HMG-CoA reductase inhibitors, known commonly as statins are one of the most widely prescribed medications worldwide. Statins reduce circulating cholesterol levels and are very effective at reducing one’s risk for all-cause and cardiovascular mortality. Though generally well tolerated, statin-associated muscle symptoms (SAMS) present in more than a quarter of statin users. The most common SAMS is myalgia or muscle pain. Statin myalgia often presents in the absence of myofibre damage, making its origin and treatment ambiguous. There are numerous rodent models for statin myopathy in the literature, but surprisingly there is no representation of statin myalgia that we are aware of. This is shocking given the high prevalence of statin myalgia compared to statin myopathy. Recently, our lab published an in vitro model of statin myalgia that focused on elevated xCT transporter activity and interstitial glutamate. This model explains that pain perceived in statin myalgia is the result of statins’ downstream ability to elevate skeletal muscle interstitial glutamate concentrations, thereby activating peripheral nociceptors. The studies herein aimed to create an in vivo rodent model of statin myalgia based on the aforementioned in vitro model. We hypothesized that glutamate, sampled by way of skeletal muscle microdialysis, would be elevated in the skeletal muscle interstitium of rats following statin treatment. Drawing conclusions on the role of glutamate in statin myalgia was not a straightforward process and required multiple model adjustments due to confounding variables. Additionally, many of the recognized effects of statins that were assumed from human and in vitro studies did not translate well to our rodent model. This was the first attempt at creating an in vivo model of statin myalgia and evidence suggests that a rodent model may not be an appropriate representation of what occurs in humans. While these studies also raised doubt on the efficacy of rodent models for SAMS investigations in general and highlighted the importance of having standardized models, certain limitations and assumptions of our model must be addressed before concrete conclusions can be drawn. / Thesis / Master of Science in Medical Sciences (MSMS) / Statins, a class of cholesterol-lowering medications, are one of the most widely prescribed medications worldwide. They have been demonstrated to be very effective at reducing one’s risk of cardiovascular-related death. Statins are generally very well tolerated, however, the most common negative side effects of their use are muscle related and include muscle pain, muscle inflammation and muscle damage. Muscle pain is the most common of these symptoms to present and interestingly, often presents without any clinical indication of muscle damage. The lack of a physical explanation for what is causing this pain makes treating statin-associated muscle pain quite difficult. A lot of effort has gone into determining the mechanism(s) for statin-associated muscle damage, however, there is a gap when it comes to investigating the mechanism(s) for statin-associated muscle pain. The studies herein, therefore, aimed to bridge this gap and investigated a potential mechanism for statin-associated muscle pain in a rodent model. The foundation for this model was built on a cell culture model that was previously developed in our lab. Our data suggest that a rodent model for statin-associated muscle pain may not be an appropriate representation of what occurs in humans. In particular, reduced blood cholesterol and substantial skeletal muscle oxidative stress were not demonstrated in our model as they have been in humans and in cell culture studies. This raised concern around the efficacy of rodent models for statin associated muscle symptoms in general and highlighted the importance of having standardized models. The differences between human/cell culture studies and rodent models also made it difficult to draw firm conclusions on whether the mechanism for statin myalgia investigated herein is supported.

