Thermogenesis in cafeteria-fed LA/N-cp (corpulent) rats

The capacity for diet-induced thermogenesis was accessed in groups of 20 week-old lean and corpulent LA/N-cp rats to determine if an impairment in adaptive energy expenditure might be associated with their obese state. Initial body weights of the corpulent rats were twice those of the lean genotype, and the rate of weight gain during cafeteria feeding was four times as rapid as occurred in lean rats. Measurements of resting oxygen consumption were similar in both lean and corpulent rats. Isoproterenol stimulation resulted in a marked increase in oxygen consumption in lean but not in corpulent rats. Acute exposure to a 5°C cold environment resulted in significant decreases in colonic and rectal temperatures in both genotypes but body temperatures recovered more rapidly in lean than in corpulent rats. Cafeteria feeding resulted in an improved cold tolerance only in lean rats. These observations are consistent with an impaired mechanism of diet-induced thermogenesis in the corpulent genotype which may contribute to the development of their obesity.     

Metabolism of chlorodiphenyl ethers and Irgasan DP 300.

1. In the rat chlorodiphenyl ethers are metabolized via two routes. The predominant reaction is aromatic hydroxylation; scission of the ether bond is a minor metabolic process. 2. In all cases, primary hydroxylation takes place ortho and meta to the ether bond. Ortho-hydroxylation leads to the formation of 'predioxins' in cases where the parent compounds contain a chlorine atom in one of the ortho positions in the second ring. 3. 5-Chloro-2-(2,4--dichlorophenoxy)phenol (Irgasan DP 300), a compound that meets the structural requirements of a predioxin, did not yield chlorodibenzo-p-dioxins or hydroxylated derivatives thereof. 4. Irgasan DP 300 is excreted unchanged in faeces and urine (partly conjugated) but is also hydroxylated to five different monohydroxy metabolites which were found in urine; three of these were also present in faeces. As a result of scission of the ether bond 2,4-dichlorophenol occurred in urine and faeces, and 4-chlorocatechol in urine. 5. Neither in the case of Irgasan DP 300, nor in that of chlorodiphenyl ethers with an ortho chlorine atom, could metabolic cyclization to chlorodibenzofurans or their hydroxylated derivatives be detected.     

Poor accuracy of freehand cup positioning during total hip arthroplasty

Several studies have demonstrated a correlation between the acetabular cup position and the risk of dislocation, wear and range of motion after total hip arthroplasty. The present study was designed to evaluate the accuracy of the surgeon’s estimated position of the cup after freehand placement in total hip replacement. Peroperative estimated abduction and anteversion of 200 acetabular components (placed by three orthopaedic surgeons and nine residents) were compared with measured outcomes (according to Pradhan) on postoperative radiographs. Cups were placed in 49.7° (SD 6.7) of abduction and 16.0° (SD 8.1) of anteversion. Estimation of placement was 46.3° (SD 4.3) of abduction and 14.6° (SD 5.9) of anteversion. Of more interest is the fact that for the orthopaedic surgeons the mean inaccuracy of estimation was 4.1° (SD 3.9) for abduction and 5.2° (SD 4.5) for anteversion and for their residents this was respectively, 6.3° (SD 4.6) and 5.7° (SD 5.0). Significant differences were found between orthopaedic surgeons and residents for inaccuracy of estimation for abduction, not for anteversion. Body mass index, sex, (un)cemented fixation and surgical approach (anterolateral or posterolateral) were not significant factors. Based upon the inaccuracy of estimation, the group’s chance on future cup placement within Lewinnek’s safe zone (5–25° anteversion and 30–50° abduction) is 82.7 and 85.2% for anteversion and abduction separately. When both parameters are combined, the chance of accurate placement is only 70.5%. The chance of placement of the acetabular component within 5° of an intended position, for both abduction and anteversion is 21.5% this percentage decreases to just 2.9% when the tolerated error is 1°. There is a tendency to underestimate both abduction and anteversion. Orthopaedic surgeons are superior to their residents in estimating abduction of the acetabular component. The results of this study indicate that freehand placement of the acetabular component is not a reliable method. No benefits or funds were received in support of this study.     

Platelet activity before and after coronary artery bypass grafting

The normal response of the platelet can be altered either by increased pro-aggregatory stimuli or by diminished anti-aggregatory substances. Increased platelet activation occurs in the cardiovascular disease states of stable angina pectoris and acute coronary syndromes. Also, cardiac surgery involving cardiopulmonary bypass is associated with extensive contact between blood and synthetic surfaces and leads to a strong activation of platelets. Using light transmission aggregometry method, we tested platelet sensitivity to ADP and spontaneous activity in the platelet-rich plasma of patients before and after coronary artery bypass grafting (CABG). The median values of EC50 for ADP were significantly lower at days 3 and 5 after surgery (0.33 and 0.37 microM, respectively) than before surgery (0.65 microM). The medians percentages of spontaneous platelet aggregation were significantly higher after than before surgery (16 and 15% at days 3 and 5 after surgery, respectively, vs. 5% before surgery). Thus, there is a significant increase of spontaneous platelet aggregation and platelet hyperreactivity to ADP in patients after CABG compared with those before surgery.     

