Quantifying fear potentiated startle using absolute versus proportional increase scoring methods: implications for the neurocircuitry of fear and anxiety

Abstract Rationale. The fear-potentiated startle paradigm [increased startle in the presence of a conditioned fear stimulus (CS)] has become increasingly popular as a tool for evaluating the potential efficacy of putative anxiolytic compounds. However, when the tested compounds also influence baseline startle, it is unclear how comparisons with control groups can best be made. Objective. To evaluate the validity of absolute difference (startle amplitude on CS minus non-CS test trials) vs. proportional increase (the absolute difference score divided by startle amplitude on non-CS test trials) scoring methods. Methods. The effect on proportional increase and absolute difference scores of baseline shifts that occur with or without concomitant increases in fear was evaluated in rats. A reliable measure should yield similar scores across shifting baselines, provided that fear levels remain constant. Results. Preexisting baseline differences, and those brought about by different startle-eliciting noise burst intensities, by strychnine injections, or by CRH infusions, each increased absolute difference scores without markedly influencing proportional change scores. These baseline differences were not associated with different fear levels. Increases in baseline startle brought about by unsignaled footshocks or by a second CS – increases which are associated with increased fear – partially occluded additional CS-induced increases using either measure. Conclusions. Across different baselines, CS-elicited fear is most accurately reflected in proportional change scores. Under certain conditions saturation effects may interfere with an accurate assessment using either measure. However, these same saturation effects may provide opportunities to explore the neural circuitry of fear and anxiety in novel ways. Electronic Publication     

Biologically active steroidal glycosides from Tribulus terrestris

The steroidal saponin constituents obtained from Tribulus terrestris were tested for their antimicrobial and cytotoxic effects. The spirostanol-based steroidal saponins 1-3 exhibited remarkable activity against fungal organisms (Candida albicans and Cryptococcus neoformans) and cancer cell lines [human malignant melanoma (SK-MEL), human oral epidermoid carcinoma (KB), human breast ductal carcinoma (BT-549), and human ovary carcinoma (SK-OV-3)], while none of the compounds possessing the furostanol framework 4-7 showed activity. The most active spirostanol glycoside, compound 3 exhibited a broad range of anticancer activity against cell lines, SK-MEL, KB, BT-549 and SK-OV-3 at IC50s of 6.0, 7.0, 6.0 and 8.2 micrograms/ml, respectively, while compounds 1 and 2 showed selective cytotoxicity against SK-MEL at 6.7 and 9.1 micrograms/ml, respectively. The minimum inhibitory concentrations (MIC) in antifungal bioassay for compounds 1-3 varied from 1.5 to 6.2 micrograms/ml, which prompted to conclude certain structural features are required for these bioactivities.     

Evaluation of the ability of seven herbal resources to answer questions about herbal products asked in drug information centers

STUDY OBJECTIVE: To evaluate the ability of seven widely known herbal references and electronic databases to answer questions about herbal products asked at drug information centers. DESIGN: Cross-sectional study. SETTING: Five academic and institutional drug information centers. METHODS: Fifty-seven herbal-related questions were obtained from academic and institutional drug information centers. Seven herbal references and electronic databases were evaluated for their ability to answer these 57 questions: The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines, 1st edition; Physicians' Desk Reference (PDR) for Herbal Medicines, 2001 edition; Tyler's Honest Herbal: A Sensible Guide to the Use of Herbs and Related Remedies, 4th edition; The Lawrence Review of Natural Products, 2001; Natural Medicines Comprehensive Database (electronically updated, 2001); The Natural Pharmacist (electronically updated, 2001); and AltMedDex (electronically updated, 2001). RESULTS: Natural Medicines Comprehensive Database outperformed all other products evaluated, providing direct answers to 61% of questions. AltMedDex and The Natural Pharmacist performed similarly to one another, answering 49% and 44% of questions, respectively. The Lawrence Review of Natural Products, PDR for Herbal Medicines, The Complete German Commission E Monographs, and Tyler's Honest Herbal were the least helpful in providing direct answers to the questions (24%, 21%, 11%, and 9%, respectively). CONCLUSION: Natural Medicines Comprehensive Database, AltMedDex, and The Natural Pharmacist outperformed all other evaluated herbal references and electronic databases in their ability to answer questions about herbal products posed in clinical practice.     

