Indiana University-Purdue University Indianapolis (IUPUI) / Enhancing osteoblast proliferation, survival, and extracellular matrix protein secretion are potential therapeutic approaches to treat bone fractures and diseases such as osteoporosis. BENS is a traditional medicine used in many countries such as India for thousands of years to treat many diseases including bone diseases. In this study, molecular, cell-based and in vivo approaches were utilized to investigate the effects of BENS on bone and cartilage regeneration. An osteosarcoma cell line (MG63) was incubated in serum free media with and without 0.8 mg/ml of BENS. BENS significantly increased cell survival up to 30 days and these cells retained their ability to proliferate in fresh media with serum. After adding BENS, there were statistically significant decreases in the expression of both anti-apoptotic and pro-apoptotic proteins. An in vivo non-critical size segmental bone defect Xenopus system was used to evaluate the ability of BENS to enhance cartilage formation. After a small segment of the anterior hemisection of the tarsus bone was excised, the frogs were divided into three groups and given subcutaneous injections of either phosphate-buffered saline or BENS once daily for 30 days and then bone/cartilage formation evaluated. The total cartilage area/total section area was significantly increased (2.6 fold) in the BENS treated samples. In an osteoporotic rat model, the anabolic properties of BENS on bone mass were assessed by histomorphometric analyses. Ovariectomized (OVX) rats received daily intraperitoneal injections for 4 weeks. Bone formation rates (BFRs) for the cortical periosteal bone surface of the midshaft tibia were 383.2, 223.9, 308.8, 304.9, and 370.9 µm3/µm2/year, and for the trabecular surface were 82.2, 113, 212.1, 157, and 165 µm3/µm2/year for the sham, OVX, PTH, 3 mg/kg BENS, and 30 mg/kg BENS groups, respectively. BENS increased both trabecular and cortical BFRs. It generated better results on cortical periosteal bone surface than did PTH. Taken together, these findings suggest that BENS promotes osteoblast survival due to its effects on altering the balance between pro-apoptotic and anti-apoptotic proteins. In addition, in vivo studies revealed that BENS enhanced cartilage formation in Xenopus and BFRs in rats. Therefore, BENS may possess anabolic bone/cartilage properties.

