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

Currently, opioids are extensively used in clinical practices in order to treat pain in patients. However, prolonged administration of opioids are not feasible due to the development of side effects especially tolerance, constipation, addiction and dependence. Our drug design is mainly aimed to reduce opioid induce side effects such as development of tolerance. The first strategy examined involves design and synthesis of peptide based single molecules that have a mu agonist and delta agonist pharmacophore in combination with a COX2 inhibitory pharmacophore. A new molecule, 3-17 having good delta agonist activity, partial COX2 inhibitory activity and weak mu agonist activity was produced. Moreover, Investigation of the bioactivities of the synthesized ligands including 3-17 in terms of their ligand receptor interactions were probed using NMR conformational analysis along with docking analysis to the respective homology modeled mu and delta opioid receptors as well as the COX2 enzyme. As a further continuation of this work, instead of peptide based mu agonist and delta agonist type pharmacophore, the highly mu selective fentanyl pharmacophore was used in combination with a pyrazole based and a pyrazolone based COX pharmacophore. Based on the SAR study and docking analysis of synthesized ligands to the homology modeled mu opioid receptor, an ideal tolerant position without significant loss of mu opioid agonist activity for fentanyl were found. The second strategy involves design and synthesis of a peptide based single molecule that has a mu agonist and a delta antagonist pharmacophore in combination with a NK1 antagonist pharmacophore. A novel molecule (4-2) containing delta antagonist activity, weak mu agonist activity and NK1 antagonist activity was identified. Its homology modeled mu opioid receptor bound conformation was compared with that of reference ligands. Docking analysis of modified 4-2 to the homology modeled mu opioid receptor revealed that it can be further modified to obtain better mu agonist activity. 4-2 showed antinociception for 45 min period of time after injection in tail flick assay. In addition to studies that were directed to avoid tolerance development due to opioid administration, peptide based potential analgesics such as biphalin was modified by introducing more peptidomimetic character in order to enhance its blood brain barrier permeability and proteolytic stability. The novel molecule (6-7) was produced in this study and its antinociception lasted for 30 min period of time after injection in the tail flick assay.

No description available.

Thesis (MNutr (Interdisciplinary Health Sciences. Human Nutrition))--Stellenbosch University, 2008. / Background This study aimed to define the prevalence of side-effects and the change in weight and BMI during radical radiotherapy for head and neck malignancies (HNM) at Tygerberg Academic Hospital (TBH), Western Cape, South Africa. Acute side-effects may delay or prevent the delivery of a complete curative radiotherapy dose. Weight loss has been shown to significantly worsen prognosis and increase prevalence of treatment complications. However, weight maintenance may lead to beneficial outcomes. Assessing the impact of radical radiotherapy on patients with HNM is therefore critical and can promote development and implementation of medical and nutritional interventions. Methods Patients were weighed before and weekly during radiotherapy. Blood was drawn before, during and at the end of radiotherapy so that the Prognostic Inflammatory and Nutritional Index (PINI) could be calculated. Selected clinical data, clinical grades of mucositis and the diagnosis of a fungal infection of the oral cavity were extracted from clinical records. The McMaster Head and Neck Radiotherapy Questionnaire and a Lifestyle and Dietary Questionnaire were administered weekly. Descriptive statistics and the following were used: ANOVA, Repeated Measures ANOVA and McNemar Chi-square tests. Results Thirty-eight patients were recruited and 21 completed the study. Follow-up occurred over a maximum of nine weeks. A decrease in the weight (p = 0.01) and BMI (p = 0.01) and increase in the PINI (p = 0.04) occurred during radiotherapy. The mean absolute weight loss was 3.2kg (4.8), the mean percentage weight loss was 4.5% (6.7) and the mean decrease in BMI was 1.2kg/m2 (1.8). There was an increase in the prevalence of malnutrition (p = 0.02), as defined in this study. Oral mucositis occurred in all participants from Week 4; the majority developing Grade II or III Mucositis. Fungal infection of the oral cavity was prevalent throughout radiotherapy, with the highest prevalence (30%) in Week 4. Increases in severity of symptoms related to the mouth (p = 0.0000), throat (p = 0.05) and skin domains (p = 0.0000) occurred. Fifty-nine percent of inpatients and 45% of outpatients were prescribed supplementation drinks and most participants reported that a dietitian had not consulted them, in each week of radiotherapy. Discussion Severe side-effects in the mouth, throat and skin were experienced and a decline in nutritional status was observed. The poor nutritional status prior to commencing and weight loss during radiotherapy could have increased the severity of side-effects. The induction of the acute phase response indicated that this could have contributed to the decline in nutritional status observed. In addition, the infrequent nutritional support is likely to have further contributed to the lack of weight maintenance. Conclusion This first study conducted in South Africa has demonstrated the prevalence of significant side-effects and change in weight and BMI in this patient population. It is recommended that more effective analgesic medication is prescribed and that measures are taken to improve oral hygiene of participants to prevent fungal infection of the oral cavity. Improved nutritional support in terms of regular dietetic follow-up of all patients and more frequent prescription of supplementation drinks during radiotherapy is also recommended.

