Decreased hyperthermic effect of MK-801 in selectively bred hypercholinergic rats

The Flinders Sensitive Line (FSL) of rats has been selectively bred to have increased sensitivity to cholinergic agonists. However, these rats exhibit altered responsiveness to a number of noncholinergic agents, such as apomorphine, buspirone and ethanol. This study compared the FSL and control Flinders Resistant Line (FRL) rats in terms of their hyperthermic response to the phencyclidine (PCP) receptor agonist, MK-801 (0.2 mg/kg SC) and their MK-801 binding characteristics. We have found that FSL rats react with a delayed hyperthermia, having a significantly lower hyperthermia for the first 120 min of observation. Thereafter the response does not differ in FSL and FRL rats. Both groups had similar affinities and numbers of [3H]MK-801 binding sites in the hippocampus/cerebral cortex. Pretreatment with scopolamine (1 mg/kg SC) failed to affect MK-801-induced hyperthermia in either line of rats. These findings suggest that selective breeding of FSL rats attenuated the secondary mechanisms involved in the PCP receptor-mediated hyperthermic response. However, by itself cholinergic supersensitivity does not appear to be a major factor in the blunted responsiveness of FSL rats to MK-801.     

Patients' Expectations of Asthma Treatment

A multicomponent model has been developed to explain patients' unmet expectations of medical care. The model proposes that expectations are related to patients' personal experiences with illness, perceived vulnerability to disease, transmitted knowledge, and perceived severity of disease. The objective of this cross-sectional study was to determine whether this model can be applied to patients' unrealistic expectations of treatment outcomes, specifically expecting to be cured of asthma. In total, 230 patients observed in a primary care practice in New York City were interviewed in person with open-ended questions about their expectations of asthma treatment. Responses were analyzed with qualitative techniques to generate categories of expectations. Patients had a mean age of 41 ± 11 years, 21% were white, 30% African American, 42% Latino, and 7% other groups. Major categories of expectations were generated from patients' responses and included symptom relief (expected by 52%), cure (36%), improved physical function (21%), and improved psychological well-being (15%). The category of expecting a cure was assessed with patients' responses to the following items representing components of the model: 1) resource utilization and medication requirements for asthma (representing severity of disease); 2) perceived quality of asthma care and satisfaction with care (representing past asthma experiences); 3) the Asthma Self-Efficacy Scale (representing perceived vulnerability to exacerbations); and 4) experiences of social network contacts with asthma and the Check Your Asthma IQ survey (representing transmitted knowledge). In bivariate analysis, patients who expected a cure were more likely to be Latino or Native American or Asian (p = 0.02), to have never required oral corticosteroids (p = 0.004), to be dissatisfied with the status of their asthma (p = 0.008), to know others who were limited by asthma (p = 0.03), to have worse Asthma Self-Efficacy Scale scores (p = 0.002), to have worse Check Your Asthma IQ scores (p = 0.04), and to currently be taking inhaled corticosteroids (p = 0.03). In multivariate analysis, worse asthma self-efficacy (p = 0.008), never having required oral corticosteroids (p = 0.005), and currently taking inhaled corticosteroids (p = 0.05) remained associated with expecting a cure. As a result of this study, we found that patients have multiple expectations of asthma treatment, including realistic expectations such as symptom relief and improved function, as well as unrealistic expectations, specifically to be cured of asthma. A multicomponent model of patient and disease characteristics was associated with this unrealistic expectation. These findings indicate that clinicians can intervene in diverse areas to foster realistic expectations of treatment outcomes among asthma patients.     

