Cannabis and Depression: A Twin Model Approach to Co-morbidity.

Cannabis use disorder (CUD) co-occurs with major depressive disorder (MDD) more frequently than would be expected by chance. However, studies to date have not produced a clear understanding of the mechanisms underlying this co-morbidity. Genetically informative studies can add valuable insight to this problem, as they allow the evaluation of competing models of co-morbidity. This study uses data from the Australian Twin Registry to compare 13 co-morbidity twin models initially proposed by Neale and Kendler (Am J Hum Genet 57:935-953, 1995). The analysis sample comprised 2410 male and female monozygotic and dizygotic twins (average age 32) who were assessed on CUD and MDD using the SSAGA-OZ interview. Data were analyzed in OpenMx. Of the 13 different co-morbidity models, two fit equally well: CUD causes MDD and Random Multiformity of CUD. Both fit substantially better than the Correlated Liabilities model. Although the current study cannot differentiate between them statistically, these models, in combination, suggest that CUD risk factors may causally influence the risk to develop MDD, but only when risk for CUD is high.

Observational Study of Methotrexate in the Treatment of Bronchiolitis Obliterans Syndrome.

BACKGROUND: Methotrexate (MTX) is potential change in immunosuppression after lung transplantation that may help to slow down the decline in lung function in bronchiolitis obliterans syndrome (BOS). METHODS: We sought to analyze the safety and efficacy of MTX in patients with BOS, by retrospective case review. RESULTS: Thirty lung allograft patients were treated with MTX for BOS after one bilateral lower lobe, nine single, 16 bilateral, and four heart-lung transplants. Twenty-one patients had MTX treatment for a minimum of 6 months, and their serial lung function was analyzed for efficacy. In these patients, there was a significant overall increase in mean forced expiratory volume in 1 second (FEV1) of 149 mL (P < .02) at 3 months, with an increase observed in 14 of 21 patients. At 6 months, there was a mean increase in FEV1 of 117 mL (P < .05). At 12 months, there was a mean non-significant increase of FEV1 of 60 mL (P = .19) observed in 18 patients who had MTX for this time period. The rate of decline in FEV1 before MTX was 118.5 mL/month and at 3 months after MTX increased to 49.5 mL/months (P < .0005) in the FEV1. Nine patients had been treated with MTX for less than 6 months; two died within 6 months of starting MTX, five tolerated the drug poorly with nausea and tiredness, and one developed leucopenia. One patient requested discontinuation of the medication after failing to halt the rapid progressive decline in lung function after 1 month. CONCLUSIONS: Methotrexate therapy provides a potential therapeutic strategy in managing the progressive decline in lung function observed in BOS. This is hampered by the observation of poor tolerability and side effects.

Alcohol use disorders in Australia.

Alcohol use disorders are common in Australia and are often unrecognised. Alcohol places a significant burden on our healthcare system by increasing the risk of injuries as well as many chronic medical conditions. Diagnosis requires a high index of suspicion and can be aided by the use of specific questionnaires, such as the Alcohol Use Disorder Identification Test-C. The current available laboratory tests are of limited sensitivity and specificity, but can nevertheless aid in the diagnosis in some circumstances. Newer tests, such as ethyl-glucuronide and phosphatidylethanol, are more sensitive and specific but are costly and not widely available. The effective management of alcohol use disorder entails psychosocial or pharmacological treatments or a combination of both. In those who cannot reduce alcohol consumption, harm reduction strategies can be applied to reduce the burden of harm to the drinkers as well as the community at large.

Is Specialized Integrated Treatment for Comorbid Anxiety, Depression and Alcohol Dependence Better than Treatment as Usual in a Public Hospital Setting?

AIM: To assess the effectiveness of a 12 week specialized, integrated intervention for alcohol dependence with comorbid anxiety and/or mood disorder using a randomized design in an outpatient hospital setting. METHODS: Out of 86 patients meeting the inclusion criteria for alcohol dependence with suspicion of comorbid anxiety and/or depressive disorder, 57 completed a 3-week stabilization period (abstinence or significantly reduced consumption). Of these patients, 37 (65%) met a formal diagnostic assessment of an anxiety and/or depressive disorder and were randomized to either (a) integrated intervention (cognitive behavioural therapy) for alcohol, anxiety and/or depression, or (b) usual counselling care for alcohol problems. RESULTS: Intention-to-treat analyses revealed a beneficial treatment effect of integrated treatment relative to usual counselling care for the number of days to relapse (χ(2) = 6.42, P < 0.05) and lapse (χ(2) = 10.73, P < 0.01). In addition, there was a significant interaction effect of treatment and time for percentage days of abstinence (P < 0.05). For heavy drinking days, the treatment effect was mediated by changes in DASS anxiety (P < 0.05). There were no significant treatment interaction effects for DASS depression or anxiety symptoms. CONCLUSIONS: These results provide support for integrated care in improving drinking outcomes for patients with alcohol dependence and comorbid depression/anxiety disorder. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01941693.

