M.Tech. / Purpose: Posterior mechanical neck pain is considered a debilitating musculoskeletal problem and is one of the most common reasons for visiting an emergency department (Murphy, 2000). Anti-inflammatory creams and gels are readily available to individuals suffering from musculoskeletal pain. The purpose of this study was to determine the effectiveness of Traumeel®S ointment together with chiropractic spinal manipulative therapy as a treatment form for posterior mechanical neck pain, with regards to pain, disability and cervical spine range of motion. Method: This study was a comparative study and consisted of two groups of fifteen. The participants were between the ages of eighteen and forty-five, with a half male to female ratio. The potential participants were examined and accepted according to the inclusion and exclusion criteria. Group A received chiropractic spinal manipulative therapy followed by the application of aqueous cream over the upper trapezius muscle area of the posterior neck. This was the placebo group. Group B received chiropractic spinal manipulative therapy followed by the application of Traumeel®S ointment over the upper trapezius muscle area of the posterior neck. This was the experimental group. Objective and subjective findings were based on the above treatment protocols. Procedure: Treatment consisted of seven consultations over a three week period. Objective and subjective readings were taken at the beginning of the first, fourth and seventh consultations. Subjective readings were taken from the Vernon-Mior Neck Pain and Disability Index as well as from the Visual Analogue Scale (VAS). Objective readings were taken from measurements taken from the Cervical Range of Motion device (CROM). At the first to the sixth consultations participants received spinal manipulative therapy with either the application of aqueous cream or the application of Traumeel®S ointment depending on whether they were in group A or group B. Results: Clinically and statistically significant improvements in both group A and group B were seen over the course of the study with regards to cervical spine range of motion, pain and disability. Conclusion: The results show that both treatment protocols were effective in decreasing cervical spine pain and disability and increasing cervical spine ROM. Group B receiving Traumeel®S ointment did show a greater increase in cervical spine ROM clinically, but statistically there was no significant difference between the two groups.

Although unintentional weight loss (UWL) and depressive symptoms are critical outcomes following diagnosis and treatment for head and neck cancer (HNC), there is a limited understanding of how they influence one another over time. As part of a large, prospective study on HNC outcomes, growth curve modeling was used to evaluate 564 patients’ trajectories of depressive symptoms and percentage UWL and analyze longitudinal associations between these variables across the first year following HNC diagnosis. The hypothesized temporal precedence model was not supported—pretreatment depressive symptoms predicted neither total percentage weight loss at 6 months (t(561) = -1.50, p = .13), nor rates of curvilinear change in percentage weight loss over time (t(561) = 1.38, p = .17). The opposite temporal precedence model also lacked support—early weight loss predicted neither level of depressive symptoms at 6 months (t (432) = 0.24, p = .81), nor rates of linear change in depressive symptoms over time (t (432) = 1.31, p = .19). Instead, a pattern of concurrent covariation emerged—changes in depressive symptoms over time were associated with concurrent changes in UWL (t (1148) = 2.05, p = .041) and changes in UWL over time were associated with concurrent changes in depressive symptoms (t (556) = 2.43, p = .015). That is, to the extent that depressive symptoms increased on a monthly basis, patients lost incrementally more weight than was lost due to the passage of time, and to the extent that weight loss increased on a monthly basis, depressive symptoms also increased. Together, these bidirectional results depicted an ongoing transactional interplay between depressive symptoms and UWL across time, such that changes in either variable resulted in deviations from the average trajectory of the other variable. Patient-reported pain and eating abilities emerged as potential mechanisms through which these variables influence one another. The results have important clinical implications, indicating that ongoing screening and treatment for depression and weight loss throughout the first year after HNC could benefit patients’ psychological and nutritional outcomes alike.

