The muscarinic agonist carbachol stimulates a rapid increase in ^32Pi incorporation into phosphatidic acid (PA) and phosphatidylinositol (PI) in calcium tolerant myocytes prepared from heart tissue. The density of muscarinic receptors, determined by [^3H]-QNB binding, is greater in the atria than in the ventricles. 250 uM carbachol decreased specific [^3H]-QNB binding to muscarinic receptors on myocyte membranes by fifty percent. Trifluoperazine, also a phospholipase C inhibitor, inhibited the carbachol stimulated increase in ^32Pi incorporation into PA and PI and did not interfere with muscarinic receptor binding. Therefore, isolated canine myocytes provide a suitable model system to further study the muscarinic receptor stimulated phospholipid effect, and its role in mediating biochemical processes and physiological function in the heart.

Apart from the nutrition factor, a threshold cell density of 10 8 cells per ml was established as an independent mediator which could elicit phenotypic tolerance under nutrient-rich conditions, producing phenotypes which were markedly different from those observable under starvation in terms of drug specificity. Such cell density effects could be attributed to (i) impeded diffusion of drug and nutrient molecules, which simultaneously suppressed the deleterious effects of antibiotics and elicited cellular protection responses, and (ii) a hitherto undefined quorum sensing-like induction signal which was detectable in spent media of nutrient-supplemented but not starving populations. This finding indicates that bacteria can initiate active defense through cell density sensing even in the absence of starvation stress. / Bacteria respond swiftly to environmental perturbations, often becoming insensitive to bactericidal antibiotics. The underlying basis of this tolerance phenomenon, which presumably involves physiological adaptation mechanisms that counteract antibiotic-induced lethality in bacteria, remains poorly-defined. In this study, the fundamental issues of antibiotic tolerance development were addressed, with a focus on elucidating the environmental cues and genetic determinants that regulate this phenotypic switching process. / By examining the relationship between exogenous nutrition status and antibiotic susceptibility in bacteria, amino acids deprivation was identified as a prerequisite condition for tolerance development, during which a repertoire of drug-sepcific phenotypes evolved according to the relative abundances of other key essential nutrients. Sustainability of tolerance was highly dependent on a lack of carbon source and the duration of nutrition stress. Importantly, organisms which experienced prolonged starvation (over 24 h) were found to harbor subpopulations which remained drug-tolerant in nutrient-rich medium, suggesting that antibiotic persisters originated from starvation-induced precursor organisms. / Comparative transcriptomic analysis showed that transient tolerance elicited by amino acids starvation was characterized by global metabolic down-regulation, whereas emergence of sustainable phenotypes was tightly coupled to a metabolically active state. Gene knockout analysis on established tolerance determinants, such as hipA, phoU and glpD, revealed that their roles in tolerance development were condition and drug specific, suggesting that the cellular network governing starvation-mediated tolerance was highly complex. Studies on selected determinants further revealed the functional roles of multiple stress signaling and protection systems, including the stringent and SOS responses, heat shock proteins, oxidative defense enzymes, and several novel determinants. Among them, the SOS response was specifically required for development of tolerance to fluoroquinolones, whereas products of two novel genes, yhfZ and yqgB, were predominantly involved in protection against both fluoroquinolones and aminoglycosides. Taken