Consequences of intrauterine growth restriction on ventilatory and thermoregulatory responses to asphyxia and hypercapnia in the newborn guinea-pig

The purpose of this study was to determine the effects of prenatal growth restriction on the ventilatory and thermoregulatory responses to asphyxia and hypercapnia in the newborn guinea-pig. Spontaneously growth-restricted (SGR) animals born to unoperated dams, and growth-retarded (GR) neonates born to dams in which a uterine artery had been ligated at mid gestation, were studied and compared with control neonates. Ventilatory responses to progressive asphyxia and steady-state hypercapnia were tested at 3-6 days of age using a barometric plethysmograph. The animals were then killed and the brains prepared for histological and immunohistochemical analysis. During progressive asphyxia, SGR neonates (n = 5) had a significantly increased minute ventilation compared with both control (n = 6) and GR (n = 5) neonates. Rectal temperature fell significantly in GR and SGR neonates after progressive asphyxia, but was unchanged in control neonates. The ventilatory responses to steady-state hypercapnia were not different in the GR, SGR and control neonates. The immunoreactive expression of glial fibrillary acidic protein, tyrosine hydroxylase, substance P and met-enkephalin in the medulla was also not different between the three groups. It was concluded that prenatal growth restriction is associated with alterations in the respiratory and thermoregulatory responses to asphyxia and hypercapnia, with greater effects observed when in utero growth restriction arises spontaneously, compared with that produced experimentally over approximately the last half of gestation.     

The diffusion of innovation: factors influencing the uptake of telehealth

The actual use of telehealth, particularly for clinical consultations, has in many cases been less than anticipated. The literature identifies a number of factors or barriers. These include legal issues, technical difficulties, time and convenience, cost and training/familiarity with the equipment. No single factor has been identified as being consistently present. Rogers' diffusion of innovation theory suggests that organizational structures and cultures will affect health professionals' perceptions of telehealth. The introduction of telehealth services affects existing work practices and workflows. We believe that it is necessary to develop strategies for the introduction of telehealth applications which take into account the idiosyncrasies of the health service sector, and the particular structures and cultures of individual organizations within that sector.     

Regulation of anandamide tissue levels by N-arachidonylglycine

N-arachidonylglycine (NAGly), the carboxylic analog of the endocannabinoid anandamide, occurs in rat and bovine brain as well as in peripheral sites and shows activity against tonic, formalin-induced pain. It was also observed, using cell membrane preparations, that it inhibits the hydrolytic activity of fatty acid amide hydrolase (FAAH) on anandamide (N-arachidonylethanolamide). These data suggested that it may serve as an endogenous regulator of tissue anandamide concentrations. In this report, we show findings derived from mass spectrometric analyses, indicating that blood levels of anandamide in rats given 10 mg/kg p.o. of NAGly were increased significantly by more than 9-fold when compared with vehicle-treated controls. In vitro evidence in RAW 264.7 cells using a deuterium-labeled NAGly demonstrated that it was not a precursor or source of arachidonic acid for the observed 50% rise in anandamide levels, suggesting that the increase was due to some effect other than increased biosynthesis of anandamide. Moreover, the findings presented here suggest that NAGly can serve as a model for the design of agents to provide pharmacological control of tissue anandamide concentrations.     

Characterization of Mycotypha metabolites found to be inhibitors of cell adhesion molecules

Three inhibitors of cell adhesion based on LFA-1/ICAM-1 were isolated from the cultured broth of the fungal strain Mycotypha sp. UMF-006. These compounds were identified by spectroscopy to be cytochalasin E (1), 5,6-dehydro-7-hydroxy derivative of cytochalasin E (2) and delta 6,12-isomer of 2 (3). All these components inhibited adhesion of HL-60 cells to CHO-ICAM-1 cells at IC50 values of 30 micrograms/ml for 1, 75 micrograms/ml for 2, and 90 micrograms/ml for 3.