8-OH-DPAT, but not deramciclane, antagonizes the anxiogenic-like action of paroxetine in an elevated plus-maze

OBJECTIVE: To investigate whether a 5-hydroxytryptamine (5-HT) reuptake inhibitor (paroxetine) has an anxiogenic-like effect and what possible pharmacological mechanism underlies that action. METHODS: We used the rat elevated plus-maze paradigm followed by measurement of locomotor activity. Some of the rats were subjected to handling and adaptation to the experimental situation, while the rest were naive to the test situation. Paroxetine was administered as a single treatment and in combination with the 5-HT1A receptor agonist (8-OH-DPAT) or 5-HT2A/2C receptor antagonist (deramciclane). RESULTS: The administration of paroxetine induced an anxiogenic-like action in rats adapted to handling, but not in handling naive animals. Treatment with paroxetine (0.1-2 mg/kg) reduced the number of open arm visits and time spent in open arms, and the ratio between open and total arm entries in the elevated plus-maze. Paroxetine also decreased the number of line crossings and head-dips. Paroxetine caused the strongest anti-exploratory action at a dose of 0.5 mg/kg. Paroxetine did not suppress the locomotor activity of rats, showing that the described anti-exploratory effect was behaviourally specific to the plus-maze. Pretreatment with 8-OH-DPAT (0.05 mg/kg) completely reversed the anxiogenic-like action of paroxetine, whereas treatment with deramciclane (2 mg/kg) affected only the number of closed arm visits. Deramciclane (0.5-2 mg/kg) and 8-OH-DPAT (0.01-0.1 mg/kg) changed neither exploratory behaviour nor locomotor activity if given as single treatments to the habituated rats. CONCLUSION: The 5-HT reuptake inhibitor, paroxetine, at a low dose (0.5 mg/kg) induces an anxiogenic-like action in handling adapted rats. The effectiveness of 8-OH-DPAT against paroxetine probably supports a role of both pre- and postsynaptic 5HT-ergic mechanisms in the anxiogenic-like action of paroxetine.     

2-Phenylpyrroles as conformationally restricted benzamide analogues. A new class of potential antipsychotics. 2

A series of 2-phenylpyrrole Mannich bases was synthesized and screened in pharmacological models for antipsychotic activity and extrapyramidal effects. Structure modifications of 5-(4-fluorophenyl)-2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]pyrrole (1), the prototype of a new class of sodium-independent atypical dopamine D-2 antagonists, resulted in 2-[[4-(7-benzofuranyl)-1-piperazinyl]methyl]-5-(4-fluorophenyl)pyrrole (15), which was an even more potent and selective D-2 antagonist than the parent compound. The excellent oral activity in the apomorphine-induced climbing behavior and the conditioned avoidance response tests and the absence of catalepsy make this compound particularly promising as a potential antipsychotic with a low propensity to induce acute extrapyramidal side effects.     

Thyroid and growth responses of young Zucker obese and lean rats to a low protein-high carbohydrate diet

Experiments were conducted to study the effects of a low protein-high carbohydrate diet on growth and thyroid function in obese and lean male and female Zucker rats. The nine feeding regimens included animals ad libitum fed either a 22% casein and 59% carbohydrate diet (control) or an 8% casein and 73% carbohydrate diet (low protein) and appropriate pair-fed groups to control for the lean rats eating less than the obese rats and the rats fed the low-protein diet eating less than those fed the control diet. The rats were 4 weeks old at the start of the experiment which lasted 7 weeks. Final body size, tibia length and nonfat dry mass of the lean rats were dependent primarily on the amount of protein consumed, whereas growth of the obese rats was related to total energy intake rather than to protein intake. The relative hyperphagia, decreased efficiency of energy utilization and increased oxygen consumption and serum T3 concentrations in the lean rats fed the low-protein diet were consistent with the development of an adaptive thermogenesis, allowing the excess non-protein energy to be dissipated through excess heat production. There was no evidence for such an adaptive thermogenesis in the obese rats. The suggestion that the obese rats were already overeating for protein and storing the excess energy as fat and that the decreased thyroid response might be part of a protective mechanism against overheating was discussed.     

Ethopharmacological studies differentiate the effects of various serotonergic compounds on aggression in rats

A series of experiments was performed to investigate the effects on aggression of various drugs affecting serotonergic transmission in rats. Using ethologically derived behavioural categories, the behaviour of treated animals was described. Drug effects were observed in two aggression models: resident–intruder aggression (RI) in male rats, and maternal aggression in lactating females during the postpartum period (MA). The 5-HT_1A agonists, buspirone, iosapirone, and 8-OH-DPAT, decreased aggression in RI and MA but simultaneously led to a marked decrease in social interest and activity, indicative of a nonspecific anti-aggressive profile. Nonselective 5-HT agonists, such as RU 24969, eltoprazine (DU 28853), and TEMPP, reduced aggression quite specifically and did not decrease social interest or exploration, but sometimes even increased these behaviours. In RI and MA, the behavioural effects of these drugs were roughly similar. By contrast, MA was more sensitive to the treatment with the 5-HT reuptake blocker fluvoxamine, which blocked RI aggression only nonspecifically at the highest dose. DOI, a 5-HT₂ and 5-HT_1C agonist, decreased aggressive behaviour and increased inactivity, without affecting social interest and exploration in RI as well as MA. This was, however, accompanied by “wet dog shaking,” characteristic of 5-HT₂-receptor stimulation. The nonspecific 5-HT agonist (and 5-HT₃ antagonist) quipazine also induced “wet dog shaking” at doses that suppressed aggression, social interest and exploration but increased inactive behaviours (sitting and lying). The discussion attempts to delineate a role for 5-HT receptor subtype involvement in the modulation of aggression, with the restrictions we clearly face with regard to the lack of specific serotonergic agonists and antagonists for certain receptor subtypes. By and large, male and female rats react similarly to treatment with serotonergic drugs stressing the consistent role of 5-HT in different forms of aggression. © 1992 wiley-Liss, Inc.