectal ultrasound (TRUS)-guided prostate biopsy aims to reduce the 21–47% false negative rate1 of clinical 2D TRUS-guided sextant biopsy, but still has a substantial false negative rate. This could be improved via biopsy needle target optimization, accounting for uncertainties due to guidance system errors and image registration errors. As an initial step toward this broader goal, we elucidated the impact of biopsy needle delivery error on the probability of obtaining tumour samples and on core involvement. These are both important parameters to patient risk stratification and treatment decision. Methods: We investigated this for cancer of all grades, and separately for intermediate/high grade (≥Gleason 4+3) cancer. We used expert-contoured gold-standard prostatectomy histology to simulate targeted biopsies using an isotropic Gaussian needle delivery error from 1 to 6 mm, and investigated the amount of cancer obtained in each biopsy core as determined by histology. Results: Needle delivery error resulted in core involvement variability that could influence treatment decisions; the presence or absence of cancer in 1/3 or more of each needle core can be attributed to needle delivery error of 4 mm (as observed in practice2). Conclusions: Repeated biopsies of the same tumour target can yield percent core involvement measures with sufficient variability to influence the decision between active surveillance and treatment. However, this may be mitigated by making more than one biopsy attempt at selected tumour targets.

Background: Fine and gross motor dysfunction in chronic alcoholic patients is prevalent, but not extensively studied. Brain autopsy studies of brain regions involved in motor movements indicate cerebellum and frontal lobes are particularly sensitive to alcohol-induced damage, in contrast to motor cortex. Methods: Using functional magnetic resonance imaging (fMRI), we compared the pattern of activation of the cerebral cortex and cerebellum during repetitive, self-paced dominant (DH) and nondominant (NDH) index finger tapping in eight uncomplicated alcohol-dependent patients after approximately 2 weeks of abstinence and in nine normal controls. Results: Whereas alcoholic patients tapped significantly more slowly than normal controls, a greater percentage of pixels were activated in the ipsilateral cortex during DH tapping. Furthermore, alcoholics tapped significantly less efficiently (tapping rate divided by percent pixels activated [weighted by pixel intensity] in a given region of interest [ROI]) than normal controls in every ROI examined while using DH, but only in ipsilateral hemi-cerebellum using NDH. Finally, the alcohol-dependent patients did not demonstrate the greater mean pixel activation, percentage activated pixels, and lesser activation efficiency in the ipsilateral cortex during NDH compared to DH tapping that was observed in the normal control group. Conclusions: These findings are compatible with motor inefficiency and compensatory alterations of cortical-cerebellar circuits. Further studies are needed to determine whether these deficits recover with prolonged abstinence and how they relate to cognitive inefficiency throughout the clinical course of alcoholism.

This article represents a symposium of the 2002 joint meeting of RSA and ISBRA held in San Francisco. Presentations were Neuropathology of alcohol-related cerebellar damage in humans, by Antony J. Harding; Neuropathological evidence of cerebellar damage in an animal model of alcoholism, by Roberta Pentney and Cynthia Dlugos; Understanding cortical-cerebellar circuits through neuroimaging study of chronic alcoholics, by Peter R. Martin and Mitchell H. Parks; and Functional reorganization of the brain in alcoholism: neuroimaging evidence, by John E. Desmond, S.H. Annabel Chen, Michelle R. Pryor, Eve De Rosa, Adolf Pfefferbaum, and Edith V. Sullivan.

