Central opioid receptors differentially regulate the nalmefene-induced suppression of ethanol- and saccharin-reinforced behaviors in alcohol-preferring (P) rats.

The exact opioid-sensitive receptors participating in EtOH-seeking behaviors remains unclear. Previous studies have reported higher densities of micro-opioid receptor binding in the nucleus accumbens (NACC) of P relative to NP rats; however, no differences were seen in delta-receptor binding. In contrast to the NACC, substantially lower levels of micro-receptor binding have been observed in the ventral tegmental area (VTA) of both P and NP rats, albeit no line differences have been observed. In the present study, opioid receptors in the NACC, VTA, and hippocampus were evaluated for their capacity to regulate both EtOH- and saccharin-motivated behaviors in the genetically selected alcohol-preferring (P) rat. To accomplish this, nalmefene, an opiate antagonist with preferential binding affinity for the micro-opioid receptor was unilaterally or bilaterally infused during concurrent availability of 1 h daily EtOH (10% v/v) and saccharin (0.025 or 0.050% w/v) solutions. Rats performed under a two-lever fixed ratio (FR) schedule in which four responses on one lever produced the EtOH solution, and four on a second lever produced the saccharin solution. The results demonstrated that when responding maintained by both EtOH and saccharin are matched at basal levels, unilateral (1-60 microg) or bilateral (0.5-10 microg) microinjections of nalmefene into the NACC produced selective dose-dependent reductions on responding maintained by EtOH. Unilateral (40, 60 microg) and bilateral (10 microg) VTA infusions were also observed to selectively reduced EtOH responding; however, greater nalmefene doses were required and the magnitude of suppression on EtOH responding was markedly less compared with the NACC. The greater sensitivity of nalmefene to suppress EtOH responding in the NACC is likely due to the greater number of opioid receptors in the NACC relative to the VTA. Only bilateral infusion of the 40 microg dose in the NACC and VTA suppressed responding maintained by both EtOH and saccharin. In contrast, intrahippocampal infusions dose dependently suppressed EtOH- and saccharin-maintained responding over a range of doses (1-20 microg). The present study provides evidence that nalmefene suppresses EtOH-motivated behaviors via blockade of opioid receptors within the NACC and VTA, and under various dose conditions both reinforcer and neuroanatomical specificity can be observed.     

Comparison of the potential therapeutic effects of interleukin 2 or interleukin 4 secretion by a single tumour.

Engineering of a variety of rodent tumour cells to secrete either interleukin 2 (IL-2), or interleukin 4 (IL-4), has been demonstrated to reduce their tumorigenicity. However the mechanisms of action of secreted IL-2 and IL-4 have not been compared in a single rodent tumour. Here we demonstrate that the weakly immunogenic murine fibrosarcoma FS29 had reduced growth rate and in some cases was rejected by syngeneic animals, when modified to secrete either IL-2 or IL-4, but not IL-5. Immunohistochemical analysis of tumour nodules undergoing regression showed stimulation of a largely lymphocytic infiltrate by IL-2 and a macrophage and granulocyte infiltrate, with a small number of lymphocytes by IL-4. Indeed, secretion of low levels of IL-2 and IL-4 in combination resulted in optimal rejection, suggesting that the two cytokines might mobilise different and complementary effector cell mechanisms. Both IL-2 and IL-4-secreting cells failed to induce the rejection of admixed, unmodified FS29 cells. The loss of cytokine secreting cells from such admixtures occurred more rapidly for IL-2-secreting cells. Injection of IL-4-secreting, but not IL-2-secreting FS29 cells could protect mice from a delayed challenge with unmodified FS29 cells. These data suggest that IL-4 secretion stimulates the better long-term host anti-tumour response.     

Psychological and family functioning and quality of life in adolescents with cystic fibrosis.

BACKGROUND: The life expectancy of individuals with CF has increased to 33 years. Thus, issues such as quality of life and psychological well-being, previously thought to be of lesser importance than physical well-being, are now recognised as significant factors. This study examined the interrelationships between quality of life, family functioning, individual psychopathology and optimism of adolescents with CF. METHODS: Adolescents attending the CF clinic completed a number of questionnaires. Quality of Life was measured using the Cystic Fibrosis Questionnaire, family functioning by the Family Environment Scale (3rd edition), general psychopathology with the Symptom Checklist-90-Revised and optimism for the future by the Hunter Opinions and Personal Expectations Scale. Disease severity was assessed using the Shwachman score and spirometry at the time of questionnaire completion. RESULTS: The level of psychopathology (12.5% of those 13 years and over) in the group was lower than that reported for young people in Australia (15-20%). The results indicated that young people with a delayed diagnosis and those who are alienated from their families may be in need of additional psychosocial support. The group was hopeful and positive about their future and these attributes were independent of clinical measures of disease severity. In general, these young people scored relatively highly on the quality of life scale. For example the mean standardised score for physical functioning was 70 points, for respiratory symptoms was 63 points and for emotional state was 78 points. Increased levels of psychopathology and lack of hope for the future were however associated with lower ratings on a number of quality of life measures. Family cohesiveness, expressiveness and organization were associated with better psychological functioning in the young people. CONCLUSIONS: Adolescents with CF appear to be a psychologically well functioning and well-adjusted group. These findings support the importance of a more sophisticated model of well-being for adolescents with CF, which explores the young person's views on their quality of life and wider support frameworks rather than relying solely on measures of physical health to gauge well-being.     

Intersubject variation in the pharmacokinetics of chlorpromazine in healthy men

Interpatient variation in response to therapy with antipsychotic drugs is a major problem. This study was designed to assess the extent of variation in disease-free subjects in whom known sources of variance were controlled as much as possible. The subjects were 32 healthy, nonsmoking males of European origin, aged 18-25 years, and weighing no more than +/- 15% from the ideal weight for height. After an overnight fast, each subject ingested 50 mg of chlorpromazine. Plasma samples were harvested over a 24-hour period during which the subjects were on a standardized, caffeine-free diet. Plasma levels of chlorpromazine were measured by gas-liquid chromatography-mass spectrometry. The results showed wide intersubject variation in all pharmacokinetic parameters including maximum concentration, area under the curve, and oral clearance. Furthermore, none of the data were normally distributed. For each pharmacokinetic parameter, the distribution was leptokurtotic and skewed. As a consequence, the geometric means provided better estimates of central tendency than the arithmetic means. It seems that a major proportion of intersubject variation is an inherent problem that cannot be accounted for by differences in race, diet, smoking habits, or concomitant drug ingestion.     

Occult spinal dysraphism. Case report and review of the literature

This case report and review of the literature is presented to create a greater diagnostic awareness of occult spinal dysraphism. Early recognition is based upon an understanding of this congenital anomaly and its variable presentations. These most commonly include abnormal gait, various cutaneous manifestations, particularly subcutaneous lipomata, and less frequently urological complaints. Surgical intervention, to arrest disease progression, is the primary mode of treatment, and functional improvement is variable. Long-term prognosis is dependent upon severity of neurologic deficits prior to surgery and the type of lesion found intraoperatively. Familial occurrence has been reported and genetic counseling may be an important preventive measure. Recent radiologic investigations have been concerned with the use of ultrasonography in screening infants at risk.