together, results of gene expression and deletion studies depict the involvement of multiple protection systems in sustaining antibiotic stress for a prolonged period. This idea was supported by results of functional studies, which suggested that growth inhibition by bacteriostatic agents, impedance of antibiotic entry and neutralization of hydroxyl radicals were in each case not sufficient to produce significant phenotypic tolerance. / In conclusion, starvation and high cell density-mediated responses were identified as complementary tolerance induction factors in bacteria. Further elucidation of the core components of bacterial "multidrug tolerance regulon" should enable development of more effective strategies for combating resilient microbial infections. / Fung, Ka Chun. / Advisers: Raphael Chan; Edward Chan. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 136-152). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

DHA depletion in brain was associated with impairment on spatial learning and memory in rat. The Morris water maze test found that the n-3 deficient rats spent more time and swam a longer distance to find the hidden platform compared with the n-3 adequate group, indicating that n-3 Def rats had a poorer spatial learning ability and memory. The results suggest that learning and memory are partially related to the brain DHA status in rat. / Docosahexaenoic acid (DHA, 22-6n-3) and arachidonic acid (AA, 22:4n-6) are long-chain polyunsaturated fatty acids (LCPUFA), which are important for the structural development of mammalian central nervous system and are accumulated in large amounts in the developing brain, retina and sperm. Deficiency in DHA and AA syndromes can occur if these fatty acids and their precursors (linoleic and linolenic acid) are insufficient in diet. It had been reported that DHA deficiency in animal brain led to a poor performance in learning ability and other abnormal behavior in rodents. In addition, DHA and AA are the unique fatty acids in human milk. Many studies reported that children who were breast-fed got higher intelligent scores than those who were formula-fed. Thus, a large number of studies suggested that DHA and AA should be added into infant formula to mimic the composition of human milk. / In summary, DHA distribution, depletion and recovery were region-specific in rat brain. DHA deficiency could lead to impairment on spatial learning in rat. The underlying mechanism of learning deficit might not be attributed to changes in antioxidant enzymes in rat brain. Although impairment on spatial learning was observed in DHA-deficient rat, a meta-analysis of published data demonstrated that DHA and AA supplement in infant formula had no effect on cognitive development in children. / No significant relationship between DHA level and brain antioxidant enzyme activities was observed, including catalase (CAT), Cu-Zn superocide dismutase (Cu-Zn SOD), Mn superocide dismutase (Mn SOD) and glutathione peroxidase (GPx). These enzyme activities varied with regions of brain. A lower activity of CAT, Mn SOD and GPx in hippocampus and cortex would make them particularly susceptible to oxidation damage compared with other regions. The present results did not support the view that the spatial learning and memory impairment in DHA depletion was associated with antioxidant status in brain. / The meta-analysis indicated that breast-feeding was positively associated with a higher cognitive development than formula-feeding. However, no benefit was found for infants who received formula supplemented with DHA alone or DHA plus AA compared with those fed traditional formula based on available data. The results suggest that the beneficial effect of breast-feeding over formula-feeding can not be solely attributed to DHA and AA present in breast milk. / The objectives of present study were to (1) examine the distribution, depletion and recovery of DHA in rat