Nonclinical Model Research Articles

Evaluation of contextual renewal as a nonclinical model for cognitive deficits

Evaluation of contextual renewal as a nonclinical model for cognitive deficits

Rapid Mobilization of Murine Hematopoietic Stem and Progenitor Cells with TG-0054, a Novel CXCR4 Antagonist.

Abstract 3542Poster Board III-479 BackgroundThe interaction between SDF-1 and its receptor, CXCR4, is responsible for retaining of stem cells in the bone marrow. CXCR4 antagonist disrupts the SDF-1/CXCR4 interaction and mobilizes CD34+ hematopoietic stem cells (CD34+ HSCs) and CD133+ endothelial progenitor cells (CD133+ EPCs) from bone marrow into circulation, which can be used as a source for stem cell transplantation and other potential clinical indications. TG-0054 is a novel CXCR4 antagonist. In vitro CXCR4 antagonistic activity and in vivo stem cell mobilization activity of TG-0054 were determined in this study. Materials and MethodsIn vitro pharmacological assays, including GTP-binding assay, calcium mobilization assay, and chemotaxis assays, were performed to assess the potency of TG-0054 as a CXCR4 antagonist. In addition, receptor-binding assays against a panel of human chemokine receptors as well as other 68 cellular receptors were screened to evaluate the specificity of TG-0054. Kinetics and dose-dependent response of stem cell mobilization by TG-0054 were demonstrated in BALB/c mice. Activity of stem cell mobilization of TG-0054 when used alone or combined with G-CSF was also studied. ResultsTG-0054 blocked SDF-1-binding to CXCR4 receptor with an IC50 of 10 nM and inhibited SDF-1–induced GTP-binding (IC50 = 6 nM), chemotaxis (IC50 = 43 nM), and calcium mobilization (IC50 = 59 nM). TG-0054 showed greater than 3000-fold selectivity for CXCR4 receptor over other chemokine receptors. It is noteworthy that the IC50 for the inhibitory effect of TG-0054 on hERG potassium currents was greater than 1000 μM when human embryonic kidney (HEK) cells were used to examine the in vitro effects on the hERG potassium channel currents. In animal studies, TG-0054 rapidly and effectively mobilized CD34+ HSCs and CD133+ EPCs into circulation. Single intravenous (IV) administration of TG-0054 resulted in a rapid increase of total white blood cell (WBC) counts, as well as CXCR4+, CD34+, and CD133+ cells in peripheral blood between 1–3 hour post-injection and the cell counts returned to baseline within 6 hours. At their maximum tolerated doses (MTD), TG-0054 increased CXCR4+ cells by 28.7-fold in mice. Furthermore, TG-0054 efficiently mobilized CD34+ (14.5-fold) and CD133+ (7.9-fold) cells. The combined effects of TG-0054 and G-CSF on HSCs and EPCs mobilization from the bone marrow in mice were also investigated. G-CSF (100 μg/kg/day) was administered subcutaneously (SC) from Day 1 to Day 4 followed by a single IV injection of TG-0054 or AMD3100 on Day 5. Synergistic effects were observed in all cell types in mice receiving combination of G-CSF and 50 mg/kg of TG-0054 (total WBC 23.0-fold, CXCR4+ 29.0-fold, CD34+ 37.1-fold, CD133+ 110.8-fold of increase in combination group). ConclusionIt was concluded that TG-0054 was a potent and selective CXCR4 antagonist intended for the use of stem cell transplant and other clinical indications. It showed strong stem cell mobilization activity comparable to G-CSF when used alone, and demonstrated synergistic effects when combined with G-CSF in a nonclinical model. Disclosures:Huang:TaiGen Biotechnology Inc.: Employment. Liu:TaiGen Biotechnology Inc.: Employment. Yen:TaiGen Biotechnology Inc.: Employment. Chen:TaiGen Biotechnology Inc.: Consultancy. Chen:TaiGen Biotechnology Inc.: Consultancy. King:TaiGen Biotechnology Inc.: Employment. Hsu:TaiGen Biotechnology, Inc.: Membership on an entity's Board of Directors or advisory committees.