Thesis (MSc)--University of Stellenbosch, 2005. / ENGLISH ABSTRACT: Cryotherapy is one of the popular treatments used to alleviate muscle soreness, especially in the competitive sports arena. However, the therapeutic use of cryotherapy is unsubstantiated because of a lack of proper investigations in the literature, especially a hypothesised effect on muscle recovery. Thus, our aims were to characterise satellite cell (SC) activity in human subjects with delayed onset muscle soreness (DOMS) and to shed light on the effect of cryotherapy on SC activity. DOMS was induced in six male subjects (24 ± 3 years) by completion of a downhill-run (DHR) protocol (5 x 8 min bouts, 2 min rest between bouts) at 70 or 80% of their individual peak treadmill speed. Ice application was applied to only one leg per subject for 3 days: 30 min every 2 hours, 5 times per day. In total 5 muscle biopsies were obtained from each subject: 1 baseline and 4 post-DHR. Post-DHR biopsies: 1 from each leg on day 1 and 7 (1st group, n=3) and 1 from each leg on day 2 and 9 (2nd group, n=3). DOMS was successfully induced as indicated by significant increases in muscle soreness at days 1 and 2 post-DHR (P < 0.01), and creatine kinase activity at day 1 post-DHR (P < 0.01). No difference in muscle soreness was found between treated and untreated legs. SC quiescence and activation were characterised by their expression of the cell surface markers CD34 and CD56 respectively. No significant change in quiescent SC was observed in the untreated or treated legs over time. However, at day 1 post-DHR the number of quiescent SC was significantly lower in the untreated compared with the treated leg (P < 0.05). There was a significant increase in activated SC numbers at day 2 post-DHR in the untreated leg, which was sustained up to day 9 post-DHR (P < 0.01). However, no such increase was found in biopsies taken on days 1 and 7. Also, no change was found in the treated leg, however a significant difference between the number of activated SC in untreated and treated legs on days 2 and 9 post-DHR (P < 0.01) was seen. No significant effect of DOMS or ice treatment was observed for the expression of the myogenic regulatory factors, MyoD and myogenin. C2C12 cell cultures induced to differentiate, however, did stain using these antibodies. This is the first study to report an effect of cryotherapy at the tissue level. In conclusion, this study highlights many unanswered questions on the SC response to DOMS at tissue level, and lays a good foundation for future studies. / AFRIKAANSE OPSOMMING: Kreoterapie is een van die gewilde behandelings wat gebruik word om spierseerheid te verlig, veral in die kompeterende sport arena, maar die gebruik van kreoterapie is onbevestig as gevolg van ‘n gebrek aan voldoende ondersoeke in die literatuur, veral ‘n hipotese oor die effek op spier-herstel. Ons doelstellings was dus om satellietsel (SC) aktiwiteit te ondersoek in mens proefpersone met vertraagde aanvang spierseerheid (DOMS) en ook om lig te werp op die effek van kreoterapie op SC aktiwiteit. DOMS was in ses mans proefpersone (24 ± 3 jare) geїnduseer deur voltooїng van ‘n afdraend-hardloop (DHR) protokol (5 x 8 min rondtes, 2 min rus tussen rondtes) teen 70 of 80% van elkeen se individuele maksimum trapmeul-spoed. Ys was vir 3 dae op net een been per proefpersoon aangewend: 30 min elke 2 ure, 5 keer per dag. 5 spierbiopsies in totaal was van elke proefpersoon verkry: 1 basislyn en 4 post-DHR. Post-DHR biopsies: 1 van elke been op dae 1 en 7 (1ste groep, n=3) en 1 van elke been op dae 2 en 9 (2de groep, n=3). DOMS was suksesvol geїnduseer soos aangedui deur die betekenisvolle verhogings in spierseerheid op dae 1 en 2 post-HR (P < 0.01) en kreatien kinase aktiwiteit op dag 1 post-DHR (P < 0.01). Geen verskil in spierseerheid is gevind tussen die onbehandelde en behandelde bene nie. SC dormansie en aktivering was gekarakteriseer deur die onderskeidelike uitdrukking van die sel oppervlak merkers CD34 en CD56. Geen betekenisvolle verandering is in SC dormansie in die onbehandelde en behandelde bene waargeneem nie, maar op dag 1 post-DHR was die getal dormante SC betekenisvol laer in die onbehandelde been as in die behandelde been (P < 0.05). Daar was ‘n betekenisvolle verhoging in die getalle geaktiveerde SC op dag 2 post-DHR in die onbehandelde been wat volgehou was tot op dag 9 post-DHR (P < 0.01), maar so ‘n verhoging was nie in biopsies wat op dae 1 en 7 geneem is gevind nie. Daar is ook geen verandering in die behandelde been gevind nie, maar ‘n betekenisvolle verskil in die getal geaktiveerde SC is tussen die onbehandelde en behandelde bene op dae 2 en 9 post-DHR gevind(P < 0.01). Geen betekenisvolle effek van DOMS en ys-aanwending vir die uitdrukking van die miogeniese (myogenic) regulatoriese faktore, MyoD en myogenin, is waargeneem nie. C2C12 sel kulture wat geїnduseer is om te differensieer het wel gekleur vir hierdie antiliggame. Dit is die eerste studie wat ‘n effek van kreoterapie op weefselvlak rapporteer. Ten slotte, hierdie studie beklemtoon baie onbeantwoorde vrae oor die SC respons op DOMS op weefselvlak en dit lê ‘n goeie grondslag neer vir toekomstige studies.

