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.

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.

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.

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.

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.

Context-dependent gene expression: cis-acting negative effects of specific procaryotic plasmid sequences on eucaryotic genes.

A sequence element within pBR322 DNA mediates a cis-acting negative effect on expression from eucaryotic genes in transient expression assays. The negative element overlaps with sequences that inhibit DNA replication, but its effect is observed in the absence of detectable replication of transfected DNA.

Multiple hormone-inducible enhancers as mediators of differential transcription.

Sets of genes under a common regulatory control in a given cell type are often differentially transcribed. The possibility that this differential transcription can be modulated by the number or strength of cis-acting regulatory sequences associated with a given gene was tested by using the glucocorticoid-responsive enhancer element associated with the mouse mammary tumor virus promoter. Results indicate that differential levels of hormone-inducible gene expression can be modulated in an additive way by the number of glucocorticoid-responsive enhancers associated with this promoter. Realization of these effects shows little preference for position of the additional elements with respect to the promoter. When sequences that bind the glucocorticoid receptor in vitro with somewhat lower affinity than the enhancer were tested, these additive effects were not detected. The results support that differential transcription of genes subject to a common regulatory control can be mediated, at least in part, by the number or strength of their associated cis-acting regulatory sequences.

The mouse c-rel protein has an N-terminal regulatory domain and a C-terminal transcriptional transactivation domain.

We have shown that the murine c-rel protein can act as a transcriptional transactivator in both yeast and mammalian cells. Fusion proteins generated by linking rel sequences to the DNA-binding domain of the yeast transcriptional activator GAL4 activate transcription from a reporter gene linked in cis to a GAL4 binding site. The full-length mouse c-rel protein (588 amino acids long) is a poor transactivator; however, the C-terminal portion of the protein between amino acid residues 403 to 568 is a potent transcriptional transactivator. Deletion of the N-terminal half of the c-rel protein augments its transactivation function. We propose that c-rel protein has an N-terminal regulatory domain and a C-terminal transactivation domain which together modulate its function as a transcriptional transactivator.

Domain swapping reveals the modular nature of Fos, Jun, and CREB proteins.

The products of the Jun and Fos proto-oncogenes form a heterodimer that binds to and activates transcription from 12-O-tetradecanoylphorbol-13-acetate-responsive promoter elements (TGACTCA) and AP-1-binding sites (TGACATCA). These two proteins belong to a family of related transcription factors which contain similar domains required for protein dimerization and DNA binding but display different protein and DNA binding specificities. The basic region, required for DNA binding, is followed by a leucine zipper structure, a domain that mediates protein-protein interactions. To assess the role of these two domains in three related proteins, Fos, Jun, and CREB, we carried out extensive domain-swapping analysis. We found that (i) dimers formed by two Jun leucine zipper-containing proteins were unable to bind DNA as efficiently as a Fos-Jun combination, regardless of the source of the basic region; (ii) the Fos leucine zipper was unable to form either homo- or heterodimers with a chimeric protein containing a Fos leucine zipper; (iii) the Fos basic region was capable of binding to an AP-1 site; (iv) replacement of the Jun amino terminus with that of CREB had little effect on dimerization, whereas replacement with the amino terminus of Fos disrupted both protein-protein and protein-DNA interactions; (v) changes in relative affinities of the Fos and Jun basic regions for the AP-1 element were dependent on the secondary contributions of amino-terminal residues; and (vi) the Fos-Jun chimeric constructs cooperated in transcriptional transactivation of the Jun promoter in NIH 3T3 cells.

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.

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.

Bone mineral density of total body, spine, and femoral neck in children and young adults: a cross-sectional and longitudinal study.

Bone mineral density (BMD) of total body (TBMD), lumbar spine (L2-4), and femoral neck was measured in 266 normal subjects (136 males) aged 4-27 years (mean 13 years) using dual-energy x-ray absorptiometry (DXA). BMD of all sites increased significantly with age until 17.5 years in males and 15.8 years in females, except for femoral neck BMD in females, which peaked at age 14.1 years. Males had higher peak TBMD, which was attributed to greater weight and lean tissue mass. In contrast, despite a later timing, peak L2-4 BMD in males was not different from that in females. Before peak BMD, weight was the best predictor of TBMD and L2-4 BMD in both sexes (r2 ranged from 0.77 to 0.88), whereas femoral neck BMD was predicted equally by height and weight. Longitudinal information collected from 53 (25 boys) of these children, aged 4-16.9 years, showed that the average annualized gain in TBMD was 0.047 g/cm2 for boys and 0.039 g/cm2 for girls. No significant difference in the association between age and BMD (slopes) was found between cross-sectional and longitudinal data for either sex. We conclude that the timing for peak BMD was consistent for total body, lumbar spine, and femoral neck for each sex. The earlier peak BMD in females is most likely related to earlier puberty. The cross-sectional normative data of this study are useful in serving as a standard for serial assessment in health and disease states.

Body-composition assessment by dual-energy x-ray absorptiometry in subjects aged 4-26 y.

