The behavioral variant of Alzheimer's disease does not show a selective loss of Von Economo and phylogenetically related neurons in the anterior cingulate cortex.

BACKGROUND: The neurobiological origins of the early and predominant behavioral changes seen in the behavioral variant of Alzheimer's disease (bvAD) remain unclear. A selective loss of Von Economo neurons (VENs) and phylogenetically related neurons have been observed in behavioral variant frontotemporal dementia (bvFTD) and several psychiatric diseases. Here, we assessed whether these specific neuronal populations show a selective loss in bvAD. METHODS: VENs and GABA receptor subunit theta (GABRQ)-immunoreactive pyramidal neurons of the anterior cingulate cortex (ACC) were quantified in post-mortem tissue of patients with bvAD (n = 9) and compared to typical AD (tAD, n = 6), bvFTD due to frontotemporal lobar degeneration based on TDP-43 pathology (FTLD, n = 18) and controls (n = 13) using ANCOVAs adjusted for age and Bonferroni corrected. In addition, ratios of VENs and GABRQ-immunoreactive (GABRQ-ir) pyramidal neurons over all Layer 5 neurons were compared between groups to correct for overall Layer 5 neuronal loss. RESULTS: The number of VENs or GABRQ-ir neurons did not differ significantly between bvAD (VENs: 26.0 ± 15.3, GABRQ-ir pyramidal: 260.4 ± 87.1) and tAD (VENs: 32.0 ± 18.1, p = 1.00, GABRQ-ir pyramidal: 349.8 ± 109.6, p = 0.38) and controls (VENs: 33.5 ± 20.3, p = 1.00, GABRQ-ir pyramidal: 339.4 ± 95.9, p = 0.37). Compared to bvFTD, patients with bvAD showed significantly more GABRQ-ir pyramidal neurons (bvFTD: 140.5 ± 82.658, p = 0.01) and no significant differences in number of VENs (bvFTD: 10.9 ± 13.8, p = 0.13). Results were similar when assessing the number of VENs and GABRQ-ir relative to all neurons of Layer 5. DISCUSSION: VENs and phylogenetically related neurons did not show a selective loss in the ACC in patients with bvAD. Our results suggest that, unlike in bvFTD, the clinical presentation in bvAD may not be related to the loss of VENs and related neurons in the ACC.

Low risk of inhibitor formation in haemophilia A patients following en masse switch in treatment to a third generation full length plasma and albumin-free recombinant factor VIII product (ADVATE®).

Previous studies have suggested that development of inhibitors in previously treated patients (PTPs) may be attributable to a switch in factor VIII (FVIII) therapeutic product. Consequently, it is widely recognized that inhibitor development must be assessed in PTPs following the introduction of any new FVIII product. Following a national tender process in 2006, all patients with haemophilia A in Ireland changed their FVIII treatment product en masse to a plasma and albumin-free recombinant full-length FVIII product (ADVATE(®)). In this study, we retrospectively reviewed the case records of Irish PTPs to evaluate risk of inhibitor formation following this treatment switch. One hundred and thirteen patients participated in the study. Most patients (89%) had severe haemophilia. Only one of 96 patients with no inhibitor history developed an inhibitor. Prior to the switch in his recombinant FVIII (rFVIII) treatment of choice, this child had only experienced three exposure days (EDs). Consequently, in total he had only received 6 EDs when his inhibitor was first diagnosed. In keeping with this lack of de novo inhibitor development, we observed no evidence of any recurrent inhibitor formation in any of 16 patients with previously documented inhibitors. Similarly, following a previous en masse switch, we have previously reported that changing from a Chinese hamster ovary cell-produced to a baby hamster kidney cell-produced rFVIII was also associated with a low risk of inhibitor formation in PTPs. Our cumulative findings from these two studies clearly emphasizes that the risk of inhibitor development for PTPs following changes in commercial rFVIII product is low, at least in the Irish population.

Anterior uveitis, inflammatory bowel disease, and ankylosing spondylitis in a HLA-B27-positive woman.