Dissertation submitted in fulfillment of requirements for a Master's Degree in Technology: Chiropractic, Durban University of Technology, 2007. / Delayed onset muscle soreness (DOMS) is muscular pain which ranges from mild discomfort to severe debilitating pain, caused by eccentric exercise. It generally sets in 12 - 24 hours after the causative activity and subsides within approximately seven days. The aim of this study was to determine whether proprioceptive neuromuscular facilitated (PNF) stretching immediately after eccentric exercise was more beneficial than PNF stretching 24 hours after eccentric exercise on the muscle pain experienced in DOMS. This study was a prospective, randomised clinical trial. Thirty healthy sedentary male participants were randomly selected to participate in the study by advertising in local newspapers and pamphlet distribution in Durban and its surrounding areas. The patients' ages ranged from 20 to 32 years of age. Subjective and objective readings were taken at the beginning and end of each visit, over the three-day study period. This was done with the numerical pain rating scale and the algometer force gauge, respectively. Baseline measurements were taken before any exercise or stretching at the initial visit. All participants then were asked to do squats until fatigue to induce delayed onset muscle soreness. III The participants were divided randomly into two groups, Group A and Group B. The former group underwent PNF stretching immediately after exercise and the latter group underwent PNF stretching twenty four hours after exercise. Both groups were asked to return for two subsequent days following the initial visit and they again underwent PNF stretching at each visit. Comparison was made between the individual patients' pain perception over time, as well as between each group. Descriptive analysis was done using frequency tables (reporting counts and percentages) for categorical variables and summary statistics (reporting mean, standard deviation and range), for quantitative variables. Baseline and demographic characteristics were compared between the two treatment groups using independent t-tests for quantitative variables and Pearson's chisquare tests for categorical variables. The treatment effect was assessed using repeated measures ANOVA testing. Statistical analysis revealed that there was no difference in the improvement of pain experienced between the two groups. However, Group B (PNF stretching 24 hours after exercise) appeared to improve at a greater rate than Group A (PNF stretching immediately after exercise). A larger study needs to be conducted in order to provide statistically relevant results. / M

O presente estudo foi clínico duplo-cego randomizado, placebo controlado. Avaliou o efeito analgésico do acuponto Estômago 7 (E7) em pacientes portadores de Disfunção Temporomandibular. A possível analgesia foi estudada bilateralmente nos músculos masséter e temporal anterior. A proposição se estendeu a fim de elucidar se existem diferenças nos resultados quando se utiliza um ponto em um lado da face, se o resultado repercute do outro lado da face e se a acupuntura atua no limiar de dor do indivíduo. O estudo foi aprovado pelo Comitê de Ética em Pesquisa. A amostra constou de 56 pacientes. Todos os pacientes receberam a acupuntura real e acupuntura placebo, em sessão única. O acuponto E7 foi puncionado sempre do lado direito da face dos indivíduos. Os parâmetros utilizados para a avaliação foram a Escala Visual Analógica (EVA) e o Limiar de dor à Pressão (LDP). Avaliados antes e após o tratamento. A diminuição média do parâmetro EVA do lado direito foi de 39,73. Para o lado esquerdo, a diminuição média foi de 41,81. O parâmetro LDP aumentou imediatamente. O ponto isolado de acupuntura E7 promoveu a diminuição da dor do músculo masséter dos indivíduos. Foi possível agulhar um lado do paciente e atuar no lado oposto. O limiar de dor a pressão (LDP) medida no músculo-temporal anterior foi aumentado bilateralmente. / This was a clinical, double blind, randomized, placebo controlled study. It had the purpose of assessing the analgesic effect of acupoint Stomach 7 (S7) in patients with Temporomandibular Disorders. The possible analgesia was studied bilaterally on the masseter and anterior temporalis muscles. The proposal intended to find if there are differences in the results when a point on one side of the face is used and whether there is a repercussion on the other side of the face. Moreover, if acupuncture acts on the pain threshold of individuals. The study was approved by the Ethics Committee of Researches of the School of Dentistry of the University of São Paulo under number 544519. Fifty-six patients took part in the study. All the patients received real acupuncture and placebo acupuncture in a single appointment. Acupoint St7 was stimulated always on the right side of the patients faces. The parameters used for the assessment were the Visual Analog Scale (VAS) and the Pressure Pain Threshold (PPT), assessed before and after treatment. The mean decrease of VAS parameter on the right side was 39.73; and on the left side, the mean decrease was 41.81. The parameter PPT increased immediately. The isolated point of acupuncture St7 organized decrease of pain in the masseter muscle of patients. It was possible to puncture one side of the patient and act on the opposite side. The Pressure Pain Threshold (PPT) measured on the anterior temporalis muscle increased bilaterally.