Background Proton magnetic resonance spectroscopy may elucidate the molecular underpinnings of alcoholism-associated brain shrinkage and the progression of alcohol dependence. Methods Using proton magnetic resonance spectroscopy, we determined absolute concentrations of N-acetylaspartate (NAA), creatine/phosphocreatine (Cr), and choline (Cho)-containing compounds and myo-inositol (mI) in the anterior superior cerebellar vermis and frontal lobe white matter in 31 alcoholics and 12 normal controls. All patients were examined within 3 to 5 days of their last drink. Patients who did not relapse were again studied after 3 weeks and 3 months of abstinence by using an on-line repositioning technique that allows reliable localization of volumes of interest (VOIs). Results At 3 to 5 days after the last drink, frontal white matter metabolite concentrations were not significantly different from those of normal controls, whereas brain tissue in the VOI was reduced. Cerebellar [NAA] and [Cho] and brain and cerebellar volumes were decreased, but [Cr], [mI], and VOI brain tissue volume were not significantly different. Eight patients relapsed before 3 weeks (ER), 12 relapsed between 3 weeks and 3 months (LR), and 11 did not relapse (NR) during 3 months. Cerebellar [NAA] was reduced only in ER patients, despite the fact that ER patients drank for significantly fewer years and earlier in life than LR or NR patients. After 3 months, in the 11 continuously abstinent patients, cerebellar [NAA] and brain and cerebellar volumes increased; cerebellar [Cho], [Cr], and [mI] and VOI brain tissue did not change significantly. Conclusions Decreased [NAA] and [Cho] in cerebellar vermis indicate a unique sensitivity to alcohol-induced brain injury. Cerebellar [NAA] increased with abstinence, but reduced [Cho] persisted beyond 3 months. Further studies are needed to determine whether low cerebellar [NAA] is a risk factor for, or consequence of, malignant, early-onset alcoholism.

Preliminary screening of a minor, non-xanthine constituent of roasted coffee, 3,4-diferuloyl-1,5-quinolactone (DIFEQ), showed inhibition of the adenosine transporter at low micromolar concentration. DIFEQ is a neutral derivative of the chlorogenic acids, i.e. isomeric mono- and di-substituted coumaroyl-, caffeoyl-, and feruloyl-esters of quinic acid, formed in the roasting process of coffee. Displacement of the adenosine transporter antagonist [(3)H](S)-(nitrobenzyl)-6-thioinosine binding by DIFEQ in cultured U-937 cell preparations, expressing the human adenosine transporter protein (hENT1), showed a K(i) of 0.96+/-0.13 microM. Extracts of regular and decaffeinated coffee showed binding activities equivalent to 30-40 mg DIFEQ per three cups of coffee. Acute administration of a high dose of DIFEQ (100 mg/kg i.p.) reduced open field locomotion in mice for 20 min in correlation with brain levels of DIFEQ. Both 3,4-dicaffeoyl-1,5-quinide and 3,4-dicoumaroyl-1,5-quinide, two close structural analogs of DIFEQ also present in roasted coffee, showed similar affinities for the adenosine transporter, while the corresponding 3- and 4-mono caffeoyl- and feruloyl-quinides were one to two orders of magnitudes less active. This suggests that 3,4-dicinnamoyl-1,5-quinides in coffee could have the potential to raise extra-cellular adenosine levels, thereby counteracting the stimulant effect of caffeine.

e17580 Background: Cabozantinib is a small molecule multiple-receptor tyrosine kinase inhibitor that primarily targets MET and vascular endothelial growth factor receptor 2 (VEGFR2). We evaluated the effect of cabozantinib on BTM in RAIR DTC. We also assessed the response of BM to cabozantinib using 18F Sodium Fluoride (NaF) PET and radionuclide bone scans. Methods: This prospective analysis was performed as part of a multicenter International Thyroid Oncology Group phase II study of cabozantinibin patients with RAIR DTC who progressed on prior VEGFR-targeted therapy (NCT01811212). BTM [serum C-telopeptide (CTx), osteocalcin, N-telopeptide (NTx), procollagen type 1 (Pc1) and urinary NTx] and NaF PET or Tc-MDP scans were done at baseline and after 8 weeks of therapy. A paired t-test was used between baseline and week 8 BTM. Results: Primary study results were presented elsewhere (Shah, et al. 2015, International Thyroid Congress) showing a response rate of 36% with cabozantinib. Of 25 patients (pts) enrolled, 21 had BM, 10 of whom were on bone-modifying agents (BMA) prior to week 8. Only 2 pts had elevated BTM at baseline. In all pts who had paired BTM, there was a statistically significant decline in all BTM except NTx by week 8 (table). Pts not on BMA also had a significant decline in CTx (p 0.0003), urine NTx (p 0.0300), and Pc1 (p 0.0030) compared to baseline. 19 pts were evaluable for overall response and there was no correlation between BTM and response rate. 6/21 patients underwent paired NaF PET scans and 4/6 had minor reduction in lesion uptake at 8 weeks. Conclusions: Interestingly, most of our patients had normal baseline BTM despite BM. Cabozantinib was associated with a strikingly significant reduction in all BTM (even when BTM were within normal limits at baseline) except NTx by week 8. Minor decreases in bone lesion uptake was noted on NaF PET in 4/6 evaluable patients. Clinical trial information: NCT01811212. [Table: see text]