55. The Effects of Bisphosphonate on Short-Term Local Bone Remodeling and Bone Formation with rhBMP-2 in a Non-clinical Interbody Spine Fusion Model

BACKGROUND CONTEXT: The clinically safe and effective volume/concentration of rhBMP-2/Absorbable Collagen Sponge (ACS) has been established for select interbody constructs. However, transient peri-implant radiolucencies have been occasionally observed clinically. Previous nonclinical work has demonstrated heightened bone remodeling activity with high volume/concentration of rhBMP-2/ACS early in the healing process. In these studies, the osteoclastic activity and subsequent bone resorption was transient and new bone formation progressed over time.

On the links between self-discrepancies, rumination, metacognitions, and symptoms of depression in undergraduates

The present study aimed to test the central components of Papageorgiou and Wells’ (2003) non-clinical metacognitive model of rumination and depression that is grounded on the Self-Regulatory Executive Function (S-REF) model of emotional disorders [Wells, A., & Matthews, G. (1994). Attention and emotion: A clinical perspective. Hove, UK: Lawrence Erlbaum.]. A second aim of this study was to extend the non-clinical model with the concept of self-discrepancy in line with the S-REF model. Data of the current study were collected in a large sample of non-clinical Dutch undergraduates ( N=196), who completed a battery of questionnaires including measures of rumination, positive and negative metacognitions, depressive symptoms, and self-discrepancy (i.e., actual-ideal, actual-ought, and actual-feared discrepancies). Hypothesized relationships among these variables were tested by means of structural equation modelling. Following some theoretically consistent modifications, the model was an adequate fit to the data. With respect to the second aim of the study, self-discrepancies were directly linked to symptoms of depression as well as indirectly via the cognitive processes involved in the metacognitive model of rumination and depression. Evidence was found for positive beliefs about rumination to partially mediate the relation between self-discrepancy and rumination. Clinical implications of the findings, including implementation of a metacognitive-focused cognitive therapy of depression, and suggestions for future research are discussed.

Metabolomic approaches to phenotype characterization and applications to complex diseases

Metabolites are the key regulators of systems homeostasis. As such, concentration changes of specific groups of metabolites may reflect systemic responses to environmental, therapeutic or genetic interventions. Thus, the study of metabolites is a powerful tool for the characterization of complex phenotypes as well as for the development of biomarkers for specific physiological responses. Therefore, metabolomics is a valuable platform for studies of complex diseases and the development of new therapies, both in nonclinical disease model characterization and clinical settings.

Relationship between Applied Pressure and Temperature Change in a Simulated Model during Therapeutic Ultrasound

Summary Background and purpose Previous research has shown that the amount of pressure applied to an ultrasound head affects energy transmission. The purpose of this study was to determine the effect of application pressure on temperature during ultrasound on a non-clinical model, and to establish the accuracy of measurements obtained using a pressure sensor on the ultrasound head. Methods A repeated measures design was used to test differences in temperature of a gel target when ten different masses, ranging from 100 g to 1000 g, were applied to the ultrasound head. Eight trials were conducted giving a total of 160 measurements. The relationship between the pressure reading and the weight applied was examined. Results A one-way analysis of variance for pre- and post-test temperatures for each 100 gram mass applied to the sound head revealed no significant differences (F{9,79} = 0.86, p = 0.57). A one-way analysis of variance to examine differences in mean change scores showed no significant differences (F{9,79} = 0.86, p = 0.56). A strong relationship between readings obtained from a pressure sensor attached to the ultrasound head and the applied mass was demonstrated (r = 0.84, p = > 0.001). Conclusions Variation in pressure applied through the ultrasound head was not found to affect the temperature of the model. Further research is needed to determine if the pressure applied by the clinicians through the ultrasound head would enhance or diminish the effectiveness of therapeutic ultrasound in vivo . The pressure sensor gave an accurate indication of the force applied to the ultrasound handle.