brain; (2) investigate the effect DHA deficiency in rat brain on spatial learning behavior; (3) study the effect of DHA deficiency on antioxidant enzymes in rat brain; and (4) analyze whether DHA and AA supplementation has any beneficial effect on cognitive development and quantify their effect size in children by conducting a meta-analysis of the published data, and adult rats, the region with the highest DHA percentage was cortex, whereas in aged rats, both cortex and cerebellum were the regions with the highest DHA percentage. DHA concentration in rat brain increased with age. DHA was not proportionally depleted and recovered in different regions of rat brain when the rats were maintained on an n-3 fatty acid deficient diet for two generations. The present results demonstrated that the distribution of DHA and AA was region-specific. / Xiao Ying. / "August 2006." / Adviser: Zhen Yu Chen. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1566. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 140-156). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Tong, Kit Fong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 91-104). / Abstracts in English and Chinese. / Abstract --- p.i / Acknowledgements --- p.vi / Table of Contents --- p.vii / List of Figures --- p.x / List of Tables --- p.xii / List of Abbreviations --- p.xiii / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Cancer --- p.2 / Chapter 1.1.1 --- Tumor development --- p.2 / Chapter 1.1.2 --- Cell cycle --- p.4 / Chapter 1.1.3 --- Apoptosis --- p.9 / Chapter 1.1.3.1 --- The extrinsic pathway --- p.14 / Chapter 1.1.3.2 --- The intrinsic pathway --- p.16 / Chapter 1.1.3.3 --- The Bcl-2 family proteins --- p.17 / Chapter 1.1.3.4 --- Execution of apoptosis --- p.20 / Chapter 1.1.4 --- Melanoma --- p.22 / Chapter 1.2 --- Polyunsaturated fatty acids (PUFAs) --- p.24 / Chapter 1.2.1 --- "Chemistry, classification, metabolic conversion and sources …" --- p.24 / Chapter 1.2.2 --- Epidemiology studies --- p.27 / Chapter 1.2.3 --- Docosahexaenoic acid (DHA) --- p.28 / Chapter 1.2.3.1 --- Sources --- p.28 / Chapter 1.2.3.2 --- DHA and cancer --- p.29 / Chapter 1.3 --- Objectives --- p.33 / Chapter Chapter 2 --- Materials and Methods --- p.34 / Chapter 2.1 --- In vitro studies of DHA on growth and survival of human cancer cells --- p.34 / Chapter 2.1.1 --- Cell cultures --- p.34 / Chapter 2.1.2 --- Studies of growth inhibition of DHA on human cancer cells --- p.35 / Chapter 2.1.2.1 --- MTT assay --- p.35 / Chapter 2.1.2.2 --- Chemiluminescent-bromodeoxyuridine (Chemi-BrdU) immunoassay --- p.36 / Chapter 2.1.3 --- Studies of growth inhibitory mechanism of DHA on A375 cells. --- p.38 / Chapter 2.1.3.1 --- DNA -flow cytometry analysis --- p.38 / Chapter 2.1.3.2 --- Western blot analysis --- p.39 / Chapter 2.1.3.3 --- Caspase inhibitor studies --- p.42 / Chapter 2.1.3.4 --- Mitochondrial membrane potential analysis --- p.42 / Chapter 2.2 --- In vivo study of the anticancer effect of DHA on A375 cells --- p.44 / Chapter 2.2.1 --- Animals --- p.44 / Chapter 2.2.2 --- Cell inoculation and treatments --- p.44 / Chapter 2.2.3 --- Western blot analysis --- p.45 / Chapter 2.3 --- Statistical analysis --- p.46 / Chapter Chapter 3 --- Results --- p.47 / Chapter 3.1 --- In vitro studies of DHA on growth and survival of human canccr cells --- p.47 / Chapter 3.1.1 --- DHA reduced proliferation and survival of human cancer cells --- p.47 / Chapter 3.1.2 --- DHA modulated cell cycle of A375 cells --- p.52 / Chapter 3.1.3 --- DHA induced apoptosis in A375 cells --- p.55 / Chapter 3.1.4 --- Caspase activations were involved in the DHA-induced apoptosis in A375 cells --- p.59 / Chapter 3.1.5 --- "Caspase 3´ة 6, 8 and 9 were activated in DHA-induced apoptosis of A375 cells" --- p.62 / Chapter 3.1.6 --- DHA dissipated mitochondrial membrane potential in A375 cells --- p.66 / Chapter 3.1.7 --- DHA triggered the mitochondrial pathway of apoptosis --- p.68 / Chapter 3.1.8 --- DHA triggered the death receptor pathway of apoptosis --- p.71 / Chapter 3.2 --- In vivo study of the anticancer effect of DHA on A375 cells --- p.74 / Chapter 3.2.1 --- Effect of DHA on the growth ofA375 xenograft in athymic Bαlb/c mice --- p.74 / Chapter 3.2.2 --- DR4 and TRAIL were upregulated by DHA treatment in A375 solid tumor --- p.77 / Chapter Chapter 4 --- Discussion --- p.79 / References --- p.91