Suppression of alcohol and saccharin preference in rats by a novel Ca2+ channel inhibitor,Goe 5438

The effect of the novel 1,4-dihydronaphthyridine Ca²⁺ channel inhibitor Goe 5438 (CI-951) on voluntary ethanol consumption was examined in selectively bred alcohol-preferring (P) rats in a free choice two bottle preference test versus water. Intraperitoneally injected Goe 5438 dose-dependently (5, 10 or 20 µmol/kg, twice daily) inhibited ethanol and increased water intake over the 24 h period (injection day). The drug decreased ethanol preference, originally above 90%, by 6%, 19% and 45% at respective doses, on the injection day. That inhibitory effect of the highest dose of Goe 5438 on ethanol preference remained significant also on days 2 and 3 after injections (–51% and –18%, respectively). Goe 5438, in the highest dose, also tended to decrease granulated chow consumption during the injection day only. To further test whether the inhibition of ethanol preference is secondary to decrease in reinforcing properties of ethanol and not due to interference with satiety mechanisms, we compared the effect of two higher doses (10 and 20 µmol/kg, intraperitoneally, twice daily) of Goe 5438 on spontaneous preference for a non-caloric 0.04% saccharin solution in Sprague-Dawley rats. We observed a dose-dependent suppression of preference (by 44% and 58%, respectively) during the injection day, but not the subsequent 24 h period. However, Goe 5438 also significantly alleviated food pellet intake on the injection day. In conclusion, Goe 5438 produces potent and long-lasting inhibition of voluntary ethanol consumption, which may be secondary to attenuation of reinforcing properties of ethanol. Additionally, this particular Ca²⁺ channel inhibitor appears to have mild anorectic properties which may be conducive to acute suppression of alcohol intake.     

Systemic and mucosal antibody responses specific to SARS-CoV-2 during mild versus severe COVID-19

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Administration of antidepressants,diazepam and psychomotor stimulants further confirms the utility of Flinders Sensitive Line rats as an animal model of depression

Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression because they resemble depressed humans in that they have elevated REM sleep, reduced activity, and increased immobility and anhedonia after exposure to stressors. The present paper reviews experiments on the drug treatment of FSL and control Flinders Resistant Line (FRL) rats related to their utility as an animal model of depression, and presents new information. FSL rats exhibited exaggerated immobility in the forced swim test which is counteracted by the tricyclic antidepressants imipramine and desipramine and the serotonin reuptake blocker sertraline; the low immobility exhibited by the FRL rats is generally unaffected by these compounds. In contrast to these therapeutic effects of well recognized antidepressants, lithium and bright light treatment did not alter the exaggerated immobility of FSL rats. Novel data indicated that neither FSL nor FRL rats exhibited alterations in swim test immobility following chronic administration of the psychomotor stimulant amphetamine (2 mg/kg) and the anticholinergic scopolamine (2 mg/kg), which typically reduce immobility after acute administration. However, it was found that the calcium channel blockers verapamil (5 and 15 mg/kg) and nicardipine (10 mg/kg) did reduce the exaggerated immobility in FSL rats following chronic administration, suggesting that these compounds need to be evaluated further in humans. Previous studies have indicated no differences between FSL and FRL rats evaluated in the elevated plus maze, either at baseline or after the administration of diazepam, suggesting that the FSL rat may not differ from controls in anxiety-related behavior. Another recently published study showed that the FSL rat also did not differ from normal Sprague-Dawley rats in startle tests, indicating that the FSL rats do not exhibit behaviors shown in animal models of schizophrenia. These findings confirm the utility of FSL rats as an animal model of depression because the FSL rats do not appear to exhibit behaviors analogous to anxiety or schizophrenia and because they respond therapeutically to antidepressants and not psychomotor stimulants.     