O presente estudo avaliou a eficácia do laser de baixa potência (LBP) e do placebo no tratamento da mialgia dos músculos mastigatórios. Sessenta pacientes (média de idade de 38,83 anos ± 14,2) com mialgia dos músculos mastigatórios foram selecionados e alocados em 2 grupos, de forma randomizada: Grupo A: pacientes que foram submetidos à aplicação de laser de baixa potência (LBP) na primeira fase e à aplicação de laser placebo na segunda fase e Grupo B: pacientes que foram submetidos à aplicação de laser placebo na primeira fase e à aplicação de LBP na segunda fase. O laser e o placebo foram aplicados pontualmente nos músculos masseter e temporal bilateralmente. A presença e intensidade de dor espontânea (através da escala visual analógica - EVA), dor à palpação (através do algômetro de pressão) e máxima abertura bucal (com paquímetro) foram mensurados. Os dados foram analisados usando os testes Exato de Fisher, teste t e de Mann-Witney, adotando-se p<0,05 como nível de significância. Melhoras estatisticamente significativas foram encontradas para os fatores dor espontânea, dor à palpação total e dor no masseter direito na análise intragrupo e entre grupos. Não foram encontrados efeitos residuais diferentes em nenhum dos indicadores ao compararmos os grupos que receberam ou não o laser. Apenas o masseter direito apresentou diferença estatisticamente significativa quando foi comparada a ordem das aplicações nos grupos que receberam primeiro o laser e depois o placebo versus o grupo que recebeu primeiro o placebo e depois o laser. Esse resultado indica que não existem diferenças entre a ordem de aplicação do laser. Os resultados obtidos sugerem que houve uma melhora significativa na dor medida através da escala de pontos álgicos nos pacientes que receberam o laser, entretanto a auto avaliação de dor medida pelo EVA não foi estatisticamente diferente. Os efeitos residuais e de ordem também não foram estatisticamente significativos. / This study evaluated the effectiveness of low power laser (LBP) and placebo in the treatment of myalgia of the masticatory muscles. Sixty patients (average age of 38.83 years ± 14.2) with myalgia of the masticatory muscles were selected and allocated into 2 groups randomly: Group A: patients who underwent low-power laser application (LBP) in the first phase and the application of laser placebo in the second phase and Group B: patients who were submitted to laser placebo in the first phase and the implementation of LBP in the second phase. The laser and the placebo were applied punctually in the masseter and temporalis muscles bilaterally. The presence and intensity of spontaneous pain (by visual analogue scale - VAS), pain on palpation (through pressure algometer) and maximal mouth opening (with caliper) were measured. Data were analyzed using the Fisher Test, T test and Mann-Whitney, adopting p <0.05 significance level. Statistically significant improvements were found for spontaneous pain, pain on palpation and complete pain in the right masseter in the intra-group analysis and between groups. There were no different residual effects in any of the indicators when comparing the groups with or without the laser. Just the right masseter showed a statistically significant difference when compared with the order of applications in the groups that received first laser and then the placebo versus the group that received placebo first and then the laser. This result indicates that there are no differences between the laser application order. The results suggests that there was a significant improvement in pain measured by the scale of nociceptive points in patients who received the laser, though the self assessment of pain measured by VAS was not statistically different. Residual and order effects were not statistically significant.