Ho Yi-Fong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 120-131). / Abstracts in English and Chinese. / Abstract --- p.i / Acknowledgements --- p.iv / Table of Contents --- p.v / List of Figures --- p.ix / List of Tables --- p.xi / Abbreviations --- p.xii / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Corticosteroids in ophthalmology --- p.1 / Chapter 1.1.1 --- History of the clinical use of corticosteroids --- p.1 / Chapter 1.1.2 --- Administration --- p.1 / Chapter 1.1.3 --- General biological effects of corticosteroids --- p.4 / Chapter 1.1.4 --- Application of corticosteroids in ocular diseases --- p.5 / Chapter 1.1.5 --- Side effects of ocular corticosteroid treatment --- p.6 / Chapter 1.1.6 --- General introduction to commonly used corticosteroids in ophthalmology --- p.6 / Chapter 1.1.6.1 --- Hydrocortisone --- p.6 / Chapter 1.1.6.2 --- Dexamethasone --- p.7 / Chapter 1.1.6.3 --- Triamcinolone --- p.7 / Chapter 1.1.6.4. --- Chemical structures and relative anti-inflammatory potencies --- p.8 / Chapter 1.1.7 --- Cytotoxicity of triamcinolone --- p.12 / Chapter 1.2 --- Retinal ganglion cells --- p.13 / Chapter 1.2.1 --- Basic structures of the eye --- p.13 / Chapter 1.2.2 --- Anatomical structure of retina --- p.13 / Chapter 1.2.3 --- Functions of retinal ganglion cells --- p.18 / Chapter 1.2.4 --- Culture models to study RGCs --- p.20 / Chapter 1.3 --- Aim of study --- p.25 / Chapter Chapter 2 --- Methodology --- p.26 / Chapter 2.1 --- Intravitreal injection of TA (IVTA) --- p.26 / Chapter 2.1.1 --- Materials --- p.26 / Chapter 2.1.1.1 --- Animals --- p.26 / Chapter 2.1.1.2 --- Chemicals --- p.26 / Chapter 2.1.1.3 --- Instruments --- p.26 / Chapter 2.1.2 --- Procedures --- p.26 / Chapter 2.2 --- Peripheral Nerve - Optic Nerve Grafting (PN-ON) Procedure --- p.27 / Chapter 2.3 --- Retrograde Labeling of regenerating RGCs --- p.27 / Chapter 2.3.1 --- Materials --- p.27 / Chapter 2.3.2 --- Procedures --- p.27 / Chapter 2.3.3 --- Statistical analysis --- p.28 / Chapter 2.4 --- Immunohistochemistry --- p.28 / Chapter 2.4.1 --- Materials --- p.28 / Chapter 2.4.2 --- Procedures --- p.29 / Chapter 2.4.3 --- Statistical analysis --- p.29 / Chapter 2.5 --- Histology --- p.29 / Chapter 2.5.1 --- Materials --- p.29 / Chapter 2.5.2 --- Procedures --- p.29 / Chapter 2.6 --- Primary rat retinal ganglion cell culture --- p.30 / Chapter 2.6.1 --- Materials --- p.30 / Chapter 2.6.1.1 --- Animals --- p.30 / Chapter 2.6.1.2 --- Chemicals --- p.30 / Chapter 2.6.1.3 --- Solutions and buffers --- p.30 / Chapter 2.6.1.4 --- Instruments --- p.31 / Chapter 2.6.2 --- Preparations --- p.31 / Chapter 2.6.2.1 --- Working media --- p.31 / Chapter 2.6.2.2 --- Plate coating --- p.32 / Chapter 2.6.3 --- Cell culture process --- p.32 / Chapter 2.6.3.1 --- Dissection of retinal tissues --- p.32 / Chapter 2.6.3.2 --- Purification of RGCs --- p.33 / Chapter 2.6.3.3 --- Culture condition and cell seeding --- p.34 / Chapter 2.7 --- Corticosteroid treatment --- p.34 / Chapter 2.7.1 --- Materials --- p.34 / Chapter 2.7.2 --- Preparations --- p.34 / Chapter 2.7.3 --- Treatment --- p.35 / Chapter 2.8 --- Cell viability assay and morphometric study --- p.36 / Chapter 2.8.1 --- Materials --- p.36 / Chapter 2.8.2 --- Calcein-AM staining --- p.36 / Chapter 2.8.3 --- Cell viability --- p.37 / Chapter 2.8.4 --- Morphometry study --- p.37 / Chapter 2.9 --- TUNEL Assay --- p.38 / Chapter 2.9.1 --- Materials --- p.38 / Chapter 2.9.2 --- Procedure --- p.38 / Chapter 2.9.3 --- Statistical analysis --- p.39 / Chapter 2.10 --- Quantitative Reverse transcription - Polymerase Chain Reaction (qRT-PCR) --- p.39 / Chapter 2.10.1 --- Materials --- p.39 / Chapter 2.10.1.1 --- "Chemicals, reagents, and kits" --- p.39 / Chapter 2.10.1.2 --- Primers --- p.40 / Chapter 2.10.1.3 --- Equipment --- p.41 / Chapter 2.10.1.4 --- Software --- p.41 / Chapter 2.10.2 --- Procedures --- p.41 / Chapter 2.10.2.1 --- Cell collection and RNA isolation --- p.41 / Chapter 2.10.2.2 --- Reverse Transcription --- p.42 / Chapter 2.10.2.3 --- Real-time PCR --- p.43 / Chapter 2.10.3 --- Statistical analysis --- p.43 / Chapter 2.11 --- Western blotting --- p.44 / Chapter 2.11.1 --- Sample preparation --- p.44 / Chapter 2.11.1.1 --- Materials --- p.44 / Chapter 2.11.1.1.1 --- Chemicals and materials --- p.44 / Chapter 2.11.1.1.2 --- Equipment --- p.44 / Chapter 2.11.1.2 --- Procedures --- p.44 / Chapter 2.11.2 --- Protein assay --- p.45 / Chapter 2.11.2.1 --- Materials --- p.45 / Chapter 2.11.2.1.1 --- Chemicals and materials --- p.45 / Chapter 2.11.2.1.2 --- Equipment and software --- p.46 / Chapter 2.11.2.2 --- Procedures --- p.46 / Chapter 2.11.3 --- SDS-polyacrylamide gel electrophoresis (SDS-PAGE) --- p.46 / Chapter 2.11.3.1 --- Materials --- p.46 / Chapter 2.11.3.1.1 --- Chemicals and reagents --- p.46 / Chapter 2.11.3.1.2 --- Equipment --- p.46 / Chapter 2.11.3.1.3 --- Solutions and buffers --- p.47 / Chapter 2.11.3.2 --- Gel preparation --- p.48 / Chapter 2.11.3.3 --- Electrophoresis --- p.49 / Chapter 2.11.3.4 --- Transblotting (semi-dry transfer) --- p.49 / Chapter 2.11.3.5 --- Band visualization --- p.49 / Chapter 2.11.4 --- Immunostaining --- p.50 / Chapter 2.11.4.1 --- Materials --- p.50 / Chapter 2.11.4.1.1 --- Antibodies --- p.50 / Chapter 2.11.4.1.2 --- Chemicals and reagents --- p.50 / Chapter 2.11.4.1.3 --- Equipment --- p.50 / Chapter 2.11.4.2 --- Procedures --- p.50 / Chapter 2.12 --- Gas-chromatography-electron-capture negative-ion mass spectrometry (GC-NCI-MS) --- p.51 / Chapter 2.12.1 --- Standard and reagents --- p.51 / Chapter 2.12.2 --- Chromatography and mass spectrometry --- p.52 / Chapter 2.12.3 --- Sample collection --- p.52 / Chapter 2.12.3 --- Standard and sample preparation --- p.53 / Chapter 2.12.4 --- Validation --- p.54 / Chapter Chapter 3 --- Results / Chapter 3.1 --- Effect of triamcinolone on RGCs in vivo --- p.55 / Chapter 3.2 --- Cell viability of RGCs after IVTA plus PN-ON grafting --- p.55 / Chapter 3.3 --- Abnormal retinal morphology under different IVTA conditions --- p.59 / Chapter 3.4 --- Cell viability assay --- p.66 / Chapter 3.4.1 --- Effects of triamcinolone on RGC viability --- p.66 / Chapter 3.4.2 --- Effects of dexamethasone on RGC viability --- p.68 / Chapter 3.4.3 --- Effects of hydrocortisone on RGC viability --- p.70 / Chapter 3.4.4 --- Effects of filtered fraction of triamcinolone on RGC viability --- p.72 / Chapter 3.5 --- Morphometric study analysis of RGCs --- p.74 / Chapter 3.5.1 --- Percentage of RGCs showing neurite outgrowth --- p.74 / Chapter 3.5.2 --- Average neurite length --- p.77 / Chapter 3.5.3 --- Neurite spanning area --- p.77 / Chapter 3.5.4 --- Neurite count --- p.80 / Chapter 3.5.5 --- Neurite branching --- p.83 / Chapter 3.6 --- Determination of concentration of TA in culture media by GC-NCI-MS --- p.85 / Chapter 3.7 --- TUNEL assay --- p.90 / Chapter 3.8 --- Real-time quantitative Reverse transcription - Polymerase Chain Reaction --- p.93 / Chapter 3.9 --- Western blot --- p.99 / Chapter Chapter 4 --- Discussion --- p.102 / Chapter Chapter 5 --- References --- p.120

The purpose of this study was to investigate the effects of cocaine on spatial memory consolidation using the Morris water maze. Specifically, male and female C57BL/6 mice were trained on a spatial water task, and then administered a single posttraining injection of saline or cocaine (1.25, 2.5, 5.0, or 20.0 mg/kg).

No description available.