Antidepressant effects of nicotine in an animal model of depression

Epidemiological studies indicate a high incidence of cigarette smoking among depressed individuals. Moreover, individuals with a history of depression have a much harder time giving up smoking. It has been postulated that smoking may reflect an attempt at self-medication with nicotine by these individuals. Although some animal and human studies suggest that nicotine may act as an antidepressant, further verification of this hypothesis and involvement of nicotinic cholinergic system in depressive symptoms is required. Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression. These rats, selectively bred for their hyperresponsiveness to cholinergic stimulation, show an exaggerated immobility in the forced swim test compared to their control Flinders Resistant Line (FRL) rats. Acute or chronic (14 days) administration of nicotine (0.4 mg/kg SC) significantly improved the performance of the FSL but not the FRL rats in the swim test. The effects of nicotine on swim test were dissociable from its effects on locomotor activity. Moreover, the FSL rats had significantly higher [³H]cytisine binding (selective for the α₄β₂ nicotinic receptor subtype) but not [¹²⁵I]alpha-bungarotoxin binding (selective for the α₇ subtype) in the frontal cortex, striatum, midbrain and colliculi compared to FRL rats. These data strongly implicate the involvement of central nicotinic receptors in the depressive characteristics of the FSL rats, and suggest that nicotinic agonists may have therapeutic benefits in depressive disorders. Received: 9 June 1998/Final version: 6 August 1998     

Autoreactive, cytotoxic T lymphocytes specific for peptides derived from normal B-cell differentiation antigens in healthy individuals and patients with B-cell malignancies.

PURPOSE: To investigate potential immunotherapeutic strategies in B lymphocytic malignancies we looked for CTLs recognizing CD19 and CD20 epitopes. EXPERIMENTAL DESIGN: Three CD19 and CD20 peptides binding to HLA-A*0201 were identified and used to detect peptide specific CTLs by a quantitative real-time PCR to measure IFN-gamma mRNA expression in 23 healthy individuals and 28 patients (18 chronic lymphocytic leukemia (CLL), 7 follicular lymphoma, 2 acute lymphocytic leukemia, and 1 large cell lymphoma). Peptide-specific CTLs were expanded in culture with CD40-activated B cells to test lytic activity in three patients. RESULTS: In healthy individuals, CD8+ T-cell responses were detected in one to CD19(74-82), in three to CD20(127-135), and three to CD20(188-196). Seven of 27 patients (6 with CLL) had CD8+ T cells recognizing CD19(74-82). Seven patients responded to CD20(127-135) and three to CD20(188-196). All were CLL patients. CD19(74-82)-specific CTLs from three patients were expanded over 4 weeks. These cells were HLA-A*0201 specific and lytic for peptide-loaded antigen-presenting cells but not to malignant or unpulsed B cells. CONCLUSIONS: CTLs that recognize CD19 and CD20 epitopes exist in healthy individuals and may be increased in CLL patients. They are of low avidity and require high doses of peptide for activation. Strategies to increase T-cell avidity would be necessary for T-cell immunotherapeutic approaches using the peptides studied.     

Venous thromboembolism associated with long-term use of central venous catheters in cancer patients.

Long-term central venous catheters (CVCs) have considerably improved the management of cancer patients because they facilitate chemotherapy, transfusions, parenteral nutrition, and blood sampling. However, the use of long-term CVCs, especially for chemotherapy, has been associated with the occurrence of upper-limb deep venous thrombosis (UL-DVT). The incidence of clinically overt UL-DVT related to CVCs has been reported to vary between 0.3% and 28.3%. The incidence of CVC-related UL-DVT screened by venography reportedly varies between 27% and 66%. The incidence of clinically overt pulmonary embolism (PE) in patients with CVC-related UL-DVT ranges from 15% to 25%, but an autopsy-proven PE rate of up to 50% has been reported. Vessel injury caused by the procedure of CVC insertion, venous stasis caused by the indwelling CVC, and cancer-related hypercoagulability are the main pathogenetic factors for CVC-related venous thromboembolism (VTE). Several studies have assessed the benefit of the prophylaxis of UL-DVT after CVC insertion in cancer patients. According to the results of these studies, prophylaxis with low molecular weight heparin or a low fixed dose of warfarin has been recently proposed. However, the limitations of the experimental design of the prophylactic studies do not allow definitive recommendations. The recommended therapy for UL-DVT associated with CVC is based on anticoagulant therapy with or without catheter removal. This review focuses on the epidemiology, pathogenesis, diagnosis, prevention, and treatment of VTE in cancer patients with long-term CVC.     

