Alcohol dependence and anxiety increase error‐related brain activity

Aims Detection of errors is crucial for efficient goal‐directed behaviour. The ability to monitor behaviour is found to be diminished in patients with substance dependence, as reflected in decreased error‐related brain activity, i.e. error‐related negativity (ERN). The ERN is also decreased in other psychiatric disorders with impaired response inhibition, such as attention‐deficit hyperactivity disorder and borderline personality disorder, but increased in anxiety disorders. The objective of the current study was to assess error monitoring in alcohol‐dependent patients in relation to psychiatric comorbidity. We expected decreased error monitoring in alcohol‐dependent patients with impulse control disorders and increased error monitoring in anxious alcohol‐dependent patients. Design In a case–control design alcohol‐dependent patients were compared with healthy controls. Setting and participants A consecutive series of 29 male alcohol‐dependent patients, between 18 and 55 years of age, applying for in‐patient detoxification were recruited at Novadic Kentron Center for Addiction Treatment. Fifteen age‐matched healthy controls were recruited through advertisements in regional newspapers. Measurements Event‐related potentials were recorded while performing a speeded choice‐reaction task, from which ERN amplitudes were calculated. Axis‐I and ‐II psychiatric comorbidity were assessed using the MINI International Neuropsychiatric Interview and the Structured Interview for DSM‐IV Personality disorders. All participants completed the Temperament and Character Inventory and Profile of Mood States. Findings ERN amplitudes were increased for alcohol‐dependent patients compared to healthy controls, particularly in patients with comorbid anxiety disorders. Conclusions Increased error monitoring in alcohol‐dependent patients, particularly those with comorbid anxiety disorders, is in contrast with previous studies that suggested decreased error monitoring to be a general feature in substance use disorders. Psychiatric disorders co‐occurring with alcohol dependence, such as anxiety disorders, may indicate subpopulations of alcohol‐dependent patients, with distinct neurobiological and genetic characteristics, possibly requiring different treatment strategies.     

5-HTTLPR biases amygdala activity in response to masked facial expressions in major depression.

The amygdala is a key structure in a limbic circuit involved in the rapid and unconscious processing of facial emotions. Increased amygdala reactivity has been discussed in the context of major depression. Recent studies reported that amygdala activity during conscious emotion processing is modulated by a functional polymorphism in the serotonin transporter gene (5-HTTLPR) in healthy subjects. In the present study, amygdala reactivity to displays of emotional faces was measured by means of fMRI at 3T in 35 patients with major depression and 32 healthy controls. Conscious awareness of the emotional stimuli was prevented via backward-masking to investigate automatic emotion processing. All subjects were genotyped for the 5-HTTLPR polymorphism. Risk allele carriers (S or L(G)) demonstrated increased amygdala reactivity to masked emotional faces, which in turn was significantly correlated with life-time psychiatric hospitalization as an index of chronicity. This might indicate that genetic variations of the serotonin transporter could increase the risk for depression chronification via altering limbic neural activity on a preattentive level of emotion processing.     

Tracker-assisted laser in situ keratomileusis for myopia using the autonomous scanning and tracking laser: 12-month results

OBJECTIVE: To determine the safety, efficacy, and predictability of the Autonomous scanning and tracking laser for the correction of myopia and myopic astigmatism with laser in situ keratomileusis (LASIK) procedure. DESIGN: Retrospective, noncomparative case series. PARTICIPANTS: The first 129 consecutive eyes with up to -13.00 diopters (D) of myopia and -5.00 D of astigmatism. INTERVENTION: Myopic tracker-assisted LASIK (T-LASIK) using the Autonomous Laser (Alcon Summit Autonomous, Waltham, MA) and Hansatome microkeratome (Bausch & Lomb Surgical, Bracknell, England). MAIN OUTCOME MEASURES: Uncorrected visual acuity (UCVA), manifest spherical equivalent (MSE), best spectacle-corrected visual acuity (BSCVA), and complications were studied. RESULTS: At 12 months, the mean MSE was -0.02 +/- 1.01 D, with 79.1% of eyes within 0.5 D and 89.9% of eyes within 1 D of the intended correction. UCVA was 20/20 or better in 71.4%, 20/25 or better in 78.5%, and 20/40 or better in 92.8% of eyes. Two eyes (1.6%) lost 2 lines and five eyes (3.8%) gained 2 lines of BSCVA. Sixteen eyes (12.4%) required retreatment to correct residual myopia or astigmatism. After retreatment, 14 of 16 eyes were within 0.5 D of emmetropia. Nine eyes (6.9%) had minor flap complications; two eyes (1.6%) had grade 2 diffuse lamellar keratitis, of which one eye had associated peripheral flap melt. One eye showed slight decentration; this eye was rolling throughout the procedure. All eyes had some dryness, with 10% severe enough to require temporary punctual occlusion with plugs. CONCLUSIONS: T-LASIK for myopic astigmatism with the Autonomous Laser is relatively safe, effective, and predictable. The tracker seems to be effective, and the complications are relatively few. Retreatment rates are acceptable and can be performed safely and effectively to improve visual outcome. The outcomes are comparable with other published data.     

