Inhibition of thalamic excitability by 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol: a selective role for δ-GABAA receptors

The sedative and hypnotic agent 4,5,6,7‐tetrahydroisoxazolo[4,5‐c]pyridine‐3‐ol (THIP) is a GABA_A receptor (GABA_AR) agonist that preferentially activates δ‐subunit‐containing GABA_ARs (δ‐GABA_ARs). To clarify the role of δ‐GABA_ARs in mediating the sedative actions of THIP, we utilized mice lacking the α₁‐ or δ‐subunit in a combined electrophysiological and behavioural analysis. Whole‐cell patch‐clamp recordings were obtained from ventrobasal thalamic nucleus (VB) neurones at a holding potential of ?60 mV. Application of bicuculline to wild‐type (WT) VB neurones revealed a GABA_AR‐mediated tonic current of 92 ± 19 pA, which was greatly reduced (13 ± 5 pA) for VB neurones of δ^0/0 mice. Deletion of the δ‐ but not the α₁‐subunit dramatically reduced the THIP (1 μm )‐induced inward current in these neurones (WT, ?309 ± 23 pA; δ^0/0, ?18 ± 3 pA; α₁^0/0, ?377 ± 45 pA). Furthermore, THIP selectively decreased the excitability of WT and α₁^0/0 but not δ^0/0 VB neurones. THIP did not affect the properties of miniature inhibitory post‐synaptic currents in any of the genotypes. No differences in rotarod performance and locomotor activity were observed across the three genotypes. In WT mice, performance of these behaviours was impaired by THIP in a dose‐dependent manner. The effect of THIP on rotarod performance was blunted for δ^0/0 but not α₁^0/0 mice. We previously reported that deletion of the α₁‐subunit abolished synaptic GABA_A responses of VB neurones. Therefore, collectively, these findings suggest that extrasynaptic δ‐GABA_ARs vs. synaptic α₁‐subunit‐containing GABA_ARs of thalamocortical neurones represent an important molecular target underpinning the sedative actions of THIP.     

Attachment dimensions and group climate growth in a sample of women seeking treatment for eating disorders

Adult attachment and group process research are emerging areas of research for treating eating disorders. In this study, we examined several aspects of group processes: the weekly growth of group therapy climate, the relationship between group climate growth and outcomes, and the impact of the group on individual experiences of group climate. Further, we assessed the relationship between adult attachment dimensions and these group processes. Women (n = 264) diagnosed with an eating disorder completed attachment scales pre-treatment, eating disorder symptom scales pre- and post-treatment, and group climate scales weekly during treatment. Treatment consisted of a specialized eating disorders group-based day hospital program with rolling admissions. Engaged group climate increased and Avoidance group climate decreased across weeks of treatment. Engaged group climate growth was associated with improved eating disorder symptoms post-treatment. Higher attachment avoidance at pre-treatment was related to lower Engaged group climate at week 1, and was related to a greater impact of the group on the individual's experience of group engagement. Clinicians might improve group processes and outcomes by tailoring interventions to individuals' attachment avoidance when treating women for eating disorders.     

Psychometric properties of self-monitoring of eating disorder urges among treatment seeking women: Ecological momentary assessment using a daily diary method

ObjectivesThe psychometric properties of an ecological momentary assessment (EMA) method used to evaluate eating disorder (ED) urges were examined.MethodsParticipants, 139 women who sought treatment for an ED, completed a daily diary measuring ED urges after each meal for a three week period at the start of treatment, and a measure of ED attitudes and behaviors pre- and post-treatment.ResultsThe construct validity of this method was indicated by a two factor solution representing binge eating urges and ED compensatory behavior urges, and by significant differences between ED diagnostic groups on ED urge type. Correlations of ED urges early in therapy with outcomes provided evidence for predictive validity. Correlations at pre-treatment between ED urges and ED attitudes and behaviors supported criterion validity. EMA of ED urges showed good retest stability.ConclusionsEMA of ED urges is a valid and reliable approach that is associated with ED symptom severity, and predictive of treatment outcome.     