This cross-sectional study describes the body composition of 265 normal subjects (137 males and 128 females) aged 4-26 y determined by dual-energy x-ray absorptiometry (DXA). Lean tissue mass (LTM) and bone mineral content (BMC) increased with age in females until 13.4 and 15.7 y, respectively, and in males until 16.6 and 17.4 y, respectively. A strong relation between LTM and BMC was found for each sex (r = 0.98, P = 0.0001 for males; r = 0.98, P = 0.0001 for females). DXA percent body fat (%BFDXA) increased with age in females (r = 0.52, P < 0.001) but not in males and was higher in females than in males at all ages. Trunk to leg fat ratio (TLFR) was calculated as DXA trunk fat/leg fat. In post-pubertal age the TLFR was higher in males than in females (1.01 +/- 0.23 and 0.75 +/- 0.16, P = 0.001), but there was no sex difference in younger children. DXA weight underestimated scale weight by a mean of 0.83 kg. %BFDXA correlated with %BF by skinfold thickness measurement with good agreement for males but overestimated %BF by skinfold thickness for females. These normative data for body composition demonstrate significant sex differences in all body compartments after the pubertal years.

Stability of DNA/ANTI-DNA complexes. IV. Complement fixation.

We describe an in vitro assay to study complement fixation of antibody/dsDNA immune complexes formed from SLE sera and radiolabeled dsDNA. The method measures the amount of radiolabeled dsDNA which is part of an immune complex bound to red blood cells via the C3b complement component receptor. The assay is dependent upon active complement, red blood cells, and anti-dsDNA antibodies, but it is independent of the red blood cell donor (type O) and the age of the red blood cells (up to 10 days). The method has been compared in some detail with the Farr assay with respect to the antibody/dsDNA ratio in the immune complexes and the relative stability of the complexes as measured by their resistance to dissociation by excess unlabeled dsDNA. Our results indicate that multiple binding of antibodies to dsDNA is required for complement fixation, and that a significant percentage of those antibodies which fix complement are of high avidity. Finally, a double label assay using both [3H]- and [14C]-dsDNA indicates that the complement fixing potential of the anti-dsDNA antibodies in an SLE serum is strongly influenced by the order of mixing of the isotopes with the serum. The DNA isotope which is added to the serum first is considerably more effective at fixing complement than the isotope which is added 1 h later. The implications of these results with respect to the pathogenesis of SLE are discussed.

An accessory sex gland aggression-promoting chemosignal in male mice.

The present study investigated male murine accessory sex glands as potential sources of a urinary aggression-promoting chemosignal. Experiments 1-4 were designed to determine whether the removal of the following glands would eliminate voided urine chemosignal activity: vesicular and coagulating glands, Cowper's gland, prostate gland, or preputial gland. The findings indicate that only preputialectomy eliminated the aggression-promoting properties of voided urine, which provides evidence that this gland is a necessary condition for chemo-activity. The efficacy of the preputial gland as sufficient for chemosignal production was examined in Experiment 5. Urine from males that had an intact preputial but removed vesicular, coagulating, Cowper's, and prostate glands was assessed and shown to possess the chemocue. It was concluded that the presence of a functional preputial gland is a necessary and sufficient condition for providing an accessory sex gland aggression-promoting chemosignal.

The detection of raised levels of IgM to Proteus mirabilis in sera from patients with rheumatoid arthritis.

An analysis by ELISA of 100 rheumatoid factor (RF)-positive sera selected at random from a collection of sera from patients with various auto-immune diseases and joint pains, and 100 RF-negative sera from the same collection matched by patient age and gender, showed that the RF-positive sera had highly significantly (p < 0.0001) raised levels of IgM antibody, but not IgG antibody, to Proteus mirabilis over those of the RF-negative sera. This response was subsequently found to be associated with sera from patients who clinically had rheumatoid arthritis (RA). Sera from the RA patients had significantly greater amounts (p = 0.026) of IgM antibody to P. mirabilis than to the other organisms tested and these values were also highly significantly different (p < 0.0001) from P. mirabilis IgM antibody levels in matched RF-negative sera. Sera from RA patients also had significantly greater amounts of IgA to P. mirabilis (p < 0.0001) and greater amounts of IgM to Escherichia coli (p < 0.0001) and Klebsiella pneumoniae (p < 0.0001) than those in matched RF-negative sera. Other classes of antibody to these organisms and all classes of antibody to Pseudomonas aeruginosa were not raised in the sera of RA patients over those of RF-negative controls. The IgM response in RA patients was not specific for only one O serotype of P. mirabilis but was associated with all 11 different O serotypes of P. mirabilis tested and those of other Proteus spp. Moreover, the IgM antibodies to Proteus spp. appeared to be independent from C-reactive protein and RF.(ABSTRACT TRUNCATED AT 250 WORDS)

(+/-)-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.

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.

Penicillamine-induced ocular myasthenia gravis.

Two patients with rheumatoid arthritis (two women, 58 and 62 years old) developed reversible penicillamine-induced ocular myasthenia gravis. Both had the HLA-DR1 antigen, unlike most patients with idiopathic myasthenia gravis who show HLA-DR3, suggesting that penicillamine-induced myasthenia gravis and its idiopathic counterpart occur in patients with different genetic backgrounds. In both cases, cessation of drug treatment led to resolution of the symptoms.