It is well known that sitting posture is associated with discomfort and a number of musculoskeletal disorders. Seat manufacturers have made great strides toward developing seats for equipment which helped in alleviating the vibration transferring to the lower area of the spine; however, increased neck and head motion resulting from these seat designs may have been overlooked. Many cervical spine studies have been developed to estimate the response of the head and neck; however, these current studies do not take head and neck posture into account. The objective of this work was to study and demonstrate the difference in human biomechanical response to WBV when they use different neck postures. Four head and neck postures: up, down, to the side, and normal (straight forward) were investigated. Ten male subjects with ages ranging from 19 to 28 years were used to test each of the four postures, using the discrete sinusoidal frequencies of 2, 3, 4, 5, 6, 7, and 8 Hz at constant amplitudes of 0.8 m/s^2 RMS and 1.15 m/s^2 RMS in the x-direction (fore-and-aft). Subjects were seated in a rigid seat rigidly mounted to a vibration platform and vibration was generated using a six-degree-of-freedom man-rated shaker table. Subjects were tightly coupled to the seat back, using a neoprene vest and 5 straps, in an effort to reduce any relative motion between the seat and the subject. Subjects reported their head and neck discomfort using the Borg CR-10 scale with each of the postures, and then gave a second discomfort rating for the normal posture for each combination. Motion capture and accelerometer data were used to acquire the motion of the seat, C7 vertebrae, and center-of-head motion. The 3D motion of selected points on the heads and necks of the subjects were acquired using a twelve-camera Vicon motion capture system. Accelerometer data at the head, C7, and seat was used to verify the motion capture data. For the head-down posture, the magnitude of the discomfort function was higher than the normal posture. The head-to-side and head-up postures have shown less discomfort have shown less discomfort in the critical resonance area; however, these postures show roughly the same discomfort as the normal posture in other frequency ranges. In these postures, the subjects are using major neck-back muscles which create a stiffer system and may explain why there is a shift in the second peak in the head-to-side and head-up postures. Interestingly, the head-to-side and head-up postures show a similar trend as the normal posture, however, the peak transmissibility is attenuated. In addition, the subject's average discomfort was lower in this range compared to the normal posture. The head-down posture had the highest transmissibility and discomfort overall and suggests that workers in vibration environments should reduce any head-down postures to avoid unwanted head accelerations and discomfort. This work has demonstrated the importance of considering the head-neck posture in future seat-design studies.

Cancer cells are believed to exist in a condition of metabolic oxidative stress compared to normal cells because of inherent mitochondrial dysfunction. Cancer cells up regulate antioxidant defense mechanisms to combat the toxic effect of reactive oxygen species (ROS). Many anticancer agents block ROS detoxification mechanisms and utilize oxidative stress to cause cytotoxicity to cancer cells. However, ROS also up-regulate many pro-survival signaling pathways that may mediate resistance to chemotherapy. I hypothesize that ROS induces both cytotoxicity and pro-survival mechanisms in cells treated with chemotherapeutic agents such as the EGFR inhibitor erlotinib. This thesis explores how oxidative stress may induce both pro-survival and pro-death mechanisms in HNSCC cells and how this can be exploited to increase the cytotoxicity of erlotinib. The combined use of buthionine-[S,R]-sulfoximine, an inhibitor of glutathione and auranofin, an inhibitor of thioredoxin metabolism enhanced human head and neck cancer cell killing by a mechanism involving oxidative stress both in vitro and in vivo and sensitized cells to erlotinib in vitro. However, in other studies erlotinib as a single agent induced oxidative stress and this was mediated by NADPH oxidase 4 (NOX4). NOX4 mediated oxidative stress activated a process called autophagy which protected cancer cells from cytotoxic effect of erlotinib and inhibition of autophagy sensitized cells to erlotinib in vitro. These studies show that oxidative stress may have a dual role in cancer chemotherapy. ROS generated from various drug treatments can cause oxidative damage of cells culminating in cell death. However, it may also activate autophagy protecting cells against the stress and leading to decreased efficacy of the treatment. Hence inhibiting autophagy and hydroperoxide metabolism can be effective treatment modalities to enhance the cytotoxicity of erlotinib and achieve maximum therapeutic efficacy.