A woman developed anterior uveitis at age 24, inflammatory bowel disease at age 29, and ankylosing spondylitis at age 45 by history. There were frequent recurrences. An HLA-B27 test was positive at age 53. The literature indicates that all of these conditions together in a HLA-B27-positive woman are uncommon. Physicians should be alert to the possibility that a patient might develop another of these associated diseases years after presentation of the first condition and educate their patients accordingly.

Marijuana Craving Questionnaire: development and initial validation of a self-report instrument.

AIMS: To develop and validate a multi-dimensional questionnaire on marijuana craving. DESIGN AND MEASUREMENTS: Current marijuana smokers (n = 217) not seeking treatment completed a 47-item Marijuana Craving Questionnaire (MCQ) and forms assessing demographics, drug use history, marijuana quit attempts and current mood. FINDINGS: Exploratory and confirmatory factor analyses indicated that a four-factor solution best described the item structure. Factor subscales derived from the 17 items with significant loadings had respectable internal consistencies and were stable across settings and subgroups. The subscales exhibited low to moderate, positive intercorrelations and were significantly correlated with marijuana use history and a wide range of single-item measures of craving. CONCLUSIONS: Findings suggested that four specific constructs characterize craving for marijuana: (1) compulsivity, an inability to control marijuana use; (2) emotionality, use of marijuana in anticipation of relief from withdrawal or negative mood; (3) expectancy, anticipation of positive outcomes from smoking marijuana; and (4) purposefulness, intention and planning to use marijuana for positive outcomes. These data indicate that the MCQ is a valid and reliable instrument for assessing marijuana craving in individuals not seeking drug abuse treatment and that marijuana craving can be measured in the absence of withdrawal.

Ibogaine: complex pharmacokinetics, concerns for safety, and preliminary efficacy measures.

Ibogaine is an indole alkaloid found in the roots of Tabernanthe Iboga (Apocynaceae family), a rain forest shrub that is native to western Africa. Ibogaine is used by indigenous peoples in low doses to combat fatigue, hunger and thirst, and in higher doses as a sacrament in religious rituals. Members of American and European addict self-help groups have claimed that ibogaine promotes long-term drug abstinence from addictive substances, including psychostimulants and opiates. Anecdotal reports attest that a single dose of ibogaine eliminates opiate withdrawal symptoms and reduces drug craving for extended periods of time. The purported efficacy of ibogaine for the treatment of drug dependence may be due in part to an active metabolite. The majority of ibogaine biotransformation proceeds via CYP2D6, including the O-demethylation of ibogaine to 12-hydroxyibogamine (noribogaine). Blood concentration-time effect profiles of ibogaine and noribogaine obtained for individual subjects after single oral dose administrations demonstrate complex pharmacokinetic profiles. Ibogaine has shown preliminary efficacy for opiate detoxification and for short-term stabilization of drug-dependent persons as they prepare to enter substance abuse treatment. We report here that ibogaine significantly decreased craving for cocaine and heroin during inpatient detoxification. Self-reports of depressive symptoms were also significantly lower after ibogaine treatment and at 30 days after program discharge. Because ibogaine is cleared rapidly from the blood, the beneficial aftereffects of the drug on craving and depressed mood may be related to the effects of noribogaine on the central nervous system.

Challenges in the manipulation, assessment and interpretation of craving relevant variables.

The nature of drug craving and its role in the addictive process is a contentious issue in the addiction sciences. There are numerous disputes regarding the definition, assessment, manipulation and interpretation of craving, and progress toward resolving the enigmas of craving confronts numerous conceptual and methodological challenges. Greater attention to certain fundamental principles of measurement and manipulation should generate immediate and substantial improvements in efforts to understand and control alcohol craving. This paper provides suggestions for enhancing the measurement of self-reported alcohol craving and improving the manipulation of alcohol craving under controlled laboratory conditions. With regard to measurement, single-item scales commonly employed in craving research tend to be handicapped by limited reliability and validity. Multi-item craving scales are more likely to provide the accuracy required to accurately discriminate between different levels of craving across individuals or across different settings. Conceptual and practical considerations for the selection of multi-item craving instruments are discussed. With regard to the manipulation of alcohol craving in the laboratory, recent meta-analyses suggest that alcohol craving effects in such research may be relatively weaker than craving effects found in similar research with other addicts. Therefore, laboratory-based investigations into the nature of alcohol craving should utilize procedures and assessments that are particularly sensitive to the detection of alcohol craving. This paper offers methodological recommendations for enhancing the magnitude of alcohol craving effects generated in laboratory research.

