Indiana University-Purdue University Indianapolis (IUPUI) / Human induced pluripotent stem (iPS) cells have the unique ability to differentiate into 200 or so somatic cell types that make up the adult human being. The use of human iPS cells to study development and disease is a highly exciting and interdependent field that holds great promise in understanding and elucidating mechanisms behind cellular differentiation with future applications in drug screening and cell replacement studies for complex and currently incurable cellular degenerative disorders. The recent advent of iPS cell technology allows for the generation of patient-specific cell lines that enable us to model the progression of a disease phenotype in a human in vitro model. Differentiation of iPS cells toward the affected cell type provides an unlimited source of diseased cells for examination, and to further study the developmental progression of the disease in vitro, also called the “disease-in-a-dish” model. In this study, efforts were undertaken to recapitulate the differentiation of distinct retinal cell affected in two highly prevalent retinal diseases, Usher syndrome and glaucoma. Using a line of Type III Usher Syndrome patient derived iPS cells efforts were undertaken to develop such an approach as an effective in vitro model for studies of Usher Syndrome, the most commonly inherited disorder affecting both vision and hearing. Using existing lines of iPS cells, studies were also aimed at differentiation and characterization of the more complex retinal cell types, retinal ganglion cells (RGCs) and astrocytes, the cell types affected in glaucoma, a severe neurodegenerative disease of the retina leading to eventual irreversible blindness. Using a previously described protocol, the iPS cells were directed to differentiate toward a retinal fate through a step-wise process that proceeds through all of the major stages of neuroretinal development. The differentiation process was monitored for a period of 70 days for the differentiation of retinal cell types and 150 days for astrocyte development. The different stages of differentiation and the individually derived somatic cell types were characterized by the expression of developmentally associated transcription factors specific to each cell type. Further approaches were undertaken to characterize the morphological differences between RGCs and other neuroretinal cell types derived in the process. The results of this study successfully demonstrated that Usher syndrome patient derived iPS cells differentiated to the affected photoreceptors of Usher syndrome along with other mature retinal cell types, chronologically analogous to the development of the cell types in a mature human retina. This study also established a robust method for the in vitro derivation of RGCs and astrocytes from human iPS cells and provided novel methodologies and evidence to characterize these individual somatic cell types. Overall, this study provides a unique insight into the application of human pluripotent stem cell biology by establishing a novel platform for future studies of in vitro disease modeling of the retinal degenerative diseases: Usher syndrome and glaucoma. In downstream applications of this study, the disease relevant cell types derived from human iPS cells can be used as tools to further study disease progression, drug screening and cell replacement strategies.

Background. A sizable amount of individuals in the community are presented with various kinds of physical and mental health problems which are either undetected, untreated or inadequately treated, due to the limitations on the availability and accessibility of the services in the existing health care system, or to other social and personal reasons. The current study evaluated the effectiveness of a newly developed modality of health-enhancing treatment---the Mindfulness-based Dejian Mind-Body Intervention, as compared to that of a Group Psychoeducational Treatment, in alleviating depressive mood and improving physical health of adult individuals in the community. / Conclusions. Findings of the current study suggest that compared with the Group Psychoeducational Treatment, Dejian Mind-Body Intervention might be more effective in enhancing the emotional and physical health of community individuals presented with moderate to severe depressive mood and/or problems with bowel functioning. / Method. Forty adult volunteers with various degree of depressive mood and physical problems who expressed interest in receiving either Dejian Mind-Body Intervention or Group Psychoeducational Treatment were recruited in the current study. They were matched for gender, age, education and level of depression, and were randomly assigned to either treatment group. / Results. Both the Dejian Mind-Body Intervention and Group Psychoeducation Treatment were effective in bringing about a significant reduction in depressive mood iv among treatment completers. However, differential effectiveness emerged among those presented with moderate to severe depressive mood, where Dejian Mind-Body Intervention resulted in significantly greater treatment-related reduction in depressive mood compared with the Group Psychoeducational Treatment. Besides, Dejian Mind-Body Intervention brought about significant increase in an objective QEEG measure of positive affect, and improvements in physical health (i.e., bowel functioning) that were not evidenced in the Group Psychoeducation Treatment. / Tsui, Jin Ching. / Adviser: Agnes S.Y. Chan. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3799. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 62-68). / 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.