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22038号 / 医博第4523号 / 新制||医||1038(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 大森 孝一, 教授 松村 由美, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Cervical spine injuries are a serious threat, as they may damage the central nervous system. In the elderly, cervical fractures due to falls are very frequent. The overall weakening of the bony and ligamentous spine decreases the resistance to fractures. Fractures of the dens of the second cervical vertebra (C2) are the most frequent individual fractures in the upper spine. Osteoporosis and impaired conditions play the main role in increasing the fracture risk. Several mechanisms may induce dens fractures: hyper-extension, lateral bending, shear, torsion, but the mechanisms of fractures have not been fully understood. Osteoporosis reduces overall bone strength. Cortical bone thinning occurs in the vertebræ, and there is a general loss of bone mass. Trabecular micro-architecture of bones loses integration, leading an increasing porosity. Mechanical properties worsen, and failure occurs more easily. In this study the role of osteoporosis on the genesis of dens fractures was investigated. An existing finite element (FE) model of the human spine was employed to simulate the effect of parameters associated with osteoporosis on the loading conditions of the dens. A baseline case was first simulated. Then, cortical thickness, cortical and trabecular bulk modulus and shear modulus were decreased in steps. Three impact scenarios were simulated: a lateral fall, a backward fall, and a forward fall. Effects of osteoporotic variations on the ligamentous spine deformations were studied. A mesh convergence analysis was performed to assess the influence of mesh size on the stresses in vertebra C2. The effect of reduced cortical and trabecular bulk moduli alone on stress distribution was not that apparent. In the dens, a reduced cortical thickness, in lateral and backward fall, caused higher maximum stresses than in the baseline. Conversely, in forward fall, reduced cortical thickness caused lower stresses than in the baseline. The effect of reducing trabecular bulk and shear moduli altogether was to decrease the stresses in dens trabecular bone. In lateral and backward fall, by reducing cortical bulk and shear moduli altogether, stresses in dens cortex decreased; whereas, in forward fall, stress decreased in dens neck cortex, and increased in dens apex and waist. It is concluded that cortical thinning, and reduced bulk and shear moduli of bone compartments considerably alter the stress distribution in C2, as well as the ligamentous spine response. The extent of such variations depends also on the impact scenarios. Finally, stresses in the model were found to be sensitive to the mesh size currently used in the human spine FE model. / Halsryggsskador är ett allvarligt problem, eftersom de kan orsaka skador på det centrala nervsystemet. Bland äldre är halskotfrakturer på grund av fall väldigt frekventa. Med åldern kommer en generell försvagning av benen och förändringar av ligamenten som leder till minskad motståndskraft mot frakturer. Densfrakturer av andra halskotan (C2) är den mest frekventa individuella frakturen av övre ryggraden. Osteoporos och annan nedsättning spelar en stor roll i den ökade frakturrisken. Flera mekanismer kan orsaka densfrakturer: hyper-extension, lateral böjning, skjuvning, vridning, men fortfarande saknas en full förståelse för frakturmekanismen. Osteoporos reducerar benstyrkan. Förtunning av det kortikala benet uppkommer i koterna, och en generell minskning av benmassan. Mikroarkitekturen av det trabekulära benet förändras och leder till en ökad porositet. Mekaniska egenskaper försämras, och frakturrisken ökar. I denna studie har inverkan av osteoporos i densfrakturer undersökts. En existerande finit element modell av den mänskliga ryggraden har använts för att studera effekten på dens av olika parameter associerade med osteoporos. En referenssimulering gjordes först som skulle representera en normal halsrygg. Därefter reducerades den kortikala tjockleken, kortikala och trabekulära bulk- och skjuvmodulen stegvis. Resultatet jämfördes sedan med referenssimuleringen. Tre olika situationer simulerades: lateralt fall, fall bakåt och fall framåt. En konvergensanalys gjordes också för att undersöka inverkan av mesh-storleken på spänningarna i C2. Effekten av en reduktion av bulkmodulen av kortikala och trabekulära benet enbart var inte så uppenbar. En reduktion av den kortikala tjockleken i fall lateralt eller bakåt skapade högre spänningar jämfört med referenssimuleringarna. Däremot, i fall framåt skapade samma parameter förändring en minskning av spänningarna. Effekten av att reducera både bulk- och skjuvmodulen för det trabekulära benet sänkte spänningarna i det trabekulära benet. I fall lateralt och bakåt, en reduktion av både bulk- och skjuvmodulen av det kortikala benet gav en sänkning av spänningar i det kortikala benet. Fall framåt minskade spänningarna i det kortikala benet för halsen av dens men ökade spänningarna för apex och midjan. Studien visade att den kortikala förtunningen och reducerad bulk- och skjuvmodul av benet förändrade spänningsfördelningen i C2. Storleken av förändringen berodde också på olyckssituation. Till sist, spänningarna visade sig vara känslig mot mesh-storleken i FE modellen som användes i studien.

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