Independent effects of peripheral nerve dysfunction on lower-extremity physical function in old age: the Women's Health and Aging Study

OBJECTIVE: To determine the role of peripheral nerve dysfunction (PND) in the disablement pathway. RESEARCH DESIGN AND METHODS: Vibration perception threshold (VPT) was measured in 894 women aged > or = 65 years, and those with normal peripheral nerve function and with mild, moderate, and severe PND were identified. Lower-extremity impairments included quadriceps strength (kilograms) and three progressively difficult balance tasks (able/unable). Functional limitations included rising from a chair (able/unable) and usual pace and fast-paced walking speeds (meters/second). Level of PND was related to impairments and functional limitations in linear and logistic regression models that controlled for potentially confounding factors, including reported diabetes. RESULTS: Level of PND was associated with impaired balance (adjusted odds ratios: 2.21, 1.95, and 3.02 for mild, moderate, and severe PND, respectively, relative to normal, P < 0.05). PND was also associated with decrements in both usual and fast-paced walking speeds (-0.08, -0.08, and -0.15 m/s for usual pace and -0.13, -0.12, and -0.24 m/s for fast-paced walking speed for women with mild, moderate, and severe PND, respectively; P < 0.01 for all). Reported diabetes was not associated with these outcomes in the presence of PND. Some, but not all, of the association between PND and functional limitations was explained by the relationship between PND and impairments. CONCLUSIONS: PND is significantly associated with both lower-extremity impairments and functional limitations in older women, and PND appears to have independent effects on functional limitations. The independent effect of diabetes on these outcomes may be limited when PND is considered. Further research is needed to determine if PND is causally related to disability in old age.     

Placebo-controlled trial of varicella vaccine given with or after measles-mumps-rubella vaccine

A placebo-controlled study of varicella vaccine given either with or 6 weeks after measles-mumps-rubella (MMR) vaccine was undertaken in healthy children (mean age 16 months). A total of 101 varicella-zoster virus antibody-negative children completed the study. Serologic response to MMR vaccine was excellent (nearly 100%) and not significantly affected by the administration of varicella vaccine. Seroconversion in response to varicella vaccine was excellent and was not affected by MMR vaccine. No significant differences in fever or skin rashes between those receiving MMR vaccine with varicella vaccine or MMR vaccine with placebo were noted, but fever and skin rashes were more frequent after the first immunization (MMR with varicella vaccine or MMR vaccine with placebo) compared with the second (varicella vaccine or placebo injection). Symptoms of fatigue, irritability, and upper respiratory tract infections were more common after MMR vaccine was given regardless of whether it was given simultaneously with varicella vaccine or placebo injection.     

Serologic diagnosis of whooping cough by enzyme-linked immunosorbent assay

Pernasal swabs were obtained on 3 consecutive days from 146 children referred for hospital admission with suspected whooping cough, and immunoglobulin A and immunoglobulin M antibodies to Bordetella pertussis were measured by enzyme-linked immunosorbent assay. The clinical features in 113 of the children were considered consistent with the diagnosis. Sixty-four cases were confirmed by serology, which showed a greater sensitivity (57% vs. 35%) than pernasal swab culture with no loss of specificity (100%). Paired serum samples were necessary for diagnosis in 30 (47%) of these 64 cases. Seventeen (43%) of 40 cases confirmed by pernasal swab culture had negative serologic results. Most of these were young infants who showed a less reliable antibody response. Detection of antibodies to B. pertussis by enzyme-linked immunosorbent assay can be a valuable additional test in the differential diagnosis of whooping cough but is not appropriate as the sole diagnostic test.     

Neuroplasticity within the mesoaccumbens dopamine system and its role in tobacco dependence

The development of nicotine dependence is related to stimulation of the dopamine projections to the nucleus accumbens. This review considers the evidence that the addictive potential of nicotine depends upon its ability to elicit burst firing of these neurones and, thereby, evoke a large and sustained increase in the dopamine concentration in the extracellular space between the cells. This dopamine, it is argued, stimulates extra-synaptic dopamine receptors that mediate the responses underling the development of dependence. The review also considers the hypothesis that the two principal subdivisions of the structure, the core and shell, play different roles in the development of dependence. It proposes that the projections to the shell signal the presence of a rewarding stimulus and facilitate the acquisition of behaviours related to obtaining the reward. In contrast, the projections to the core, which are sensitised selectively by repeated exposure to the drug, mediate the transition to habit or Pavlovian responding to cues repetitively paired with the positive reinforcing properties of nicotine. Nicotine withdrawal, following a period of chronic exposure, diminishes the activity of the dopamine projections to the accumbal shell, a response that is thought to be the neural correlate of the anhedonia experienced by many abstinent smokers. The data suggest that plasticity within the principal mesoaccumbens dopamine projections play a central role in the development of nicotine dependence and that the mechanisms underlying the plasticity may provide putative targets for the treatment of tobacco dependence.