Alcohol use disorder (AUD), a term that comprises both alcohol abuse and alcohol dependence, is a highly prevalent psychiatric disorder. Over 50% of treated AUD patients also suffer from other psychiatric disorder(s). Detailed study has revealed disorders across multiple psychiatric domains with rates of co-occurrence far greater than chance, suggesting a synergistic relationship. The basis of this synergy is explored along with its multiple forms, including behavioral and neurobiologic. Specific topics include the predisposition to both AUD and co-occurring psychopathology, the vulnerability to environmental risk factors that exacerbate these predispositions, and the nature of reinforcement in acute intoxication. Co-occurrence can also modify and exacerbate the neuroadaptations underpinning chronic dependence and relapse, the manifestations of acute and protracted withdrawal, emergence of medical and psychiatric complications, and ultimately the potential for relapse. The outcomes of co-occurrence as well as the unique impact it has on proper treatment are also discussed. Throughout, the significance of recognizing co-occurrence is emphasized since, both neurobiologically and clinically, the synergies between co-occurring disorders yield a result far more complex than a mere sum of the component disorders.

Magnetic resonance imaging (MRI)-targeted, 3D transrectal ultrasound (TRUS)-guided "fusion" prostate biopsy intends to reduce the ∼23% false negative rate of clinical two-dimensional TRUS-guided sextant biopsy. Although it has been reported to double the positive yield, MRI-targeted biopsies continue to yield false negatives. Therefore, the authors propose to investigate how biopsy system needle delivery error affects the probability of sampling each tumor, by accounting for uncertainties due to guidance system error, image registration error, and irregular tumor shapes.T2-weighted, dynamic contrast-enhanced T1-weighted, and diffusion-weighted prostate MRI and 3D TRUS images were obtained from 49 patients. A radiologist and radiology resident contoured 81 suspicious regions, yielding 3D tumor surfaces that were registered to the 3D TRUS images using an iterative closest point prostate surface-based method to yield 3D binary images of the suspicious regions in the TRUS context. The probabilityP of obtaining a sample of tumor tissue in one biopsy core was calculated by integrating a 3D Gaussian distribution over each suspicious region domain. Next, the authors performed an exhaustive search to determine the maximum root mean squared error (RMSE, in mm) of a biopsy system that gives P ≥ 95% for each tumor sample, and then repeated this procedure for equal-volume spheres corresponding to each tumor sample. Finally, the authors investigated the effect of probe-axis-direction error on measured tumor burden by studying the relationship between the error and estimated percentage of core involvement.Given a 3.5 mm RMSE for contemporary fusion biopsy systems,P ≥ 95% for 21 out of 81 tumors. The authors determined that for a biopsy system with 3.5 mm RMSE, one cannot expect to sample tumors of approximately 1 cm(3) or smaller with 95% probability with only one biopsy core. The predicted maximum RMSE giving P ≥ 95% for each tumor was consistently greater when using spherical tumor shapes as opposed to no shape assumption. However, an assumption of spherical tumor shape for RMSE = 3.5 mm led to a mean overestimation of tumor sampling probabilities of 3%, implying that assuming spherical tumor shape may be reasonable for many prostate tumors. The authors also determined that a biopsy system would need to have a RMS needle delivery error of no more than 1.6 mm in order to sample 95% of tumors with one core. The authors' experiments also indicated that the effect of axial-direction error on the measured tumor burden was mitigated by the 18 mm core length at 3.5 mm RMSE.For biopsy systems with RMSE ≥ 3.5 mm, more than one biopsy core must be taken from the majority of tumors to achieveP ≥ 95%. These observations support the authors' perspective that some tumors of clinically significant sizes may require more than one biopsy attempt in order to be sampled during the first biopsy session. This motivates the authors' ongoing development of an approach to optimize biopsy plans with the aim of achieving a desired probability of obtaining a sample from each tumor, while minimizing the number of biopsies. Optimized planning of within-tumor targets for MRI-3D TRUS fusion biopsy could support earlier diagnosis of prostate cancer while it remains localized to the gland and curable.