Abstract not available

The main theme of this thesis is that there is a common structural basis for drugs acting on the central nervous system (CNS), and that this concept may be used to design new CNS-active drugs which have greater specificity and hence less side-effects. To develop these ideas, the biological basis of how drugs modify CMS neurotransmission is described, and illustrated using dopaminergic pathways. An account is then given of the use of physicochemical concepts in contemporary drug design. The complete conformational analysis of several antipsychotic drugs is used to illustrate some of these techniques in the development of a model for antipsychotic drug action. After reviewing current structure-activity studies in several classes of CNS drugs (antipsychotics, anti-depressants, stimulants, hal1ucinogens, anticonvulsants and analgesics), a hypothesis for a common structural basis of CNS drug action is proposed- This is based on a topographical comparison of the X-ray structures of eight representative CNS-active drugs, and consists of three parts: 1.there is a common structural basis for the activity of many different CNS-active drug classes; 2. an aromatic ring and a nitrogen atom are the primary binding groups whose topographical arrangement is fundamental to the activity of these drug classes; 3. the nature and placement of secondary binding determines different classes of CNS drug activity. A four-Point model for this common structural basis is then defined using 14- CNS-active drug structures that include the original eight used in proposing the hypothesis. The coordinates of this model are: R1 (0. 3.5, 0), R2 (0, -3.5, O), N (4.8. -0.3, 1.4), and R3 (6.3, 1.3, 0), where R1 and R2 represent the point locations of a hydrophobic interaction of the common aromatic ring with a receptor, and R3 locates the receptor point for a hydrogen bond involving the common nitrogen, N. Extended structures were used to define the receptor points R1, R2 and R3, and the complete conformational space of each of the 14 molecules was considered. It is then shoun that the model may be used to predict whether a given structure is likely to show CNS activity: a search over 1,000 entries in the current Merck Index shows a high probability (82%) of CNS activity in compounds fitting the structural model. Analysis of CNS neurotransmitters and neuropeptides shows that these fit the common model well. Based on the available evidence supporting chemical evolution, protein evolution, and the evolution of neurotransmitter functions, it is surmised that the aromatic ring/nitrogen atom pharmacophore proposed in the common model supports the idea of the evolution of CNS receptors and their neurotransmitters, possibly from an aromatic amine or acety1cho1ine acting as a primaeval communicating molecule. The third point in the hypothesis trilogy is then addressed. The extensive conformation-activity analyses that have resulted in well-defined models for five separate CNS drug classes are used to map out the locations of secondary binding groups relative to the common model for anti-psychotics, antidepressants, analgesics, anticholinergics, and anticonvulsants. With this information, and knowledge derived from receptor-binding data, it is postulated that drugs having specified activity could be designed. In order to generate novel structures having a high probability of CNS-activity, a process of drug design is described in which known CNS structures are superimposed topographically using the common model as a template. Atoms regarded as superfluous may be selectively deleted and the required secondary binding groups added in predicted locations to give novel structures. It is concluded that this process provides the basis for the rational design of new lead compounds which could further be optimized for potent and specific CNS activity.

Osteoporosis is a skeletal disease affecting 44 million Americans. A primary strategy to prevent osteoporosis is to develop a high peak bone mass in youth. Oral Contraceptives (OCs) alter hormones in women and could affect bone mass development. The interaction between OCs and skeletal mineralization is poorly understood. PURPOSE: Our aims were to 1) compare bone mineral density (BMD) of young women who had a history of OC use with regularly menstruating controls, 2) compare changes in BMD in controls, women who initiate OC use, and those who have a history of use, and 3) to evaluate predictive capabilities of physical activity and years of oral contraceptives use on changes in BMD. METHODS: We recruited women, 18 to 25 years of age, with a history of OC use and controls. BMD at the hip, whole-body, and spine (AP, g/cm�� and width-adjusted lateral, g/cm��) was measured by dual-energy x-ray absorptiometry. Physical activity (METs) was measured via questionnaire and grip strength was evaluated using an isometric dynamometer. RESULTS: Groups were similar in body mass index (BMI), fat mass, grip strength, calcium intake and physical activity but controls were slightly older than OC users. In analysis of covariance (ANCOVA), controlling for age and BMI, controls had significantly greater BMD than OC users at baseline at the AP and lateral spine, hip, and whole-body (p<0.05). By ANCOVA (covariates = age at baseline, change in weight), oral contraceptive users had greater bone loss at L��� in the lateral view than controls whereas, controls had greater increases in L��� volumetric BMD, BMD of the total hip, and whole body than OC users (p<0.05). Stepwise regression results did not reveal years of oral contraceptive use, grip strength, or METs to be a significant predictor of changes in BMD at any site. CONCLUSIONS: We conclude that, in the cross-sectional analysis, oral contraceptive use by young women may compromise bone health during a time when mineral is still accruing. In the prospective analysis, regularly menstruating controls had greater BMD accrual or less bone loss over a 12-month time period than women with a history of oral contraceptive use. / Graduation date: 2005