Evaluation of the efficacy of 2- versus 3-dimensional computed tomography

Simulated 3-dimensional (3-D) representation of computerized data is a valuable diagnostic tool in evaluation of tumors of the central nervous system. Several reports exist regarding the clinical value of 3-D imaging, but there is little objective evidence to quantify improved performance from the images. The purpose of this study was to quantify the efficacy of simulated 3-D versus 2-D image interpretation in a nonclinical model. A 3-tiered, 3-D model was constructed, and objects were placed in varied positions. CT was then performed on each of the models. Fifty-three subjects were shown the CT images and asked to reconstruct the model as depicted by either 2-D or simulated 3-D images. Performance between subject groups was different depending on clinical experience. In addition, it was found that the 3-D representation of data allowed for a significantly faster performance of the task of image interpretation and reconstruction of the model. (Otolaryngol Head Neck Surg 1999;121:414-7.)

Nonclinical model for assessing gastric effects of bisphosphonates.

Gastrointestinal intolerance has been associated with amino bisphosphonate therapy in the clinic. The objective of this study was to develop a model for assessing bisphosphonate-induced gastric damage that may aid in the development of future bisphosphonate therapies. Rats were dosed concomitantly with indomethacin (40 mg/kg, subcutaneously) and an amino or pyridinyl bisphosphonate (orally at. 150, 225 or 300 mg/kg). The bisphosphonates studied were pamidronate and alendronate (primary amino bisphosphonates) and risedronate and NE-97221 (pyridinyl bisphosphonates). Macroscopically, alendronate induced significantly (P < 0.05) more antral damage (both lesion length and number) than pamidronate and risedronate at 225 and 300 mg/kg, and more than NE-97221 at 300 mg/kg. NE-97221 induced significantly more antral damage (lesion length) than risedronate at 225 mg/kg and a greater number of lesions compared to pamidronate and risedronate at 225 and 300 mg/kg. The model was validated histologically, and macroscopic findings correlated with histologic evidence of antral mucosal necrosis and inflammatory infiltration of the lamina propria. The calcium chelators EGTA and EDTA did not induce gastric damage in this model when dosed according to the same protocol as the nitrogen-containing bisphosphonates. This suggests that calcium chelation does not account for the gastric effects in this model. The fasted, indomethacin-treated rat provides a novel nonclinical model to assess gastric effects of bisphosphonates, which may aid in the development of future bisphosphonate therapies. These data suggest that when expressed on an actual or anticipated clinical dose basis for osteoporosis (pamidronate, 150 mg; alendronate, 5-10 mg; risedronate and NE-97221, 5 mg), primary amino bisphosphonates may have a greater potential for inducing gastric damage than do pyridinyl bisphosphonates.

Myocardial protection in normal and hypoxically stressed neonatal hearts: The superiority of hypocalcemic versus normocalcemic blood cardioplegia