Merkel cell carcinoma in a patient with GATA2 deficiency: a novel association with primary immunodeficiency.

A 55-year-old woman with GATA2 deficiency and neurofibromatosis 1 was diagnosed with Merkel cell carcinoma (MCC). This polyomavirus-associated cutaneous malignancy has previously been associated with immunosuppression and acquired immunodeficiencies such as HIV/AIDS. However, MCC has not been previously reported in the setting of underlying primary or inherited immunodeficiency.

Baclofen for the Treatment of Alcohol Dependence and Possible Role of Comorbid Anxiety.

AIM: To conduct a double-blind, placebo-controlled randomized clinical trial of baclofen in the treatment of alcohol dependence. METHODS: Out of 69 participants consecutively screened, 42 alcohol-dependent patients were randomized to receive placebo, baclofen 30 mg/day or baclofen 60 mg/day for 12 weeks. All subjects were offered BRENDA, a structured psychosocial therapy for alcohol dependence that seeks to improve motivation for change, enhance strategies to prevent relapse and encourage compliance with treatment. RESULTS: Intention-to-treat analyses revealed that alcohol consumption (heavy drinking days, drinks per drinking day) significantly reduced across all three groups during the treatment period. There were no statistically significant advantages to treatment on time to first heavy drinking day (relapse) (P = 0.08), nor time to first drink (lapse) (P = 0.18). A post hoc analysis stratifying according to whether there had been a comorbid anxiety disorder, revealed a beneficial effect of baclofen 30 mg/day versus placebo on time to lapse and relapse (P < 0.05). There was also a beneficial effect for baclofen 60 mg/day relative to placebo on time to relapse in this comorbid group (P < 0.05). Both doses of baclofen were well tolerated. There were no serious adverse events. CONCLUSIONS: In spite of the small sample for a 3-arm clinical trial, this study suggests a specific role of baclofen in alcohol-dependent individuals with comorbid anxiety. Replication in larger, fully-powered studies is required.

Online questionnaire development: using film to engage participants and then gather attitudes towards the sharing of genomic data.

How can a researcher engage a participant in a survey, when the subject matter may be perceived as 'challenging' or even be totally unfamiliar to the participant? The Genomethics study addressed this via the creation and delivery of a novel online questionnaire containing 10 integrated films. The films documented various ethical dilemmas raised by genomic technologies and the survey ascertained attitudes towards these. Participants were recruited into the research using social media, traditional media and email invitation. The film-survey strategy was successful: 11,336 initial hits on the survey website led to 6944 completed surveys. Participants included from those who knew nothing of the subject matter through to experts in the field of genomics (61% compliance rate), 72% of participants answered every single question. This paper summarises the survey design process and validation methods applied. The recruitment strategy and results from the survey are presented elsewhere.

The efficacy and biobehavioural basis of baclofen in the treatment of alcoholic liver disease (BacALD): study protocol for a randomised controlled trial.

BACKGROUND: Effective treatments for alcohol use disorders in those with significant liver disease are critically lacking. The primary aim of the current study is to explore the effectiveness and biobehavioural basis of low and high dose baclofen in improving treatment outcomes for alcohol dependence in people with alcoholic liver disease (The BacALD study). METHODS: This double-blind, placebo-controlled study will randomize 180 participants to a 12-week regime of either baclofen (30 mg/day baclofen, 75 mg/day baclofen) or placebo. Participants must meet the ICD-10 criteria for alcohol dependence in addition to alcoholic liver disease (ALD) defined as the presence of symptoms and/or signs referable to liver disease or its complications with or without cirrhosis. Primary outcome measures will include total abstinence duration, and time to lapse and relapse. Furthermore, 60 of the ALD patients enrolled in the trial will also participate in a pharmacokinetic and cue-reactivity component, along with an additional 30 healthy volunteers matched for age and gender randomised to a 1 week regime of either 30 mg/day baclofen or 75 mg/day baclofen. At week 1, plasma levels of baclofen and ß-p-chlorophenol-γ-hydroxybutric acid will be measured at 0, 1 and 4 h following baclofen administration and psychophysiological responses to alcohol-associated stimuli will be assessed in a cue reactivity paradigm. Recruitment commenced in late March 2013. CONCLUSIONS: This trial will demonstrate the efficacy and safety of two doses of baclofen in patients with alcoholic liver disease and will explore the biobehavioural mechanisms of the treatment effect.

