Drug effects on multiple and concurrent schedules of ethanol- and food-maintained behaviour: context-dependent selectivity.

BACKGROUND AND PURPOSE: Drugs that more potently or effectively reduce ethanol-maintained behaviour versus an alternative are considered selective and are considered promising pharmacotherapies for alcoholism. Such results are often obtained using separate groups or multiple schedules where ethanol and the alternative are available alone or sequentially. Recently, we observed that when ethanol and food were available sequentially under a multiple schedule, fluvoxamine and varenicline were selective; yet this selectivity disappeared when ethanol and food were concurrently available. EXPERIMENTAL APPROACH: We examined the generality of these findings by comparing doses of several drugs required to decrease ethanol- and food-maintained responding under a multiple schedule and under a concurrent schedule. Effects were determined for chlordiazepoxide, 2,5-dimethoxy-4-iodoamphetamine (DOI), meta-chlorophenylpiperazine (mCPP), morphine, naltrexone and d-amphetamine. KEY RESULTS: Under the multiple schedule, ED50 values for decreases in ethanol-maintained responding were significantly different and lower than ED50 s for decreases in food-maintained responding (demonstrating selectivity) for each drug except for chlordiazepoxide (which was equipotent) and naltrexone (which did not affect responding). However, this selectivity vanished or even inverted under the concurrent schedule, such that ED50 values for decreasing ethanol- and food-maintained responding were not different (or, following DOI, the ED50 for food-maintained responding was lower than for ethanol-maintained responding). CONCLUSIONS AND IMPLICATIONS: Results are consistent with those seen following fluvoxamine and varenicline administration, and suggest that selectivity is assay-dependent. These results indicate the need for careful interpretation of selective drug effects, especially when obtained in situations where ethanol or the alternative is the only programmed reinforcement available.

Fluvoxamine and desipramine on fixed-ratio responding: effects of reinforcement magnitude.

Fluvoxamine, a serotonin reuptake blocker, was previously shown to decrease ethanol-maintained behavior at doses lower than those needed to decrease food-maintained behavior. While these effects could have been due to different response rates and histories of the two groups being compared, a subsequent study found differential effects using a within-subjects design, in which rates of responding were well equated. Another explanation for such differential effects is that food and ethanol reinforcement differ in a quantitative fashion. This is difficult to resolve when comparing between behaviors maintained by different events. To examine how such quantitative differences in reinforcement magnitude might influence the effects of fluvoxamine, we used a multiple schedule of fixed-ratio 30 responding in the pigeon. In each of the three fixed-ratio 30 components, behavior was maintained by a different duration of grain presentation (2, 4, and 8 s). The effects of fluvoxamine and also desipramine were examined. Both dose-dependently decreased fixed-ratio responding. Their effects were independent of the duration of grain presentation maintaining responding. These results do not support the idea that the differential effects of fluvoxamine on ethanol-maintained behavior, as compared with food-maintained behavior, are a result of quantitative differences in reinforcement magnitude.

Laser welding for vascular anastomosis using albumin solder: an approach for MID-CAB.

BACKGROUND AND OBJECTIVES: To improve minimally invasive direct coronary artery bypass surgery (MID-CAB), new techniques of vascular anastomosis that are faster and more reliable need to be developed. STUDY DESIGN/MATERIALS AND METHODS: Common carotids in a canine model were transected and an end-to-end anastomosis was performed by using one of four techniques (1) continuous 6-0 polypropylene closure (suture; n=6), (2) vascular clip (VCS; n=6), laser welding using 50% albumin solder with (3) a 1.32-micro laser (1.32las; n=6), and (4) a 1.9-micro diode laser (1.9las; n=4). Times for anastomosis (TA) were compared between groups by t-test. Pressures at which anastomosis failed (leak point pressure, LPP) were determined and compared by analysis of variance. RESULTS: TA was faster for 1.32las and 1.9las at 8.4+/-0.7 and 7.8+/-0.3 min, respectively, when compared with suture at 13.8+/-1.0 min (P=0.001, confidence interval [CI]-8.1, -2.6 for 1.32las and CI -8.9, -3.1 for 1.9las). There was no statistical difference between VCS (8.3+/-3.3 min) and any other group (P > 0.17). LPPs (mm Hg) were similar for all groups: 350+/-37 for 1.32las, 280+/-31 for 1.9las, 347+/-46 for suture, and 358+/-53 for VCS, P=0.68. CONCLUSIONS: In this study, laser welding using 50% human albumin solder resulted in faster anastomotic times. Anastomoses were equivalent to conventional sutured anastomoses in failing at similar pressures. Laser welding using human albumin solder may be advantageous in improving coronary anastomoses during MID-CAB, but long-term anastomotic strength and histologic evaluation need to be investigated.

CoMFA-based prediction of agonist affinities at recombinant D1 vs D2 dopamine receptors.