Objectives: The ideal cardioplegic calcium (Ca +2 ) concentration in newborns continues to be debated. Most studies examining cardioplegia calcium concentrations have been done with a nonclinical model (i.e., isolated heart preparation), the results of which may not be clinically applicable, and they have not examined the effect of calcium concentration in a clinically relevant stressed (hypoxic) heart. Methods: Twenty neonatal piglets 5 to 18 days old were placed on cardiopulmonary bypass, and their aortas were crossclamped for 70 minutes with hypocalcemic or normocalcemic multidose blood cardioplegic infusions. Group 1 ( n = 5; low Ca +2, 0.2 to 0.4 mmol/L) and group 2 ( n = 5; normal Ca +2, 1.0 to 1.3 mmol/L) were nonhypoxic (uninjured) hearts. Ten other piglets were first ventilated at an Fio 2 of 8% to 10% (O 2 saturation 65% to 70%) for 60 minutes (i.e., causing hypoxia) and then reoxygenated at an Fio 2 of 100% with cardiopulmonary bypass, which produces a clinically relevant stress injury. They then underwent cardioplegic arrest (as described above) with a hypocalcemic ( n = 5, group 3) or normocalcemic ( n = 5, group 4) blood cardioplegic solution. Myocardial function was assessed with pressure volume loops and expressed as a percentage of control values. Coronary vascular resistance was measured during each cardioplegic infusion. All values were reported as the mean ± standard error. Results: In nonhypoxic hearts (groups 1 and 2), good myocardial protection was achieved at either concentration of cardioplegia calcium, as demonstrated by preservation of postbypass systolic function (104% vs 99% end-systolic elastance), minimally increased diastolic stiffness (152% vs 162%), no difference in myocardial water (78.9% vs 78.9%), and no change in adenosine triphosphate levels or coronary vascular resistance. Low-calcium blood cardioplegia solution repaired the hypoxic reoxygenation injury in stressed hearts (group 3), resulting in no statistical difference in myocardial function, coronary vascular resistance, or adenosine triphosphate levels compared with nonhypoxic hearts (groups 1 and 2). Conversely, when a normocalcemic cardioplegia solution was used in hypoxic hearts (group 4), there was marked reduction in postbypass systolic function (49% ± 4% end-systolic elastance; p < 0.05), increased diastolic stiffness (276% ± 9%; p < 0.05), increased myocardial water (80.1% ± 0.2%; p < 0.05), rise in coronary vascular resistance ( p < 0.05), and lower adenosine triphosphate levels compared with groups 1, 2, and 3. Conclusions: This study demonstrates that, in the clinically relevant, intact animal model, good myocardial protection is independent of cardioplegia calcium concentration in nonhypoxic (noninjured) hearts; hypoxic (stressed) hearts are extremely sensitive to the cardioplegic calcium concentration; and normocalcemic cardioplegia is detrimental to neonatal myocardium subjected to a preoperative hypoxic stress. (J T HORAC C ARDIOVASC S URG 1996;112:1193-201)

The Delivery and Use of Contraceptive Services in Rural Tunisia

This article summarizes a 1981 report published by the National Family Planning and Population Office an agency of the Ministry of Public Health of Tunisia. The report provides insights into the fertility and contraceptive behavior of rural Tunisian women and the problems that they face in obtaining family planning services as well as implications for future programs. The report examines family planning attitudes and practice contraceptive availability and accessibility and the unmet demand for family planning in 1 of Tunisias 21 administrative regions the province of Jendouba. The results of 2 special studies are presented here: the 1979 Contraceptive Prevalence Survey a representative sample of 1827 currently married women aged 15 to 49 living in Jendouba; and a 2 1/2 year pilot community based experiment known as Family Planning for Rural Couples (PFPC) which was designed to increase contraceptive availability and use among rural families in 1/2 of the province. 2 most significant findings are the substantial unmet demand for family planning and the inaccessibility of traditional service outlets for the majority of the provinces rural women. Contraceptive users and nonusers alike reported that it was difficult to get to a family planning service provider. The largely urban based health facilities in Jendouba have not adequately met the family planning needs of women living in widely scattered settlements particularly those interested in obtaining the pill and barrier methods. The PFPC outreach experiment provided a low cost nonclinical service delivery model for rural Tunisia that would increase availability and accessibility of family planning services. Results confirm that when contraceptives are distributed at the household and community levels there can be a dramatic initial increase in new acceptor rates. However the pilot project also demonstrates that effective referral mechanisms and permanent resupply points in the community together with sustained information and education activities are essential in order to achieve and maintain high levels of contraceptive use. (authors modified) (summary in FRE)