Magnetic resonance imaging (MRI)-targeted, 3D transrectal ultrasound (TRUS)-guided “fusion” prostate biopsy aims to reduce the ~23% false negative rate of clinical 2D TRUS-guided sextant biopsy. Although it has been reported to double the positive yield, MRI-targeted biopsy still yields false negatives. Therefore, we propose optimization of biopsy targeting to meet the clinician’s desired tumor sampling probability, optimizing needle targets within each tumor and accounting for uncertainties due to guidance system errors, image registration errors, and irregular tumor shapes. We obtained multiparametric MRI and 3D TRUS images from 49 patients. A radiologist and radiology resident contoured 81 suspicious regions, yielding 3D surfaces that were registered to 3D TRUS. We estimated the probability, P, of obtaining a tumor sample with a single biopsy. Given an RMS needle delivery error of 3.5 mm for a contemporary fusion biopsy system, P ≥ 95% for 21 out of 81 tumors when the point of optimal sampling probability was targeted. Therefore, more than one biopsy core must be taken from 74% of the tumors to achieve P ≥ 95% for a biopsy system with an error of 3.5 mm. Our experiments indicated that the effect of error along the needle axis on the percentage of core involvement (and thus the measured tumor burden) was mitigated by the 18 mm core length.

Alcohol use disorder (AUD), a term that comprises both alcohol abuse and alcohol dependence, is a highly prevalent psychiatric disorder. Over 50% of treated AUD patients also suffer from other psychiatric disorder(s). Detailed study has revealed disorders across multiple psychiatric domains with rates of co-occurrence far greater than chance, suggesting a synergistic relationship. The basis of this synergy is explored along with its multiple forms, including behavioral and neurobiologic. Specific topics include the predisposition to both AUD and co-occurring psychopathology, the vulnerability to environmental risk factors that exacerbate these predispositions, and the nature of reinforcement in acute intoxication. Co-occurrence can also modify and exacerbate the neuroadaptations underpinning chronic dependence and relapse, the manifestations of acute and protracted withdrawal, emergence of medical and psychiatric complications, and ultimately the potential for relapse. The outcomes of co-occurrence as well as the unique impact it has on proper treatment are also discussed. Throughout, the significance of recognizing co-occurrence is emphasized since, both neurobiologically and clinically, the synergies between co-occurring disorders yield a result far more complex than a mere sum of the component disorders.

In this article, we review the diagnosis, classification, and differential diagnosis of problematic hypersexuality. The estimated frequency, morbidity, comorbidity, mortality, and the associated societal issues underscore the necessity for improved recognition, better understanding, and more effective treatment for this disorder. In general, hypersexual behavior does not seem to be evaluated, classified, or monitored in the same manner as other innate behaviors like feeling, thinking, sleep, or eating, despite the fact that hypersexual behavior is among the criteria for several psychiatric disorders. More widespread clinical use of acceptable diagnostic criteria for problematic hypersexuality would further elucidate the relationships among problematic hypersexuality and other psychiatric disorders.

Thiamine is required for all tissues and is found in high concentrations in skeletal muscle, heart, liver, kidneys and brain. A state of severe depletion is seen in patients on a strict thiamine-deficient diet in 18 days, but the most common cause of thiamine deficiency in affluent countries is alcoholism. Thiamine diphosphate is the active form of thiamine, and it serves as a cofactor for several enzymes involved primarily in carbohydrate catabolism. The enzymes are important in the biosynthesis of a number of cell constituents, including neurotransmitters, and for the production of reducing equivalents used in oxidant stress defenses and in biosyntheses and for synthesis of pentoses used as nucleic acid precursors. Because of the latter fact, thiamine utilization is increased in tumor cells. Thiamine uptake by the small intestines and by cells within various organs is mediated by a saturable, high affinity transport system. Alcohol affects thiamine uptake and other aspects of thiamine utilization, and these effects may contribute to the prevalence of thiamine deficiency in alcoholics. The major manifestations of thiamine deficiency in humans involve the cardiovascular (wet beriberi) and nervous (dry beriberi, or neuropathy and/or Wernicke-Korsakoff syndrome) systems. A number of inborn errors of metabolism have been described in which clinical improvements can be documented following administration of pharmacological doses of thiamine, such as thiamine-responsive megaloblastic anemia. Substantial efforts are being made to understand the genetic and biochemical determinants of inter-individual differences in susceptibility to development of thiamine deficiency-related disorders and of the differential vulnerabilities of tissues and cell types to thiamine deficiency.