We have previously shown that using agonist affinity at recombinant receptors selectively expressed in clonal cells as the dependent variable in three-dimensional quantitative structure-activity relationship studies (3D-QSAR) presents a unique opportunity for accuracy and precision in measurement. Thus, a comparison of affinity's structural determinants for a set of compounds at two different recombinant dopamine receptors represents an attainable goal for 3D-QSAR. A molecular database of bound conformations of 16 structurally diverse agonists was established by alignment with a high-affinity template compound for the D1 receptor, 3-allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4, 5-tetrahydro-1H-benzazepin. A second molecular database of the bound conformations of the same compounds was established against a second template for the D2 receptor, bromocriptine. These aligned structures suggested three-point pharmacophore maps (one cationic nitrogen and two electronegative centers) for the two dopamine receptors, which differed primarily in the height of the nitrogen above the plane of the catechol ring and in the nature of the hydrogen-bonding region. The ln(1/KL) values for the low-affinity agonist binding conformation at recombinant D1 and D2 dopamine receptors stably expressed in C6 glioma cells were used as the target property for the CoMFA (comparative molecular field analysis) of the 16 aligned structures. The resulting CoMFA models yielded cross-validated R2 (q2) values (standard error of prediction) of 0. 879 (1.471, with five principal components) and 0.834 (1.652, with five principal components) for D1 and D2 affinity, respectively. The simple R2 values (standard error of the estimate) were 0.994 (0.323) and 0.999 (0.116), respectively, for D1 and D2 receptor. F values were 341 and 2465 for D1 and D2 models, respectively, with 5 and 10 df. The predictive utility of the CoMFA model was evaluated at both receptors using the dopamine agonists, apomorphine and 7-OH-DPAT. Predictions of KL were accurate at both receptors. Flexible 3D searches of several chemical databases (NCI, MDDR, CMC, ACD, and Maybridge) were done using basic pharmacophore models at each receptor to determine the similarity of hit lists between the two models. The D1 and D2 models yielded different lists of lead compounds. Several of the lead compounds closely resembled high-affinity training set compounds. Finally, homology modeling of agonist binding to the D2 receptor revealed some consistencies and inconsistencies with the CoMFA-derived D2 model and provided a possible rationale for features of the D2 CoMFA contour map. Together these results suggest that CoMFA-homology based models may provide useful insights concerning differential agonist-receptor interactions at related receptors. The results also suggest that comparisons of CoMFA models for two structurally related receptors may be a fruitful approach for differential QSAR.

Molecular genetics of psychopathologies: a search for simple answers to complex problems.

Molecular genetics is helping define the contribution of genetic involvement in behavioral disorders. At this time, however, a severely limiting factor for DNA linkage studies of these disorders remains the definition of the phenotype. An example of this is found in the group of studies examining linkage of schizophrenia to the 5q location. Although various broad clinical interpretations of the schizophrenia phenotype were used to test for linkage, all but one study reported findings negative for linkage of schizophrenia to the 5q area. We offer a strategy based on family studies using segregation data of behavioral subtypes. We apply this strategy using molecular genetic technology to our study of psychopathology in patients. This approach offers the possibility of a clearer definition of the phenotype and is suggested for use in both linkage and association studies of neuropsychiatric disorders.

Alcohol and drug abusers subtyped by antisocial personality and primary or secondary depressive disorder.

Our data show that when substance abusers are subtyped simultaneously by antisocial personality disorder and the onset of depression relative to alcohol or drug abuse, groups of people with unique personality and affective profiles are identified. The profiles are represented by measures of affect-related personality variables such as trait anxiety, trait depression, histrionic traits, sensation seeking, and novelty seeking. These measures were chosen in an attempt to show that a "low arousal" personality type may be associated with antisocial personality and may thus indirectly be linked to a certain type (i.e., ASP/nondepressed) of substance abuser. By using a multi-symptomatic typological schema (i.e., a constellation of diagnostic categories rather than just one), we can show that different personality or affective profiles are indeed associated with certain subtypes of substance abusers and that depressed people who use drugs or alcohol are different affectively from antisocial types. We also show that the relationship between "low" and "high" arousal personality profile and subtypes based on co-morbid psychopathology is highlighted even more when we take into account the onset of dysthymia or depression that is primary versus secondary to substance abuse. Our findings are in accord with others' descriptions of the "affective arousal" dimensions of personality and are the first to link these dimensions with subtypes based on ASP and depression.

Effects of menstrual phase on intake of nicotine, caffeine, and alcohol and nonprescribed drugs in women with late luteal phase dysphoric disorder.

To investigate the possibility that cigarette smoking and other drug use are affected by menstrual phase in smokers with Late Luteal Phase Dysphoric Disorder (LLPDD), we examined daily diaries rating menstrual symptomatology, smoking, alcohol and nonprescription drug use, and caffeine intake in nine female smokers meeting criteria for LLPDD. Menstrual symptomatology peaked during the premenstrual phase. Smoking, alcohol, and nonprescription drug intake were increased during menses; caffeine intake was unaffected by phase. No systematic intrasubject correlation between symptomatology and smoking was detected. It was concluded that in women with LLPDD, smoking and alcohol and nonprescription drug intake appear to vary as a function of menstrual phase. The lack of intrasubject correlations between symptomatology and intake, and the failure of peak intake to coincide with peak symptomatology, however, indicate that these effects cannot be explained simply as "self-medication" of acute episodes of dysphoric mood.