Pharmacovigilance is “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem”. To date, no comprehensive study has been performed to evaluate the pharmacovigilance system in the public health sector in South Africa. The primary aim of this study was to evaluate the current status of pharmacovigilance systems within the public healthcare sector in South Africa, and the level of functioning of these systems, in order to provide relevant recommendations, where necessary, for improvement, using the Indicator-based Pharmacogivilance Assessment Tool (IPAT). National and provincial entities were deemed compulsory (n=14), while facilities were selected via random, stratified sampling to obtain a representation at each facility level (n=101). The IPAT was amended for relevance at each level of data collection. Indicators are classified as core and supplementary and compliance with core indicators shows the level of functioning National entities obtained an IPAT score of 36 out of a maximum of 72, achieving 50% compliance. Province D and Province G obtained overall IPAT scores of 29 and 12 respectively out of a maximum of 40, achieving an overall 72.5% and 30% compliance respectively Results at provincial and facility levels were not fully representative due to a limited response rate of 22.2% and 65.3% respectively. Regional/tertiary facilities and district facilities displayed increased awareness and implementation of pharmacovigilance activity than the lower levels of Community Health Centres (CHCs) and Primary Health Centres (PHCs). South Africa”s public healthcare system possesses the infrastructure for a well functioning pharmacovigilance system. However there are gaps in level of functioning at a national, provincial and facility level. Addressing these gaps would show a marked improvement in the system and go a long way towards the contribution of medicine safety information not only locally, but to aid other developing nations.

Orientador: Alan Roger dos Santos Silva / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-23T07:58:37Z (GMT). No. of bitstreams: 1 Faria_KarinaMorais_M.pdf: 4445653 bytes, checksum: 36b816cb52f434b02b350071fe5e34ea (MD5) Previous issue date: 2013 / Resumo: O tratamento do câncer de cabeça e pescoço está associado a uma série de toxicidades bucais. Neste contexto, evidências clínicas recentes demonstraram que a radioterapia em cabeça e pescoço provoca alterações na microvascularização e na inervação pulpar. Entretanto, estas alterações não foram demonstradas por meio de estudos morfológicos do tecido pulpar oriundo de pacientes oncológicos. Portanto, esta dissertação se propôs a investigar os efeitos diretos da radioterapia sobre a microvascularização, a inervação e a matriz extracelular da polpa de pacientes com câncer de cabeça e pescoço que foram submetidos à radioterapia. Foram utilizadas 40 amostras de polpa dental humana que foram divididas em dois grupos. No grupo irradiado, foram utilizadas 23 amostras de polpa obtidas de pacientes que haviam concluído radioterapia na região de cabeça e pescoço. O grupo controle foi composto por 17 amostras de polpas obtidas de pacientes sem histórico de radioterapia. Os espécimes dos dois grupos foram processados histologicamente e submetidos à coloração por meio da técnica da hematoxilina e eosina para avaliação morfológica da microvascularização, da inervação e da matriz extracelular das polpas. Adicionalmente, foi realizada análise da expressão imunoistoquímica (IHQ) de proteínas relacionadas à vascularização (CD-34 e actina músculo liso), à inervação (S-100; NCAM/CD56 e neurofilamento) e à matriz extracelular (vimentina) da polpa. O estudo morfológico identificou a presença e a preservação da microvasculatura, dos feixes neurais e da matriz extracelular em todas as amostras. A análise IHQ confirmou os achados morfológicos e demonstrou expressão preservada dos marcadores analisados em todas as amostras. Em conclusão, os efeitos diretos da radioterapia não são capazes de gerar alterações morfológicas na microvasculatura, na inervação e na matriz extracelular da polpa dental de pacientes com câncer de cabeça e pescoço / Abstract: The treatment of head and neck cancer is associated with a series of oral toxicities. In this context, recent clinical evidence demonstrated that head and neck radiotherapy causes changes in the microvasculature and innervation. However, such changes have not been demonstrated by morphological studies of the pulp tissue derived from cancer patients. Therefore, this essay aimed to investigate direct effects of radiation on the microvasculature, innervation and extracellular matrix of the pulp from patients with head and neck cancer who underwent radiotherapy. Forty samples of human dental pulp were used and were divided into two groups. In the irradiated group, 23 samples from patients who concluded head and neck radiotherapy were used. The control group was composed with 17 pulp samples obtained from patients without previous history of radiotherapy. Samples from both groups were histologically processed and stained with hematoxylin and eosin for a morphological evaluation of the microvasculature, innervation and extracellular matrix of the pulps. Subsequently, an immunohistochemical (IHC) analysis of proteins related to vascularization (CD-34 and smooth muscle actin), innervation (S-100, NCAM/CD56 and neurofilament) and extracellular matrix (vimentin) of the pulps was performed. The morphological study identified the presence and preservation of the microvasculature, nerve bundles and extracellular matrix of all studied samples. The IHC analysis confirmed the morphological findings and demonstrated a preserved expression for the studied markers in all samples. In conclusion, direct effects of radiotherapy are not able to generate morphological changes in the microvasculature, innervation or extracellular matrix of the dental pulp from patients with head and neck cancer / Mestrado / Estomatologia / Mestra em Estomatopatologia