Tobacco craving: intensity-related effects of imagery scripts in drug abusers.

Two experiments were conducted to determine whether active imagery would elicit tobacco craving in smokers with histories of drug abuse who were not interested in quitting smoking. In Experiment 1, the authors used scripts that contained positive, negative, or neutral affective content with and without descriptions of smoking urge. Scripts with urge content and negative affect scripts increased subjective reports of tobacco craving. An interaction between affective manipulation and urge content was observed on self-reported mood. In Experiment 2, positive affect scripts that varied in amount of urge content produced an orderly increase in tobacco craving as a function of urge intensity, suggesting that changes were specific to the imagery manipulation. In both experiments, increases in tobacco craving were positively correlated with craving for drug of choice, suggesting that stimuli that engender smoking urges may occasion craving for other drugs of abuse.

Smoking after nicotine deprivation enhances cognitive performance and decreases tobacco craving in drug abusers.

This study investigated the effects of nicotine deprivation and smoking on cognitive abilities and tobacco craving. Twenty smokers with histories of drug abuse completed the Questionnaire on Smoking Urges (QSU) and two cognitive tests before and after smoking two cigarettes during two 90-min sessions. After two cigarettes were smoked at Session 1, subjects were tobacco abstinent for 18 h until Session 2 the next morning. Response time on a logical reasoning test was unchanged by tobacco deprivation and was faster after smoking on Session 2. Deprivation slowed responding on a letter search test, which was reversed by smoking to pre-deprivation baseline. Tobacco deprivation increased scores on the QSU; smoking after deprivation reduced craving scores to smoking baseline levels. These results confirmed the utility of the QSU to measure changes in craving induced by tobacco deprivation and smoking. Further, the data suggest that deprivation-induced deficits and smoking-induced enhancements in performance may be specific to certain cognitive domains.

Solid-phase extraction cleanup and liquid chromatography with ultraviolet detection of ephedrine alkaloids in herbal products.

A solid-phase extraction (SPE) cleanup and a liquid chromatographic (LC) method with UV detection is presented for analysis of up to 7 ephedrine alkaloids in herbal products. Alkaloids from herbal products are extracted with acidified buffer, isolated on a propylsulfonic acid SPE column, eluted with a high-ionic-strength buffer, and separated by LC with detection at 255 nm. LC separation is performed by isocratic elution on a YMC phenyl column with 0.1 M sodium acetate-acetic acid (pH = 4.8) containing triethyl-amine and 2% acetonitrile. Ephedrine alkaloids are completely separated in 15 min. Average recovery of 5 common alkaloids from 3 spiked matrixes is 90%, with an average relative standard deviation (RSD) of 4.4% for alkaloid spikes between 0.5 and 16 mg/g. Average quantitation of ephedrine and pseudoephedrine from 6 herbal products is 97% of declared label claims, and average quantitation of synephrine from an herbal dietary product is 85% of label claim (RSD, 3.2%). Recoveries of synephrine, norephedrine, ephedrine, pseudoephedrine, N-methylephedrine, and N-methylpseudoephedrine spiked in 4 herbal products averaged 95%. Results of ruggedness testing and of a second laboratory validation of the procedure are also presented.

Laboratory validation study of drug evaluation and classification program: alprazolam, d-amphetamine, codeine, and marijuana.