Gender differences in premorbid, entry, treatment, and outcome characteristics in a treated epidemiological sample of 661 patients with first episode psychosis.

OBJECTIVES: Gender differences in psychotic disorder have been observed in terms of illness onset and course; however, past research has been limited by inconsistencies between studies and the lack of epidemiological representative of samples assessed. Thus, the aim of this study was to elucidate gender differences in a treated epidemiological sample of patients with first episode psychosis (FEP). METHODS: A medical file audit was used to collect data on premorbid, entry, treatment and 18-month outcome characteristics of 661 FEP consecutive patients treated at the Early Psychosis Prevention and Intervention Centre (EPPIC), Melbourne, Australia. RESULTS: Prior to onset of psychosis, females were more likely to have a history of suicide attempts (p=.011) and depression (p=.001). At service entry, females were more likely to have depressive symptoms (p=.007). Conversely, males had marked substance use problems that were evident prior to admission (p<.001) and persisted through treatment (p<.001). At service entry, males also experienced more severe psychopathology (p<.001) and lower levels of functioning (GAF, p=.008; unemployment/not studying p=.004; living with family, p=.003). Treatment non-compliance (p<.001) and frequent hospitalisations (p=.047) were also common for males with FEP. At service discharge males had significantly lower levels of functioning (GAF, p=.008; unemployment/not studying p=.040; living with family, p=.001) compared to females with FEP. CONCLUSIONS: Gender differences are evident in illness course of patients with FEP, particularly with respect to past history of psychopathology and functioning at presentation and at service discharge. Strategies to deal with these gender differences need to be considered in early intervention programs.

The effect of glasses on visual function following cataract surgery in a cataract camp.

AIM: To investigate visual and functional impact of glasses following cataract surgery in a high-volume cataract camp as measured by the World Health Organization Prevention of Blindness Visual Function Questionnaire (WHO/PBD-VFQ-20). METHOD: Subjects were administered the WHO/PBD-VFQ three times: (1) preoperatively; (2) 3 months postoperatively, before glasses; and (3) 6 months postoperatively, after 3 months with glasses. Patients were given prescription glasses or +2.50 readers at the 3-month follow-up. RESULTS: 315 patients enrolled in the study; 113 patients had complete WHO/PBD-VFQ and visual acuity data from all three administrations. The mean preoperative visual acuity in the surgical eye was 20/327. Following cataract surgery but before glasses, visual acuity improved to 20/57. Total WHO/PBD-VFQ and subscale scores improved significantly at the 3-month point. With glasses, visual acuity improved to 20/43. Total WHO/PBD-VFQ scores did not change following glasses, although the overall and near vision subscales did improve significantly. Glasses were worn once per week or less in 56% of patients. CONCLUSION: Postoperative glasses result in modest improvements in visual acuity. Total WHO/PBD-VFQ scores did not change significantly following glasses, but the overall and near vision subscales did improve. The net beneficial effect of glasses was small relative to cataract surgery itself.

Sural neuropathy: etiologies and predisposing factors.

Isolated sural neuropathy is an uncommon diagnosis. We identified 36 patients with isolated sural neuropathy. Sixteen had various forms of ankle trauma, in three of whom the associated sural neuropathies developed following medical intervention. Three patients developed sural neuropathy associated with vasculitis, and there were single patients with schwannoma and ganglionic cyst. In patients without a history of trauma, structural causes, such as schwannoma or ganglionic cysts and vasculitis, should be considered and managed as appropriate.

Developments in rheumatology consultant manpower provision: the BSR/arc Workforce Register 2003-05.