Urinary C-peptide excretion in obese and anorectic children.

To assess the total insulin secretion in children in different nutritional states we have analysed the 24 h urinary C-peptide excretion in 32 obese children (16 boys and 16 girls) 8-15 years of age as well as in 7 girls with anorexia nervosa 11-16 years of age. Obese children had a median urinary C-peptide excretion rate of 0.27 nmol/kg/24 h, which was not different from that of a group of normal-weight children. In the group of anorectic girls, on the other hand, the median value 0.47 nmol/kg/24 h was significantly (p less than 0.05) higher than for normal-weight girls of the same age (median = 0.26 nmol/kg/24 h). These results indicate that in obese children insulin secretion, measured as the 24 h urinary C-peptide excretion per kg body weight, is the same as in normal-weight children. Total insulin secretion is consequently increased. In anorexia nervosa, on the other hand, the higher C-peptide excretion per kg body weight compared with normal-weight children, indicates that insulin secretion is increased in relation to body weight.

Katayama fever in scuba divers. A report of 3 cases.

Katayama fever or acute schistosomiasis probably occurs more commonly than is recorded. Interviews with a 3-man scuba diving team who had had contact with a large dam in an endemic area of the eastern Transvaal Lowveld at the same time and contact area on the same day during late summer of 1986 are discussed. Two, who had not previously been exposed to infected water, presented with Katayama fever, due to Schistosoma mansoni infection, 21 days after contact and it took 30-36 months for them to recover fully after several treatments. The third patient, a keen water-sportsman and resident in the endemic area for a period of 10 years, presented with a mild infection, probably due to acquired immunity initiated during previous contacts with infected water; he took about a year to recover. The pathogenesis, clinical features, diagnosis and treatment of the 3 cases are described in the light of recent observations made elsewhere on Katayama fever cases and the effects of chemotherapy on the course of illness. The necessity of obtaining basic information on the travel and water-contact activities of patients in order to make a diagnosis is emphasised.

Sarcoidosis in children: differentiation from juvenile rheumatoid arthritis.

Sarcoidosis is rare in young children, and is characterized by skin, joint, and eye changes. Differentiated clinically from juvenile rheumatoid arthritis (JRA) by milder constitutional symptoms and characteristic joint abnormalities, sarcoidosis is confirmed by demonstrating noncaseating granulomas in skin, conjunctival, or synovial biopsies. Recent reports have shown children with features of both sarcoidosis and juvenile rheumatoid arthritis, some with similarly affected family members. We cared for four children with sarcoidosis and severe joint manifestations. Two had a personal or family history of JRA. Three of the four children had ichthyosiform cutaneous manifestations, which may suggest an association between severe joint disease and ichthyosiform changes. Because of the difficulty in making a diagnosis on clinical grounds alone, biopsy of cutaneous lesions is recommended in children with these symptoms.

Norfloxacin in the treatment of complicated and uncomplicated urinary tract infections. A comparative multicenter trial.

In a multicenter, prospective treatment study, 59 patients with complicated or uncomplicated urinary tract infections (UTIs) were treated with norfloxacin (400 mg orally twice daily) and compared with 45 patients treated with trimethoprim/sulfamethoxazole. Norfloxacin was relatively safe and highly effective in treating both uncomplicated UTIs (86 percent cure rate) and complicated UTIs (75 percent cure rate). Failure of trimethoprim/sulfamethoxazole therapy was associated with initial bacterial resistance, e.g., from Pseudomonas aeruginosa and Serratia marcescens; such multiresistant bacteria were successfully treated with norfloxacin. Thus, norfloxacin appears to extend the range of oral agents available to treat UTIs.

The role of postnatal testosterone in the development of sexually dimorphic behaviors in DBA/1Bg mice.

The DBA/1 Y chromosome causes an increment in aggression and pubertal testosterone levels. The purpose of the following experiments was to determine whether pubertal testosterone is necessary for the normal development of both aggression and copulation in males. If it is, then the effect of the DBA/1 Y chromosome may be mediated by its influence on pubertal testosterone. Individuals were either castrated at 30 days of age (CAS30) or sham operated (Sham or CAS50). At 50 days of age, the CAS30 individuals were sham operated and replaced with testosterone, while the CAS50 group was castrated and replaced with the same quantity of testosterone. The shams were sham operated at 50 days of age. CAS30 individuals were less aggressive than the CAS50 group, while they were no less aggressive than the sham operated group. Additionally, no groups differed in male copulatory behaviors. The results are discussed in relation to Y chromosomal and developmental mechanisms of sexually dimorphic behaviors.