The Drug Evaluation and Classification (DEC) program is used by police agencies to identify drivers impaired because of drug use and to determine the class(es) of drug causing the impairment. The primary goal of this study was to determine the validity of the DEC evaluation in predicting whether research volunteers were administered alprazolam, d-amphetamine, codeine, or marijuana. A secondary goal was to determine the accuracy of Drug Recognition Examiners (DREs) in detecting if subjects were dosed with these drugs. Community volunteers (n = 48) were administered alprazolam (0, 1, 2 mg), d-amphetamine (0, 12.5, 25 mg), codeine (0, 60, 120 mg), or marijuana (0, 3.58% THC) in a double-blind, randomized, between-subject design. A single drug dose or placebo was administered at each experimental session, and blood samples were obtained before and after dosing. With the exception of marijuana, plasma drug concentration was at or near maximum during the DEC evaluation. The ability of the DEC evaluation to predict the intake of alprazolam, d-amphetamine, codeine, or marijuana was optimal when using 2-7 variables from the evaluation. DREs' decisions of impairment were consistent with the administration of any active drug in 76% of cases, and their drug class decisions were consistent with toxicology in 32% of cases, according to standards of the International Association of Chiefs of Police. These findings suggest that the DEC evaluation can be used to predict accurately acute administration of alprazolam, d-amphetamine, codeine, and marijuana and that predictions of drug use may be improved by focusing on a subset of variables.

Mechanisms of alcohol craving and their clinical implications.

Craving for alcohol is frequently given as a reason for drinking and is often used as a surrogate measure in studies of alcoholism and its treatment. Despite this wide use, there is little consensus on what craving for alcohol means, the best way to measure it, what mechanism accounts for the urge to drink, or what is its true relationship to alcohol use. This chapter reviews theoretical and measurement issues about the possible mechanisms involved in craving for alcohol and the clinical implications of evidence supporting them. Until recently, most instruments for assessing craving assumed it was a univariate construct and usually contained only one or a few items. Several multi-item and multidimensional rating instruments have now been developed that offer the promise of more useful assessment of clinically relevant behavior. Most models of craving have assumed that a consistent and positive relationship exists between craving and drinking. The incentive sensitization model and the cognitive theory of drug use and drug urges may account better than the older models for the frequent clinical observation of a dissociation between craving and drinking. However, no single model or theory of craving accounts for the wide variation in findings reviewed here, suggesting that multiple mechanisms may be involved. A comprehensive, multidisciplinary approach is necessary to elucidate the nature of craving for alcohol and its implications for pharmacological and psychosocial treatment of alcoholism.

The efficacy of local anaesthetics administered by general dental practitioners.

AIM: To obtain empirical evidence for the efficacy of local anaesthesia in dentistry. DESIGN: Retrospective analysis of serial administrations of local anaesthesia. METHODS: Dentist and patient evaluations of the success of differing techniques (infiltration and block) of anaesthesia in a variety of general practice procedures. Results were analysed for correlation between dentist and patient using a 5-point scale. RESULTS: Complete data were analysed for 331 administrations. In the hands of experienced dentists over 93% of operations were assessed by both dentist and patient as comfortable or completely comfortable. Dentists were generally able to judge patient comfort (P < 0.001). Administrations requiring repeat injections were less comfortable. Dentists judged infiltration administrations more comfortable than block administrations (P < 0.001), but patient judgements of comfort failed to distinguish between differing techniques at the P < 0.05 level. CONCLUSIONS: Some variations in success rate exist between dentists the most dental procedures under local anaesthetic in general practice were assessed as being comfortable or better by both dentists and patients.

Chest radiographic data acquisition and quality assurance in multicenter studies.

BACKGROUND: Multicenter studies rely on data derived from different institutions. Forms can be designed to standardize the reporting process allowing reliable comparison of data. OBJECTIVE: The purpose of the report is to provide a standardized method, developed as a part of a multicenter study of vertically transmitted HIV, for assessing chest radiographic results. MATERIALS AND METHODS: Eight hundred and five infants and children were studied at five centers; 3057 chest radiographs were scored. Data were entered using a forced-choice, graded response for 12 findings. Quality assurance measures and inter-rater agreement statistics are reported. RESULTS: The form used for reporting chest radiographic results is presented. Inter-rater agreement was moderate to high for most findings, with the best correlation reported for the presence of bronchovascular markings and/or reticular densities addressed as a composite question (kappa = 0.71). The presence of nodular densities (kappa = 0.56) and parenchymal consolidation (kappa = 0.57) had moderate agreement. Agreement for lung volume was low. CONCLUSION: The current tool, developed for use in the pediatric population, is applicable to any study involving the assessment of pediatric chest radiographs for a large population, whether at one or many centers.