OBJECTIVES: To summarize the changes and continuing inequalities in rheumatology service provision in the UK between 2001 and 2005. METHODS: Questionnaires about demographics and workload were sent to all consultants on the BSR/arc Workforce Register in January 2003 and 2005. RESULTS: A total of 94% of 506 consultants responded in 2003 and 89% of 542 in 2005. About 19% of the consultants practice rheumatology with acute medicine. Levels of optimal provision exceed 60% in England and Wales, but are below 50% in Scotland and Northern Ireland. The levels of provision in London are substantially higher than anywhere else. The median number of hours worked per week has increased from 35.2 in 2003 to 41 in 2005. CONCLUSIONS: Rheumatology continues to expand. There is inequality with better provision in England (especially London) and Wales than Scotland and Northern Ireland. Patterns of nurse and Senior House Officer (SHO) provision correlate with consultant numbers. Thus, the catalyst for improved service is consultant expansion.

Evaluation of a hypertension screening programme in Independence, Belize.

This study assesses the effectiveness of a hypertension-screening programme in Independence, Belize. Forty-nine of the 101 patients screened were found to have elevated blood pressure readings and were advised to seek medical care. Four months later, interviews with 35 of the 49 patients from the hypertensive group revealed that 85.7% of the patients had sought medical care. Women, elderly patients and patients with a previous history of hypertension were more likely than men, younger patients and those without a history of hypertension to seek follow-up medical care. The screening programme successfully directed a high proportion of patients with elevated blood pressure to seek appropriate medical care.

Evaluation of a hypertension screening programme in Independence, Belize / Evaluación de Programa de Pesquizaje de la Hipertensión en Independencia, Belice

This study assesses the effectiveness of a hypertension-screening programme in Independence, Belize. Forty-nine of the 101 patients screened were found to have elevated blood pressure readings and were advised to seek medical care. Four months later, interviews with 35 of the 49 patients from the hypertensive group revealed that 85.7 of the patients had sought medical care. Women, elderly patients and patients with a previous history of hypertension were more likely than men, younger patients and those without a history of hypertension to seek follow-up medical care. The screening programme successfully directed a high proportion of patients with elevated blood pressure to seek appropriate medical care

Este estudio evalúa la efectividad de un programa de pesquizaje de la hipertensión en Independencia, Belice. Se halló que 49 de 101pacientes sometidos al pesquizaje produjeron lecturas de alta presión sanguínea y tensión arterial, y se les aconsejó buscar atención médica. Cuatro meses después, entrevistas con 35 de los 49 pacientes del grupo hipertenso revelaron que el 85.7% de los pacientes habían buscado atención médica. Las mujeres, los pacientes mayores y los pacientes con una historia previa de hipertensión presentaban una probabilidad mayor a buscar atención médica de seguimiento, que los hombres, los pacientes más jóvenes y aquéllos sin una historia de hipertensión. El programa de pesquizaje tuvo éxito en hacer que una alta proporción de pacientes con presión sanguínea alta buscaran adecuada atención médica.

Investigation of platelet glycoprotein IIIa polymorphism using flow cytometry in patients with rheumatoid arthritis.

OBJECTIVES: Previous work has shown that the human platelet antigen (HPA) 1b polymorphism of platelet glycoprotein IIIa (GPIIIa) is implicated in the development of ischaemic vascular disease. HPA1b positive platelets have a lower threshold for activation and may exert a greater thrombotic tendency than those without the 1b allele. However, platelets heterozygous for the polymorphism are also more sensitive to aspirin than those homozygous for the 1b allele, which have a similar sensitivity to those without the 1b allele. A flow cytometric method has become available to identify this polymorphism. The aim of our study was to evaluate the use of this assay in patients with rheumatoid arthritis (RA) and to determine the incidence of the 1b allele in these patients. We also compared platelet aggregation and platelet/white blood cell interaction in patients with or without this polymorphism. METHODS: We enrolled 99 patients and measured platelet aggregation in whole blood and platelet-rich plasma (prp), platelet/white blood cell interaction and C-reactive protein (CRP). RESULTS: Thirty-four of the 99 patients were unsuitable for analysis because their baseline expression of GPIIIa was outwith the normal range, making the results outwith the limits of the flow cytometric method. The incidence of the 1b allele in the patients was 29%, with incidence being higher in females, although this failed to reach statistical significance. The number of circulating platelet aggregates and adenosine diphosphate (ADP)-induced aggregation in prp was significantly higher in those patients with the 1b allele. CONCLUSIONS: This method may be of use as an initial screening test.