Structure-activity relationships at human and rat A2B adenosine receptors of xanthine derivatives substituted at the 1-, 3-, 7-, and 8-positions

In the search for improved selective antagonist ligands of the A2B adenosine receptor, which have the potential as antiasthmatic or antidiabetic drugs, we have synthesized and screened a variety of alkylxanthine derivatives substituted at the 1-, 3-, 7-, and 8-positions. Competition for 125I-ABOPX (125I-3-(4-amino-3-iodobenzyl)-8-(phenyl-4-oxyacetate)-1-propylxanthine) binding in membranes of stably transfected HEK-293 cells revealed uniformly higher affinity (<10-fold) of these xanthines for human than for rat A2B adenosine receptors. Binding to rat brain membranes expressing A1 and A2A adenosine receptors revealed greater A2B selectivity over A2A than A1 receptors. Substitution at the 1-position with 2-phenylethyl (or alkyl/olefinic groups) and at N-3 with hydrogen or methyl favored A2B selectivity. Relative to enprofylline 2b, pentoxifylline 35 was equipotent and 1-propylxanthine 3 was >13-fold more potent at human A2B receptors. Most N-7 substituents did not enhance affinity over hydrogen, except for 7-(2-chloroethyl), which enhanced the affinity of theophylline by 6.5-fold to 800 nM. The A2B receptor affinity-enhancing effects of 7-(2-chloroethyl) vs 7-methyl were comparable to the known enhancement produced by an 8-aryl substitution. Among 8-phenyl analogues, a larger alkyl group at the 1-position than at the 3-position favored affinity at the human A2B receptor, as indicated by 1-allyl-3-methyl-8-phenylxanthine, with a K(i) value of 37 nM. Substitution on the 8-phenyl ring indicated that an electron-rich ring was preferred for A2B receptor binding. In conclusion, new leads for the design of xanthines substituted in the 1-, 3-, 7-, and 8-positions as A2B receptor-selective antagonists have been identified.     

C-reactive protein as a predictor for incident diabetes mellitus among middle-aged men: results from the MONICA Augsburg cohort study, 1984-1998

BACKGROUND: Previous studies have suggested that low-grade systemic inflammation is involved in the pathogenesis of type 2 diabetes mellitus. OBJECTIVE: To investigate the association between C-reactive protein (CRP), the classic acute-phase protein, and incident type 2 diabetes mellitus among middle-aged men. METHODS: A total of 2052 initially nondiabetic men aged 45 to 74 years who participated in 1 of the 3 MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) Augsburg surveys between 1984 and 1995 were followed up for an average of 7.2 years. Incidence of diabetes was assessed by questionnaire mailed to participants in 1998. High-sensitive CRP was measured by an immunoradiometric assay. RESULTS: A total of 101 cases of incident diabetes occurred during the follow-up period. The age-standardized incidence rate was 6.9 per 1000 person-years. Men with CRP levels in the highest quartile (CRP > or = 2.91 mg/L) had a 2.7 times higher risk of developing diabetes (95% confidence interval, 1.4-5.2) compared with men in the lowest quartile (CRP < or = 0.67 mg/L) in a Cox proportional hazards model adjusted for age and survey. After further adjustment for body mass index, smoking, and systolic blood pressure, the observed association was significantly reduced and became nonsignificant. CONCLUSIONS: Low-grade systemic inflammation is associated with an increased risk of type 2 diabetes mellitus in middle-aged men. Inflammation could be one mechanism by which known risk factors for diabetes mellitus, such as obesity, smoking, and hypertension, promote the development of diabetes mellitus.     

Rats recovering from unilateral barrel-cortex ischemia are capable of completing a whisker-dependent task using only their affected whiskers

Rats use their vibrissae for a variety of exploratory tasks including location of objects and discrimination of texture. This study examines recovery in vibrissal function following a unilateral ischemic injury to the somatosensory cortex. Vibrissal function was examined in adult food-restricted rats performing on a two-texture discrimination device. Animals were trained and tested until the criteria of >80% correct choices was demonstrated on three consecutive days. Ischemic rats were constrained to use the affected whiskers by clipping the ipsilateral vibrissae. One group was tested after ischemia, a second group was trained before ischemia and then tested, and a third group was pre-trained and received whisker stimulation and tested post-ischemia. Nai;ve animals recovering from ischemia took longer to reach criteria than intact or unilateral trimmed control animals. Pre-trained animals with compression ischemia receiving whisker stimulation with sucrose water completed the task to criteria in the fewest number of trials. The results indicate that recovery of vibrissal function occurs following a unilateral ischemic injury. Histological analysis in animals without whisker stimulation indicates that the number of normal appearing cortical barrels following ischemia was inversely correlated to the number of trials needed to complete the behavioral task. This suggests that the natural recovery of the ability to discriminate textures is related to the degree of damage to the barrel cortex. The relationship between cortical barrels and behavioral recovery did not hold for the ischemic animals receiving whisker stimulation. This latter group demonstrated recovery despite marked anatomical lesions suggesting that the intervention influenced reorganization.