Clinical and molecular characterization of a family affected with X-linked ocular albinism (OA1)

Thirty-one members of a family affected with X-linked ocular albinism (OA1) were studied to characterize the clinical phenotype and identify the disease-causing mutation. The family members were examined with ophthalmoscopy, electroretinography, and Goldmann perimetry. Linkage analysis was performed with markers from the OA1 locus. Exons 2 and 8 of the OA1 gene were assayed with the polymerase chain reaction (PCR). The six affected males had visual acuities ranging from 20/40 to 20/200. All had nystagmus, iris transillumination, and foveal hypoplasia. The eldest affected male had 20/40 vision and was asymptomatic. The level of the visual acuity of the affected males was not related to the degree of retinal pigmentation. All seven female carriers had normal visual function but were found to have iris transillumination defects and variable retinal pigmentary appearance ranging from minimal pigmentary disturbance, patchy and diffuse hypopigmentation, to classic 'mud-splattered' appearance. Linkage analysis was consistent with a disease-causing mutation at the OA1 locus. PCR analysis revealed a deletion which includes at least the portion of the OA1 gene between exons 2 and 8. Affected males with X-linked ocular albinism can have a visual disability that ranges from almost none to legal blindness, and the female carriers can have variable retinal pigmentary appearance. Mutation screening of the OA1 gene can be used to confirm the diagnosis in isolated males of some families, and genetic linkage analysis can be used to accurately identify carriers even when the specific mutation cannot be identified.

Laboratory validation study of drug evaluation and classification program: ethanol, cocaine, and marijuana.

The Drug Evaluation and Classification (DEC) program is used by police agencies to determine if individuals are behaviorally impaired because of drug use, and, if impaired, to determine the class of drug(s) causing the impairment. Although widely used, the validity of the DEC evaluation has not been rigorously tested. The primary goal of this study was to determine the validity of the variables of the DEC evaluation in predicting whether research volunteers had been administered ethanol, cocaine, or marijuana; a secondary goal was to determine the accuracy of trained police officers (Drug Recognition Examiner, DRE) in detecting whether subjects had been dosed with ethanol, cocaine, or marijuana. Community volunteers (n = 18) with histories of drug use received ethanol (0, 0.28, 0.52 g/kg), cocaine (4, 48, 96 mg/70 kg), and marijuana (0, 1.75, 3.55% THC) in a double-blind, randomized, within-subjects design. A single drug dose or placebo was administered during each of nine experimental sessions, and blood samples were obtained before and periodically after dosing. With the exception of marijuana, plasma drug concentration was at or near the observed maximum during the DEC evaluation. The ability of the DEC evaluation to predict the intake of ethanol, cocaine, or marijuana was optimal when using 17-28 variables from the evaluation. When DREs concluded impairment was due to drugs other than ethanol, their opinions were consistent with toxicology in 44% of cases. These findings suggest that the DEC evaluation can be used to predict accurately acute administration of ethanol, cocaine, or marijuana, and that predictions of drug use may be improved if DREs focused on a subset of variables.

Coalition building: a strategy for creating HIV/AIDS awareness on a college campus.

Coalition building was a successful strategy for creating HIV/AIDS awareness on the Dillard University campus. The purpose of the coalition building was to increase University students' knowledge and awareness of HIV/AIDS. The success of coalition building is predicated upon knowing whose assistance is needed and the development of positive relationships with those individuals. Coalition building in this instance required building relationships within the internal and external environments of the University. Hence, students, their organizations, faculty and community agencies were involved. An invitation to participate in the coalition was extended to twenty-one active campus organizations represented by the Student Government Association (SGA). The Santa Filomena Student Nurses Association (SF-SNA) served as the lead student organization. Faculty liaisons were solicited during a University faculty forum. Community agencies played a significant role in HIV/AIDS awareness at Dillard. One agency provided training and curriculum development, targeting minority health care providers. A questionnaire (Assessment Tool) was developed to obtain demographic data and a self-assessment of students' knowledge of HIV/AIDS. After meetings with coalition members, a HIV/AIDS Awareness Program was conducted on the University campus. The project was funded by Project FACE of Florida A&M University Foundation. Since students responded very favorably to the project, plans were made to provide ongoing HIV/AIDS awareness on the University campus.