Euclea undulata Thunb. var myrtina is a widely distributed shrub in South Africa. The roots are used by traditional healers for the treatment of diabetes. Research indicates that roots contain epicatechin, lupeol as well α-amyrin-3O-β-(5-hydroxy) ferulic acid. It was found that α-amyrin-3O-β-(5-hydroxy) ferulic acid inhibits α-glucosidase while epicatechin lowers glucose levels in the blood. Existing literature also indicates the presence of the naphthoquinone 7-methyl-juglone in the roots, although it was not detected in all cases. Due to its cytotoxic nature, 7-methyl-juglone poses a potential threat when E. undulata is used as medicinal treatment. In order to assist the effective and safe use of this plant as a treatment for diabetes, this project aims to determine whether the presence of these metabolites is seasonal. It further aims to contribute to more sustainable harvesting methods by investigating stems and leaves in addition to the roots for the presence of these metabolites. / Environmental Sciences / M. Sc. (Environmental Science)

Heroin use and dependency is a growing concern within South Africa, individuals face difficulty in remaining abstinent from the use of heroin due to constant relapse. The opioid antagonist known as the naltrexone pellet implant offers an alternative form of aid to relapse prevention in the recovery and abstinence from heroin dependency. This qualitative study explored the subjective experiences and perceptions of heroin dependent individuals, that made use of the naltrexone pellet implant. This study was rooted in the interpretive, qualitative paradigm where a phenomenological research design was used. Participants were selected using a purposive, snowball sampling technique and four individuals who had made use of the naltrexone pellet implant for the aid in heroin dependency for a minimum of three-months were interviewed. Interpretative Phenomenological Analysis (IPA) was used to extract recurrent themes across participants. The findings suggested that the use of the naltrexone pellet implant was beneficial in the aid for relapse prevention from heroin use. Furthermore, the exploration of difficulties that were faced in remaining abstinent, the attempt to make use of the naltrexone pellet implant and the physical and psychological aspects regarding the use of this alternative method of remaining abstinent were explored in this study. / Psychology / M.A. (Psychology (Research Consultation))

In many cultures and religions of the world the belief in transcendental realities, like God, the Devil and other benevolent and malevolent spirits are widespread. These realities are constructed in different ways, depending upon context. In light of the development Western industrial societies have undergone, it follows that the belief in transcendental realities may have given way to beliefs that are steeped more, in empiricism. However, understanding the belief in transcendental realities seems to be gaining renewed interest in various social science disciplines in light of the fact that claims of experiences of spirit possession are escalating. The implication this understanding has on the treatment a patient receives is likely to depend upon the training of the practitioner consulted. It follows that the experiences of patients who believe they are possessed by a spirit is as equally important to practitioners of psychology as it is to theologians. Psychologists would likely ascribe a spirit possession to a psychological experience; while theologians will attest to the presence of a spiritual illness. This project focussed on Free Church pastors in Germany and their perceptions of spirit possession and mental illness. To explore Free Church pastors understanding of spirit possession and mental illness is critical in light of the overlap of symptoms. Misdiagnosis may result in a client receiving treatment which may not be appropriate. Interviews with Free Church pastors were conducted. The results were analysed and 4 themes were identified. Based on these interviews conclusions could be drawn which ultimately made it clear that the German free church pastors’ theological training needs to be supplemented in the area of psychology and that the pastors are unable to cope in the area of ‘spirit possession or mental illness’ / Psychology / D.Litt. et Phil. (Psychology)

The purpose of the study was to develop best practice guidelines to prevent permanent hearing loss associated with the management of multi-drug resistant tuberculosis (MDR-TB) through raised awareness and monitoring. The Human Immunodeficiency Virus (HIV) and MDR-TB are global public health problems requiring urgent scale-up of treatment services. Irreversible sensorineural hearing loss (SNHL) is one of the adverse drug reactions of the current World Health Organization (WHO) recommended MDR-TB chemotherapy fuelling another public health problem, that disabling hearing loss, which is the second highest contributor of Years Lived with Disability (YLD) according to the World Health Report (2003). Expansion of MDR-TB treatment threatens to increase incidence of SNHL unless there is urgent implementation of intervention towards preservation of hearing for patients on treatment. This empirical study determined and documented the incidence of SNHL in HIV positive and HIV negative patients on MDR-TB treatment, the risk factors for SNHL, from the time treatment initiation to SNHL. Based on the findings, developed and improved the understanding of best practice guidelines for monitoring and prevention of MDR-TB treatment-related SNHL. The empirical study recruited a cohort of 173 patients with normal hearing status, after diagnosis with MDR-TB and enrolled on MDR-TB therapy over thirteen month period. Patients in the cohort received monthly hearing sensitivity testing during the intensive MDR-TB therapy when injectable aminoglycoside antibiotics are part of the treatment regimen. The three study endpoints included completion of the eight-month intensive treatment phase without developing hearing loss, development incident hearing loss or loss to follow up. Data was analysed using STATA statistical software and summarised using frequencies, means, proportions, and rates. The study documented incidence of SNHL, time to hearing loss and risk factors for hearing loss. Recommendations to prevent and monitor hearing loss are made based on the the study findings. / Health Studies / D. Litt. et Phil. (Health Studies)