Sexual addictions may be systematically studied using operationalized diagnostic criteria in a variety of studies employing conventional research methodologies such as is being done in the investigations of a variety of Axis I disorders. Although descriptive investigations into the sexual addictions were on par with that of other major mental disorders in the last century, further investigations did not keep pace with that of other mental disorders. Programmatic research into the sexual addictions is poised to be guided by understanding both neurobiological mechanisms involved in sexual behaviors and multicausal, biopsychosocial approaches. A comprehensive understanding of sexual addiction would involve addressing issues in the areas of nosology, epidemiology, family studies, diagnostic criteria, genetics, neurobiology, comorbidity, and empirically based treatments. The authors suggest current research questions and priorities that, when addressed, can contribute to significant advances in the un...

Alcoholism can result in a number of severe consequences to the central nervous system, including Korsakoff's psychosis, delusions, delirium, Wernicke's encephalopathy, and cerebellar degeneration. Many of these disorders have a substantially higher prevalence than had been previously believed. Neuropathologic and neuroimaging studies have been instrumental in identifying the changes undergone by the alcoholic brain and the factors that may contribute to alcohol-induced brain damage. Biologic differences appear to make women especially susceptible to central nervous system insult from alcohol abuse. The damage caused by alcohol may be associated, in part, with thiamine deficiency, neuronal excitotoxicity, and magnesium wasting.

Longitudinal magnetic resonance spectroscopy (MRS) studies require accurate repositioning of the volume of interest (VOI) over which measurements are made. In this work we present and evaluate a method for the image-guided repositioning of brain volumes of interest. The point-based registration technique we developed allows the repositioning to be performed on-line (i.e. while the patient is in the scanner). MR image volumes were acquired from six subjects, three scans each over the course of a month. During the first scan, two spectroscopy VOIs are visually selected: one in the frontal white matter, the other in the superior cerebellar vermis. The coordinates of 13 internal brain landmarks are also identified. During both subsequent scans, the same 13 landmarks are identified, and the transformation that registers the first set of landmarks to the subsequent set is computed. This result is used to automatically map the position of the spectroscopy VOIs from the first volume to the current volume. For the six subjects evaluated to date, we show an average repositioning error of the spectroscopy VOIs in the order of 1 mm. This accuracy allows us to conclude that any variations in the MR spectra are unlikely to be due to repositioning error.

To address tissue-specific variation in sensitivity to thiamine deficiency, three human cell types were grown in medium with various thiamine concentrations. The activity of a cytosolic and a mitochondrial thiamine diphosphate-dependent enzyme was examined. Each cell type displayed a unique response to thiamine depletion with respect to α-ketoglutarate dehydrogenase and transketolase activity and to inhibition of cell growth. Loss of α-ketoglutarate dehydrogenase activity was similar in lymphoblasts and fibroblasts, whereas loss of activity in neuroblastoma cells was significantly more resistant to thiamine depletion. Transketolase activity in neuroblastoma cells was only moderately resistant to thiamine depletion, with the activity in fibroblasts being the most and in lymphoblasts the least resistant. Total transketolase activity was 33% higher in fibroblasts than in lymphoblasts and neuroblastoma cells, indicating a differential requirement for production and maintenance of transketolase activity in this cell type. Compared with normal lymphoblasts, those derived from patients with thiamine-responsive megaloblastic anemia were 100 to 1000 times more sensitive to thiamine depletion. Although fibroblasts from these patients also demonstrated a 1000-fold increase in sensitivity with respect to transketolase activity, α-ketoglutarate dehydrogenase activity demonstrated no enhanced sensitivity. The results indicate a complex, cell-type dependent regulation of intracellular pools of thiamine and its phosphorylated derivatives in response to fluctuating extracellular thiamine levels.

Active human transketolase is a homodimeric enzyme possessing two active sites, each with a non-covalently bound thiamine diphosphate and magnesium. Both subunits contribute residues at each site which are involved in cofactor binding and in catalysis. His-tagged transketolase, produced in E . coli , was similar to transketolase purified from human tissues with respect to K m apps for cofactor and substrates and with respect to cofactor-dependent hysteresis. Mutation of aspartate 155, corresponding to a conserved aspartate residue among thiamine diphosphate-binding proteins, resulted in an inactive protein which could not bind the cofactor–magnesium complex and which could not dimerize. The results are consistent with the suggestion that aspartate 155 is an important coordination site for magnesium. In support of this interpretation, binding of cofactor by wild type apo-transketolase required the presence of magnesium. Additionally, monomeric apo-his-transketolase required both magnesium and cofactor binding for dimer formation.