The pig as a model for the study of radiation effects on the lung

PURPOSE: The treatment of thoracic malignancies is frequently limited by the 'tolerance' of normal lung tissue. In order to learn more about the factors that influence lung tolerance an animal model that closely mimics the clinical exposure situation is required. The lungs of pigs are similar to those of man in a variety of ways and the animal's size permits the irradiation of partial tissue volumes comparable with those used clinically; very rarely in man is the whole lung irradiated. In this report, the available data for the effects of irradiation on pig lung are reviewed as they relate to the key issues in radiotherapy. RESULTS: The dose-effect relationships for exposure to single doses indicate that for a significant impairment in both early and late lung function and for the histological detection of fibrosis, the dose-related changes in pig and man are similar. Studies with dose-fractionation using X-rays indicate a large dependence of the iso-effective dose on fraction number and fraction size, and the parameters obtained were not significantly influenced by the time of assessment after irradiation. A simple power-law function fitted the whole data set better than the linear-quadratic model, with a fraction number exponent (N) of 0.44+/-0.06 for treatments given in 1-30 fractions. The alpha/beta values ranged from 0.6 to 4.86 Gy, tending to increase with the length of the follow-up period; however; the majority of these alpha/beta values were not significantly different from zero at the 5% level. Studies of the effect of changes in the volume of lung tissue irradiated indicated the need for care in the use of the terms 'tolerance' and 'iso-effective' dose. Doses that were iso-effective for the severity of regional damage were not matched by those for total lung function. The same level of damage in a small volume compared with a large volume had less effect, i.e. was better tolerated in terms of changes in total lung function. CONCLUSION: Iso-effective doses in pig and humans are lower than those for the more common laboratory animal species. This observation may be related to the differences in anatomical structure of the lungs in the different species.     

Antitumor effects of a monoclonal antibody that binds anionic phospholipids on the surface of tumor blood vessels in mice.

PURPOSE: We recently reported that anionic phospholipids, principally phosphatidylserine, become exposed on the external surface of viable vascular endothelial cells in tumors, possibly in response to oxidative stresses present in the tumor microenvironment. In the present study, we tested the hypothesis that a monoclonal antibody directed against anionic phospholipids might exert antitumor effects by causing vascular damage in tumors. EXPERIMENTAL DESIGN: A new mouse immunoglobulin G3 monoclonal antibody, 3G4, was raised that binds anionic phospholipids in the presence of serum or beta2-glycoprotein I. The antibody was tested for its ability to localize to tumor vessels and exert antitumor effects in mice. RESULTS: 3G4 recognized anionic phospholipids on the external membrane of H(2)O(2)-treated endothelial cells and in vitro. It localized specifically to tumor vascular endothelium and to necrotic tumor cells after injection into severe combined immunodeficient mice bearing orthotopic MDA-MB-435 tumors. Treatment with 3G4 retarded the growth of four different tumors in mice. It reduced the growth of established orthotopic MDA-MB-231 and MDA-MB-435 human breast tumors in mice by 75% and 65% respectively, large L540 human Hodgkin's tumors by 50%, and small syngeneic Meth A fibrosarcomas by 90%. Histologic examination revealed vascular damage, a reduction in vascular density, and a reduction in tumor plasma volume. Treatment with 3G4 induced the binding of monocytes to tumor endothelium and infiltration of macrophages into MDA-MB-435 and MDA-MB-231 tumors. No toxicity to the mice was observed. CONCLUSIONS: 3G4 localizes specifically to complexes of anionic phospholipids and serum proteins on the surface of vascular endothelial cells in tumors in mice. This results in damage to tumor vasculature and suppression of tumor growth.