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Indiana University-Purdue University Indianapolis (IUPUI) / It has been proposed that the accumulation of microdamage in bone of aging individuals may play a causative and synergistic role in increased fracture incidence. If microdamage production were somehow increased, or reparative remodeling was somehow decreased, the scales may tip towards pathologic fracture. It is known that bisphosphonates increase microdamage accumulation in ribs, lumbar vertebrae, and ilium. The specific aim of this study was to histomorphometrically quantify the microdamage effect of the bisphosphonates alendronate and risedronate therapy on alveolar bone surrounding the first mandibular molar in the dog to determine if this response differs from that in non-bisphosphonate treated dogs. Thirty-four dogs were randomly assigned in two test, and one control groups. Test groups received pharmacologically equivalent doses of either alendronate (11 dogs) or risedronate (11 dogs). The control group (12 dogs) received subcutaneous injections of saline solution. The mandibular right first molar was analyzed for this study. Histomorphometric measurements were made using a x150 Nikon Optiphot-2 fluorescence microscope equipped with brightfield sources (Nikon, Inc.) using the semi-automatic Bioqant digitizing system (R & M Biometrics). There was no significant differences in cortical bone area across treatment groups for any of the regions, nor were any expected. Overall, there was almost twice as much crotical bone found in the Middle (Combined) regions compared with the Coronal (Combined) regions. The precent cortical area was universally high across all treatment groups averaging in the mid-90% range. The Apical region averaged 96.05%, followed by the Coronal region with 95.04% and the Middle region with 93.80%. The number of labeled osteons per cortical area in the alendronate and risedronate groups both tended to be lower relative to the control group (0.92/mm2 and 0.93/mm2 vs. 1.26mm2, respectively), but were not significantly different. On average, the coronal regions had nearly three times the LOn/CtAr as the Middle and Apical regions (1.90/mm2 vs. 0.63/mm2 and 0.57/mm2 respectively). Only in one region was MAR statistically higher in the Coronal (1mm) region, relative to all other regions compared. The Middle region demonstrated a low MAR. The WTh was significantly higher in the risedronate and alendronate groups than that of the control group for the Coronal region. This illustrates that with respect to the bisphosphonates, there is more formation and less resorption. In one region of a significantly lower WTh for the alendronate group relative to the risedronate group was noted. This implies a more potent inhibition in the risedronate treated groups. The WTh for the entire Coronal was statistically lower than every Middle measurement, but was not different than observed in the Apical region. This would tend to signify that in the Coronal, the turnover rate is more of a rapid nature, and therefore the osteons are not as large, while in the Apical, there were so many missing values due to the low rate of turnover, the numbers are skewed to the low end. In the Coronal (Combined) region, the risedronate (108.79 days) group exhibiting a significantly higher FP than the alendronate (62.88 days) and the control (56.13 days) groups. This would imply an increased potency of risedronate over alendronate. Regionally, the FP was significantly lower in the Coronal, relative to Middle or Apical. This is consistent with a more rapid turnover in the Coronal regions observed earlier. The Acf for alendronate (6.41/mm2 per day) and risedronate (5.69/mm2 per day) both tended to be lower by approximately 40% when compared with the control group (10.11/mm2 per day). Overall, the Acf for the Coronal region was 14.15/mm2 per day vs. 2.98/mm2 per day for the Middle and 9.13/mm2 per day for the Apical regions. This shows a significantly increased amount of turnover events taking place not just in the Coronal region, but in the region immediately adjacent to the tooth in the Coronal region. In no region did bone formation differ significantly when treated with bisphosphonates. The Coronal (1mm) region was statistically greater than every region it was measured against, individual and combined. Based on this observation, the second hypothesis that within the first molar alveolar site, bisphosphonate therapy with alendronate, and risedronate would inhibit remodeling more in the coronal region than in the middle and apical region, is rejected. When measuring microdamage accumulation (CrDn), only in the Middle (1mm) region was a significant difference across treatment groups notes. There were no other statistical differences across groups for any other regions. This observation demonstrates that bisphosphonate treatment does not increase the accumulation of microcracks in the dentate alveolar bone. Therefore, the first hypothesis that within the dentate mandible, bisphosphonate therapy with alendronate and risedronate would increase microdamage accumulation around the first molar compound to control, is rejected. When CrDn was compared by region, significant differences were noted. As expected, the Coronal (1mm) region demonstrated a significantly increased CrDN compared with the Apical and Middle regions. Coupled with the information that the BFR is increased in the Coronal and Middle (1-3mm) regions would argue for a reparative function of remodeling in the Coronal and outer Middle regions, which is in response to microdamage accumulation. Significant differences were observed in the Middle (1mm) and Middle (Combined) regions, with the alendronate group demonstrating an increased CrSDn relative to control. There was no statistical difference across treatment groups for any of the regions studied. When compared by regions, the Coronal (1mm) was statistically higher than all regions it was measured against. The Middle regions demonstrated elevated CrSDn relative to the apical region, which displayed the lowest CrSDn values of all regions. One final measure of microdamage is mean crack length. There were no statistically significant differences across any groups for any regions. The only significant differences, when observed across regions, was in reference to the Middle (1mm) region, which was significantly larger than the Coronal (1mm), Coronal (Combined), and the Middle (1-3mm) region. Otherwise, there is no observable trend, and no significant difference between regions. In conclusion, this study found that there was no an increase in microdamage in the dentate mandible of the dogs with bisphosphonate therapy, thereby rejecting the first hypothesis. While there were isolated regions of remodeling inhibition, the hypothesis that bisphosphonate therapy would inhibit remodeling more in the coronal region than in the middle and apical region is rejected. Therefore, based on the findings of this study, we conclude that bisphosphonates do inhibit remodeling in the dentate alveolus generally, but inhibition is not localized to any particular region. Finally, the administration of bisphosphonates do not result in an increase in microdamage accumulation in the dentate alveolus of dogs.

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This study has examined the effect of 3 doses of Methylphenidate (MPH) on the speed of motor and cognitive performance in children diagnosed with ADHD. Thirty children clinically diagnosed with Attention Deficit/Hyperactivity Disorder (ADHD) aged 6-12 years were recruited through the ADHD Clinic and the Severe and Disruptive Behavior Disorders Program at the Douglas Mental Health University Institute. The three doses of MPH were administered according to a double blind randomized cross-over three day trial (0.3; 0.5 0.8 mg/kg/day in a bid schedule). An improvement across all three doses of MPH on motor, cognitive and behavioural measures was observed. The improvement is significant at low doses of MPH and an increase of dose up to 0.8 mg/kg/day does not lead to further improvement of the speed of simple motor task, but might be beneficial to specific cognitive tasks. No deterioration was observed in association with higher doses of MPH.

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The purpose of the present study was sixfold: 1. To study the effects of x-irradiation on spinal cord activity. 2. To study the effects of CNS drugs on spinal cord function as reflected by changes in the ventral root potentials. 3. To ascertain whether one can alter the observed spinal response to ionizing radiation by applying CNS drugs prior to, during, and following x-irradiation of a given spinal cord segment. 4. To shed some light on the role of higher brain centers on spinal reflexes. 5. To shed some light on the loci of radiation insult to the spinal cord. 6. To establish evidence for a possible drug-irradiation interaction in mammals.

by Wai-keung Leung. / Thesis (M.D.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (p. 217-232). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.