The photochemistry of 2-(1-naphthyl)ethyl benzoates: cycloaddition and intramolecular exciplex formation.

The photochemistry of the 2-(1-naphthyl)ethyl benzoates 6 and 7 was examined in order to compare them to previously studied 2-arylethyl 4-cyanobenzoates that underwent a Norrish Type II fragmentation. The 1-naphthyl group was incorporated to provide a fluorescent chromophore for probing the intramolecular electron transfer proposed previously for the mechanism. The naphthalene fluorescence was quenched for both 6 and 7 although at very different rates. For 6, with the higher thermodynamic driving force (-68.9 kJ/mol), intramolecular electron transfer was fast in all solvents, independent of their polarity (cyclohexane to methanol). For 7, with the lower driving force (-26.5 kJ/mol) the process was fast only in polar solvents. Exciplex emission, observed for 6 (but not for 7), exhibited a large solvatochromic effect possibly indicating a high dipole moment (28 D) in polar solvents (stretched conformation) but a lower one (17 D) in nonpolar solvents (folded conformation). Finally, the 4-cyanobenzoate 6 was very unreactive photochemically. In contrast, benzoate 7 underwent a 2 + 2 cycloaddition of the ester carbonyl to the naphthalene ring to give products 8 and 9, a process for which we have found no precedent.

The genetics of cognitive processes: candidate genes in humans and animals.

It has been hypothesized that numerous genes contribute to individual variation in human cognition. An extensive search of the scientific literature was undertaken to identify candidate genes which might contribute to this complex trait. A list of over 150 candidate genes that may influence some aspect of cognition was compiled. Some genes are particularly strong candidates based on evidence for involvement in cognitive processes in humans, mice, and Drosophila melanogaster. This survey confirms that many genes are associated with cognitive variation and highlights the potential importance of animal models in the study of human cognition.

Increased anxiety and impaired memory in rats 3 months after administration of 3,4-methylenedioxymethamphetamine ("ecstasy").

Male Wistar rats were administered either (a) a high dose regime of 3,4-methylenedioxymethamphetamine (MDMA) (4 x 5 mg/kg, i.p. over 4 h on each of 2 consecutive days), (b) a moderate dose regime of MDMA (1 x 5 mg/kg on each of 2 consecutive days), (c) D-amphetamine (4 x 1 mg/kg over 4 h on each of 2 days), or (d) vehicle injections. The high MDMA dose regime and the amphetamine treatment both produced acute hyperactivity and hyperthermia. Twelve weeks later, all rats were tested in the drug-free state on a battery of anxiety tests (elevated plus maze, emergence and social interaction tests). A further 2 weeks later they were tested on a novel object recognition memory task. Rats previously given the neurotoxic dose of MDMA showed greater anxiety-like behaviour on all three anxiety tests relative to both controls and D-amphetamine-treated rats. Rats given the moderate MDMA dose regime also showed increased anxiety-like behaviour on all three tests, although to a lesser extent than rats in the high dose group. In the object recognition task, rats given the high MDMA dose regime showed impaired memory relative to all other groups when tested at a 15-min delay but not at a 60-min delay. Rats previously exposed to amphetamine did not differ from saline controls in the anxiety or memory tests. These data suggest that moderate to heavy MDMA exposure over 48 h may lead to increased anxiety and memory impairment 3 months later, possibly through a neurotoxic effect on brain serotonin systems.

(+/-)-3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') increases social interaction in rats.

A series of experiments administered a low dose range (0, 1.25, 2.5 and 5 mg/kg) of (+/-)-3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') to rats and assessed them in a variety of standard tests of anxiety. These tests included the emergence and elevated plus-maze tests, social interaction, cat odor avoidance and footshock-induced ultrasonic vocalizations. MDMA increased anxiety-related behaviours in the emergence and elevated plus-maze tests at all dose levels. A 5 mg/kg dose of MDMA also significantly reduced the time spent in close proximity to an anxiogenic cat odor stimulus. The 5 mg/kg dose also significantly reduced footshock-induced ultrasonic vocalizations. In the social interaction test, MDMA decreased aggressive behaviours at all doses tested, while the highest dose (5 mg/kg) also significantly increased the duration of social interaction. These results indicate that MDMA has both anxiogenic and anxiolytic effects depending upon the test situation employed. The facilitation of social interaction produced by MDMA in rats concurs with human experience of MDMA as a uniquely prosocial drug.