O presente estudo foi clínico duplo-cego randomizado, placebo controlado. Avaliou o efeito analgésico do acuponto Estômago 7 (E7) em pacientes portadores de Disfunção Temporomandibular. A possível analgesia foi estudada bilateralmente nos músculos masséter e temporal anterior. A proposição se estendeu a fim de elucidar se existem diferenças nos resultados quando se utiliza um ponto em um lado da face, se o resultado repercute do outro lado da face e se a acupuntura atua no limiar de dor do indivíduo. O estudo foi aprovado pelo Comitê de Ética em Pesquisa. A amostra constou de 56 pacientes. Todos os pacientes receberam a acupuntura real e acupuntura placebo, em sessão única. O acuponto E7 foi puncionado sempre do lado direito da face dos indivíduos. Os parâmetros utilizados para a avaliação foram a Escala Visual Analógica (EVA) e o Limiar de dor à Pressão (LDP). Avaliados antes e após o tratamento. A diminuição média do parâmetro EVA do lado direito foi de 39,73. Para o lado esquerdo, a diminuição média foi de 41,81. O parâmetro LDP aumentou imediatamente. O ponto isolado de acupuntura E7 promoveu a diminuição da dor do músculo masséter dos indivíduos. Foi possível agulhar um lado do paciente e atuar no lado oposto. O limiar de dor a pressão (LDP) medida no músculo-temporal anterior foi aumentado bilateralmente. / This was a clinical, double blind, randomized, placebo controlled study. It had the purpose of assessing the analgesic effect of acupoint Stomach 7 (S7) in patients with Temporomandibular Disorders. The possible analgesia was studied bilaterally on the masseter and anterior temporalis muscles. The proposal intended to find if there are differences in the results when a point on one side of the face is used and whether there is a repercussion on the other side of the face. Moreover, if acupuncture acts on the pain threshold of individuals. The study was approved by the Ethics Committee of Researches of the School of Dentistry of the University of São Paulo under number 544519. Fifty-six patients took part in the study. All the patients received real acupuncture and placebo acupuncture in a single appointment. Acupoint St7 was stimulated always on the right side of the patients faces. The parameters used for the assessment were the Visual Analog Scale (VAS) and the Pressure Pain Threshold (PPT), assessed before and after treatment. The mean decrease of VAS parameter on the right side was 39.73; and on the left side, the mean decrease was 41.81. The parameter PPT increased immediately. The isolated point of acupuncture St7 organized decrease of pain in the masseter muscle of patients. It was possible to puncture one side of the patient and act on the opposite side. The Pressure Pain Threshold (PPT) measured on the anterior temporalis muscle increased bilaterally.

O presente estudo avaliou a eficácia do laser de baixa potência (LBP) e do placebo no tratamento da mialgia dos músculos mastigatórios. Sessenta pacientes (média de idade de 38,83 anos ± 14,2) com mialgia dos músculos mastigatórios foram selecionados e alocados em 2 grupos, de forma randomizada: Grupo A: pacientes que foram submetidos à aplicação de laser de baixa potência (LBP) na primeira fase e à aplicação de laser placebo na segunda fase e Grupo B: pacientes que foram submetidos à aplicação de laser placebo na primeira fase e à aplicação de LBP na segunda fase. O laser e o placebo foram aplicados pontualmente nos músculos masseter e temporal bilateralmente. A presença e intensidade de dor espontânea (através da escala visual analógica - EVA), dor à palpação (através do algômetro de pressão) e máxima abertura bucal (com paquímetro) foram mensurados. Os dados foram analisados usando os testes Exato de Fisher, teste t e de Mann-Witney, adotando-se p<0,05 como nível de significância. Melhoras estatisticamente significativas foram encontradas para os fatores dor espontânea, dor à palpação total e dor no masseter direito na análise intragrupo e entre grupos. Não foram encontrados efeitos residuais diferentes em nenhum dos indicadores ao compararmos os grupos que receberam ou não o laser. Apenas o masseter direito apresentou diferença estatisticamente significativa quando foi comparada a ordem das aplicações nos grupos que receberam primeiro o laser e depois o placebo versus o grupo que recebeu primeiro o placebo e depois o laser. Esse resultado indica que não existem diferenças entre a ordem de aplicação do laser. Os resultados obtidos sugerem que houve uma melhora significativa na dor medida através da escala de pontos álgicos nos pacientes que receberam o laser, entretanto a auto avaliação de dor medida pelo EVA não foi estatisticamente diferente. Os efeitos residuais e de ordem também não foram estatisticamente significativos. / This study evaluated the effectiveness of low power laser (LBP) and placebo in the treatment of myalgia of the masticatory muscles. Sixty patients (average age of 38.83 years ± 14.2) with myalgia of the masticatory muscles were selected and allocated into 2 groups randomly: Group A: patients who underwent low-power laser application (LBP) in the first phase and the application of laser placebo in the second phase and Group B: patients who were