There is limited research using small-scale simulation in applied behavior analysis. We used small-scale simulation to train firearm safety skills to 3 to 5-years-old children and assessed whether the skills generalized to the natural environment through in situ assessment. Three participants completed the training and all participants learned the safety skills from simulation training. Two of the participants acquired the safety skills after the first simulation training and the third participant required one booster training before demonstrating the safety skills in the natural environment.

Attention Deficit/Hyperactivity Disorder (ADHD) was originally thought to occur only in children, but is increasingly recognised as causing functional impairment also in adulthood. The overall aim of this thesis was to achieve a comprehensive understanding of ADHD in adulthood. A questionnaire based on the DSM-IV criteria of ADHD, reported childhood symptoms, reading and spelling problems, difficulties and suffering and general assessment of functioning (GAF) was distributed to three samples: the general population (GP), outpatient psychiatry (OPP) and female prison inmates. Symptoms consistent with ADHD were more than three times higher in the OPP sample than in the GP sample (6.6 versus 2.1%). ADHD symptoms and related problems occurred in 50% of the prison inmates. A cohort of 168 patients diagnosed with ADHD in adulthood was interviewed about current ADHD symptoms and psychiatric comorbidity on axis I and II. The lifetime prevalence of psychiatric comorbidity on axis I was 92% and current comorbidity, including autism spectrum disorders and Tourette’s syndrome, was 47%. The sex-specific pattern of the comorbid disor-ders was similar to that in the general population. Forty-six per cent of the patients endorsed the specific criteria for at least one personality disorder. After a mean follow-up of six years, there was remission of adult ADHD in about 30% of the patients, regardless of whether there was ongoing medication or not. There were no differences in function and quality of life, except for global general improvement, which was better in patients currently on medication. The most prevalent long-term side effects of pharmacological treatment with mainly stimulants were decreased appetite, dry mouth, anxiousness/restlessness and an increase in pulse frequency. The discontinuation rate was about 50%: 29% discontinued because of a perceived lack of effect, followed by elevated mood or hypomania (11%). No detectable evidence of tolerance and increased need for dosage over time was observed. To conclude, Symptoms of ADHD is highly overrepresented in OPP and in female inmates compared with the GP. Furthermore, adults diagnosed with ADHD have a high lifetime prevalence of psychiatric comorbidity. Long-term pharmacological treatment with stimulants is safe with relatively mild and tolerable adverse effects. Continued medication, however, is not related to remission.