Thiamine deficiency, a frequent complication of alcoholism, contributes significantly to the development of damage in various organ systems, including the brain. The molecular mechanisms that underlie the differential vulnerabilities to thiamine deficiency of tissue and cell types and among individuals are not understood. Investigations into these mechanisms have examined potential variations in thiamine utilizing enzymes. Transketolase is a homodimeric enzyme containing two molecules of noncovalently bound thiamine pyrophosphate. In the present study, we examined a his-tagged human transketolase that was produced in and purified from Escherichia coli cells. Previous findings demonstrated that purified his-transketolase had a Km app for cofactor and a thiamine pyrophosphate-dependent lag period for attaining steady-state kinetics that was similar to transketolase purified from human tissues. Interestingly, the time of the lag period, which is normally independent of enzyme concentration, was found herein to be dependent on the concentration of the recombinant protein. This atypical behavior was due to production in E. coli. Generation of the normal, enzyme concentration-independent state required a cytosolic factor(s) derived from human cells. Importantly, the required factor(s) was found to be defective in a Wernicke-Korsakoff patient whose cells in culture show an enhanced sensitivity to thiamine deficiency.

Confabulation is a clinically well-documented accompaniment of selective types of memory impairment, especially in brain-damaged alcoholics. This study reports specific occurrences of visual confabulation consisting of spontaneous alterations of Card D of the Visual Reproduction subtest of the Wechsler Memory Scale-Revised. The resemblance of a wineglass was fashioned by a 90-degree rotation into a “bowl and stem”, observed in six of 30 brain-damaged alcoholics. There were no such instances in 132 other patients, including alcoholic controls, those with Parkinson's Disease, temporal lobe epileptics (pre- or post- surgery), and those with neurotoxic exposure. When asked, the subjects who identified the figure as a wineglass or similar drinking instrument reported that they had drawn it as originally shown to them. “Wineglass” confabulators had shorter periods of abstinence, longer drinking histories and lower intellectual functioning than their brain-damaged peers or an alcoholic control group. These findings lend support for the association of alcohol- related confabulation with visual, as well as previously-documented verbal material among brain-damaged alcoholics.

How best to measure the occurrence of adverse events during a randomized clinical trial is an issue that has not been adequately examined in the research literature. Focus of this study was on the examination of the relative frequency of occurrence of adverse events directly recorded during the conduct of the trial compared to an indirect determination of adverse events derived from data collected as part of the trial.A secondary analysis of nonserious adverse events that occurred in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) Study was undertaken. MOTHER was a randomized clinical trial of methadone versus buprenorphine in 175 opioid-dependent pregnant women.The two methods of recording adverse events failed to agree on where differences in the frequency of occurrence of adverse events between the medication conditions might exist. Moreover, indirect assessment indicated all participants had experienced at least one adverse event, yet indirect coverage of adverse events was incomplete.Findings suggest indirect examination of occurrence of adverse events should be cautiously undertaken, because indirect assessment of adverse events makes no distinction between what might be simply typical variation in behavior rather than systematic changes in behavior attributable to study condition, and lacks coverage of the full spectrum of adverse events.Contemporaneous direct measurement of adverse events likely yield reasonably valid estimates of the rate of occurrence of the adverse events, while indirect measu-rement of adverse events may not be sufficiently reliable.