submitted to laser placebo in the first phase and the implementation of LBP in the second phase. The laser and the placebo were applied punctually in the masseter and temporalis muscles bilaterally. The presence and intensity of spontaneous pain (by visual analogue scale - VAS), pain on palpation (through pressure algometer) and maximal mouth opening (with caliper) were measured. Data were analyzed using the Fisher Test, T test and Mann-Whitney, adopting p <0.05 significance level. Statistically significant improvements were found for spontaneous pain, pain on palpation and complete pain in the right masseter in the intra-group analysis and between groups. There were no different residual effects in any of the indicators when comparing the groups with or without the laser. Just the right masseter showed a statistically significant difference when compared with the order of applications in the groups that received first laser and then the placebo versus the group that received placebo first and then the laser. This result indicates that there are no differences between the laser application order. The results suggests that there was a significant improvement in pain measured by the scale of nociceptive points in patients who received the laser, though the self assessment of pain measured by VAS was not statistically different. Residual and order effects were not statistically significant.

A central component of many psychological interventions is breathing training. Breathing training protocols based on a mindfulness or a cognitive behavioral therapy (CBT) have demonstrated value in the management of psychological and medical ailments. Yet, despite the wealth of literature examining each approach, little direct comparison exists. An additional concern is the proliferation of smart phone health (mHealth) applications (apps) providing breathing training with little empirical evidence to support their clinical use. A possible explanation for the interest in breathing and mHealth apps is the growing body of literature indicating breathing training provides wide ranging health benefits through improved stasis of the autonomic nervous system (ANS). As ANS dysregulation underlies many chronic health conditions such as persistent temporomandibular disorders (TMDs), there is a need for empirical research to identify the most effective modality of breathing training and validate the clinical efficacy of breathing based mHealth apps. Study One compared the effectiveness of a mindfulness breathing meditation (MB) and a CBT based protocol teaching diaphragmatic breathing (DB) to improve biomarkers of ANS stasis. An attention control approach based on the Nolen-Hoeksema task (C) was included as a comparison group. Ninety participants were randomly assigned to either the MB, DB, or C condition. Within each condition, 30 participants were provided skills training with practice time and completed a behavioral self-regulation task. Participants in the DB condition approach had significantly lower breathing rates than those in the MB and C conditions (p < .001). DB condition participants experienced improvements on high-frequency heart rate variability (p < .05) and the standard deviation in NN intervals (p < .001), which served as indicators for ANS stasis. No differences were found between conditions on the behavioral self-regulation task (p’s > .05). Given these results, the DB training protocol was converted into a mHealth app to facilitate a clinical trial with patients suffering persistent TMDs. Study Two examined the additive benefits of including the mHealth app with standard dental care (SDC+) versus standard dental care alone (SDC). Nineteen patients seeking care for persistent TMDs were recruited. All participants were asked to track daily ratings of pain (VAS), relaxation (RR), and complete weekly assessments on several comorbid psycho-social factors. Within the SDC+ condition participants were asked to track the proximate effects of each breathing practice on VAS and RR ratings. Given a high drop-out rate (nine participants) and low overall sample size (N = 10), results are exploratory at best. Within the SDC+ condition, results indicated reliable improvements in average VAS and RR ratings from before and after SDC+ participants used the mHealth app (p’s < .05). Within a one session training paradigm, results supported the use of a DB based intervention above the use of a MB or C intervention. Future research should consider the effects of having multiple training sessions. Study Two results were complicated by a limited sample size and failed to provide a clear picture of whether the conjunctive treatment in the SDC+ condition provided additional symptom relief above traditional dental care alone. Although exploratory results indicated the mHealth app provided temporary improvements in pain and feelings of relaxation, a well powered trial is needed to clarify whether the finding represents an enduring treatment effect.

Abstract not available

Thesis (M.S.)--University of Missouri-Columbia, 2009. / Thesis advisor: Dr. Catherine Peterson. The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. "May 2009" Includes bibliographical references.