Pharmacological interventions to treat Human Immunodeficiency Virus (HIV) with antiretrovirals (ARVs), have dramatically improved the survival rates of HIV positive children maturing into adulthood. However, HIV-associated neurocognitive decline still persists in the era of ARVs. Within the framework of brain plasticity, a number of researchers have begun to assess the feasibility of cognitive rehabilitation therapy as a complement to ARVs to reverse neurocognitive decline as a result of HIV (e.g., Becker et al., 2012). Only one study has been conducted in South Africa, by Zondo & Mulder (2014), assessing the efficacy of cognitive rehabilitation in a paediatric sample. The current research builds on the above mentioned study by implementing an experimental approach to examine the effect of cognitive rehabilitation in a sample of both HIV positive and HIV negative children. Five HIV positive and six HIV negative children were assigned to either an experimental or control group. The experimental group underwent two months of cognitive rehabilitation therapy remediating sustained attention, whereas the control group took part in placebo activities. Sustained attention measures were taken before and after the intervention training sessions, using a sustained attention subtest from the Test of Everyday Attention for Children (TEA-CH). A Mann Whitney U Test revealed that the experimental group (Mdn=38.50) did not differ significantly from the control group (Mdn = 37.00) after the cognitive rehabilitation intervention, U=12.00, z= -.55, p= .66, r= -.17. But a Wilcoxon Signed Rank Test found that there was a significant improvement from pretest scores (Mdn=31.00) to posttest scores (Mdn=38.00) following the rehabilitation for HIV positive participants in the sample, T=15.00, z = -2.02, p= .04, r= -.90. This raises the possibility that cognitive rehabilitation could be used as a low cost intervention in underdeveloped contexts

Currently, clinical trials in patients are required by most regulatory authorities for the assessment of bioequivalence of topical products where the drug is not intended for systemic absorption. Hence there is a dire need for suitable methods for the assessment of bioavailability and bioequivalence of such products since clinical safety and efficacy studies are expensive, time-consuming and require very large numbers of patients. Except for topical corticosteroid products where the human skin blanching assay/vasoconstrictor assay has been approved by the US FDA for bioequivalence assessment of those products, no other method has been “officially” approved for use in those investigations. However, a few alternative methods such as tape stripping and microdialysis have been pursued and considered to have the potential for use in ioequivalence/bioavailability studies. The human skin blanching assay was used to assess the bioequivalence of commercially available topical products containing 0.05% clobetasol propionate. Both visual and chromameter data were obtained and a commercially available topical corticosteroid product, Dermovate® cream was used as both the “Test” and the “Reference” product. The results indicated that both visual and chromametric assessments were comparable to each other and that either could be used for the assessment of the bioequivalence of topical products containing clobetasol propionate. The screening procedure was optimized to identify potential “detectors” for inclusion in the bioequivalence studies. This resulted in fewer subjects being required in a bioequivalence pivotal study, still having the necessary power to confirm bioequivalence using the human skin blanching assay. Another objective of this research was to re-visit tape stripping and other possible alternative methods such as dermal microdialysis and to optimize these procedures for bioequivalence assessment of topical formulations where the drug is not intended for systemic absorption. In the past few decades, tape stripping has been used to investigate bioavailability/bioequivalence of various topical formulations. This technique involves the removal of the stratum corneum to assess drug penetration through the skin. A draft FDA guidance for tape stripping was initially published but was subsequently withdrawn due to high variability and poor reproducibility. This research project used an optimized tape stripping procedure to determine bioavailability and establish bioequivalence between three commercially available formulations containing 0.05 % m/m clobetasol propionate. Furthermore, tape stripping was validated by undertaking a study to assess the bioequivalence of a 0.05% topical cream formulation (Dermovate® cream) using the same cream as both the “Test” and “Reference” product, in which bioequivalence was confirmed. The findings highlight the potential of tape stripping as an alternative method for the assessment of bioequivalence of clobetasol propionate formulations and may possibly be extended for use in other topical products. Microdialysis is another useful technique that can assess the penetration of topically applied substances which diffuses through the stratum corneum and into the dermis. Microdialysis has previously been successfully used for in vivo bioavailability and bioequivalence assessments of topical formulations. However, the drugs which were under investigation were all hydrophilic in nature. A major problem with the use of microdialysis for the assessment of lipophilic substances is the binding/adherence of the substance to the membrane and other components of the microdialysis system. As a result, this necessitates the development of a microdialysis system which can be used to assess lipophilic drugs. Intralipid® 20% was investigated and successfully utilized as a perfusate to recover a lipophilic topical corticosteroid, clobetasol propionate, in microdialysis studies. Hence, the bioavailability of clobetasol propionate from an extemporaneous preparation was determined in healthy human volunteers using microdialysis. These findings indicate that in vivo microdialysis can be used to assess lipophilic drug penetration through the skin. A novel approach to investigate drug release from topical formulations containing 0.05% clobetasol propionate using in vitro microdialysis was also undertaken. The in vitro findings were found to be in agreement with the results obtained using tape stripping to assess bioequivalence of the same commercially available products, namely Dermovate® cream, Dovate® Cream and Dermovate® ointment. These results indicate the potential to correlate in vitro with in vivo data for bioequivalence assessment of such topical dosage forms.