Induction onto buprenorphine during pregnancy may be more challenging than induction onto methadone. This study explores factors predicting withdrawal intensities and compares trajectories of withdrawal during the induction phase between opioid-dependent women randomly assigned to methadone or buprenorphine.A secondary analysis was conducted on data from 175 opioid-dependent pregnant women inducted onto buprenorphine or methadone subsequent to stabilization on morphine sulfate. ANOVA analyses were conducted to determine differences between mean peak CINA scores by medication and completion status. General linear mixed models were fitted to compare trajectories of CINA scores between methadone and buprenorphine conditions, and between study dropouts and completers within the buprenorphine condition.Both buprenorphine and methadone patients experienced withdrawal categorized as minimal by the CINA scoring system. Significant differences in mean peak CINA scores for the first 72 hours of induction were found between the methadone (4.5; SD=0.4) and buprenorphine conditions (6.9; SD=0.4), with buprenorphine patients exhibiting higher mean peak CINA scores [F (3, 165)=9.70, p0.001]. The trajectory of CINA scores showed buprenorphine patients exhibiting a sharper increase in mean CINA scores than methadone patients [F (1, 233)=8.70, p=0.004]. There were no differences in mean peak CINA scores [F (3, 77)=0.08, p=0.52] or in trajectory of CINA scores [F (1, 166)=0.42, p=0.52] between buprenorphine study dropouts and completers.While mean peak CINA score was significantly higher in the buprenorphine condition than the methadone condition, neither medication condition experienced substantial withdrawal symptoms. Further research on factors related to successful induction to buprenorphine treatment in pregnant women is needed.

Purpose To quantify the prevalence of prescribed opioid analgesics among pregnant women enrolled in Tennessee Medicaid from 1995 to 2009. Methods Retrospective cohort study of 277,555 pregnancies identified from birth and fetal death certificates, and linked to previously validated, computerized pharmacy records. Poisson regression was used to estimate trends over time, rate ratios, and 95% confidence intervals (CI). Results During the study period, 29% of pregnant women filled a prescription for an opioid analgesic. From 1995 to 2009, any pregnancy-related use increased 1.90-fold (95% CI, 1.83–1.98), first trimester use increased 2.27-fold (95% CI, 2.14–2.41), and second or third trimester use increased 2.02-fold (95% CI, 1.93–2.12), after adjusting for maternal characteristics. Any pregnancy-related, first trimester, and second or third trimester use were each more likely among mothers who were at least 21 years old, white, non-Hispanic, prima gravid, resided in nonurban areas, enrolled in Medicaid owing to disability, and who had less than a high school education. Conclusions Opioid analgesic use by Tennessee Medicaid-insured pregnant women increased nearly 2-fold from 1995 to 2009. Additional study is warranted to understand the implications of this increased use.

We compare findings from 10 years of experience evaluating physicians referred for fitness-to-practice assessment to determine whether those referred for disruptive behavior are more or less likely to be declared fit for duty than those referred for mental health, substance abuse or sexual misconduct.Deidentified data from 381 physicians evaluated by the Vanderbilt Comprehensive Assessment Program (2001-2012) were analyzed and compared to general physician population data and also to previous reports of physician psychiatric diagnosis found by MEDLINE search.Compared to the physicians referred for disruptive behavior (37.5% of evaluations), each of the other groups was statistically significantly less likely to be assessed as fit for practice [substance use, %: odds ratio (OR)=0.22, 95% confidence interval (CI)=0.10-0.47, P.001; mental health, %: OR=0.14, 95% CI=0.06-0.31, P.001; sexual boundaries, %: OR=0.27, 95% CI=0.13-0.58, P=.001].The number of referrals to evaluate physicians presenting with behavior alleged to be disruptive to clinical care increased following the 2008 Joint Commission guidelines that extended responsibility for professional conduct outside the profession itself to the institutions wherein physicians work. Better strategies to identify and manage disruptive physician behavior may allow those physicians to return to practice safely in the workplace.

Objective The purposes of this article are 1) to review federal and state laws relevant to confidentiality in group therapy with impaired physicians and 2) to provide empirical data concerning the actual confidentiality practices and experiences of group therapists treating chemically impaired physicians. Method In the clinical research phase, 25 state medical societies identified 45 rehabilitation centers as those to which the societies preferentially referred chemically impaired physicians. Fifty-one group leaders from 33 of these rehabilitation centers completed the survey questionnaire employed in this project. Results Because of the risk of potentially irreversible social and professional injury, physician patients were exceedingly concerned about breaches of confidentiality. Co-members' infractions most often involved the violator sharing with close friends and family members the name and abuse history of a fellow physician. In contrast, transgressors rarely leaked information about a co-member's drug-related illegal behaviour. Conclusions Chemically impaired physicians would feel safer in sharing secrets in group therapy if more jurisdictions adopted legislation making co-members liable for violating confidentiality. Currently the pertinent body of law is confusing and inconsistent and provides little protection to impaired physicians who enter group therapy. The authors propose ideas for model legislation.