The dissertation aims at showing the differences in dealing with the death issue in characteristic works of art of both Czech and world literature. Above all, it pursues the comparison of two novels Život střídá smrt ("Life Becomes Death") by Petr Prouza and Nebe nemá dno ("Heaven is Bottomless") by Hana Andronikova. Both unique books belong to key Czech novels with the topic of death. Moreover, both of them deal with death from the point of personal experience, which means they are strongly autobiographical. The dissertation concentrates on creative processes and topical aspects, grasps autobiographical elements of both novels and all the identities and differences in the approach to the same topic. Therefore, the dissertation is devoted to listing the works of art dealing with death, further on to the analyses, interpretation and comparison of the novels Život střídá smrt ("Life Becomes Death") and Nebe nemá dno ("Heaven is Bottomless") together with the reflexion of reader's experience.

Since the first so-called “medical marijuana” legislation was passed in California in 1996, a total of twenty states and the District of Columbia have passed laws permitting limited use of cannabis. Despite the changes in state laws, cannabis remains illegal for any purpose under federal law. Changes in state laws have coincided with a renewed interest in the substance for the treatment of a variety of conditions. There has been a significant increase in published data over the past twenty years examining the efficacy of cannabis as an appetite stimulant, antiemetic agent, and analgesic adjuvant. The purpose of this meta-analysis was to synthesize published data on cannabis use as an analgesic agent. Five studies meeting inclusion criteria were located through searches of online databases, review of reference lists, author correspondence, and review of clinical trials databases. Meta-analysis was conducted using fixed-effects modeling. The overall effect of mean reduction of pain intensity was -4.895 (Z-score) with an associated p value of 0.003. The combined standardized mean difference (SMD) was -0.362 (CI -0.507 to -0.217), indicating on average a moderate significant reduction in pain intensity for patients with chronic pain. As the legal status of the substance evolves, additional research is needed to establish evidence-based clinical recommendations regarding the use of medicinal cannabis in pain management.

Indiana University-Purdue University Indianapolis (IUPUI) / Skeletal manifestations including short stature, osteoporosis, kyphoscoliosis, and tibial dysplasia cumulatively affect approximately 70% of patients with neurofibromatosis type 1 (NF1). Tibial pseudarthrosis, the chronic non-union of a spontaneous fracture, is a debilitating skeletal malady affecting young children with NF1. These non-healing fractures respond poorly to treatment and often require amputation of the affected limb due to limited understanding of the causative mechanisms. To better understand the cellular and molecular pathogenesis of these osseous defects, we have established a new mouse model which recapitulates a spectrum of skeletal pathologies frequently observed in patients with NF1. Nf1flox/-;Col2.3Cre mice, harboring Nf1 nullizygous osteoblasts on a Nf1+/- background, exhibit multiple osseous defects which are closely reminiscent of those found in NF1 patients, including runting (short stature), bone mass deficits, spinal deformities, and tibial fracture non-union. Through adoptive bone marrow transfer studies, we have demonstrated that the Nf1 haploinsufficient hematopoietic system pivotally mediates the pathogenesis of bone loss and fracture non-union in Nf1flox/-;Col2.3Cre mice. By genetic ablation of a single Nf1 allele in early myeloid development, under the control of LysMCre, we have further delineated that Nf1 haploinsufficient myeloid progenitors and osteoclasts are the culprit lineages mediating accelerated bone loss. Interestingly, conditional Nf1 haploinsufficiency in mature osteoclasts, induced by CtskCre, was insufficient to trigger enhanced lytic activity. These data provide direct genetic evidence for Nf1’s temporal significance as a gatekeeper of the osteoclast progenitor pool in primitive myelopoiesis. On the molecular level, we found that transforming growth factor-beta1 (TGF-β1), a primary mediator in the spatiotemporal coupling of bone remodeling, is pathologically overexpressed by five- to six- fold in both NF1 patients and in mice. Nf1 deficient osteoblasts, the principal source of TGF-β1 in the bone matrix, overexpress TGF-β1 in a gene dosage dependent fashion. Moreover, p21Ras dependent hyperactivation of the Smad pathway accentuates responses to pathological TGF-β1 signals in Nf1 deficient bone cells. As a proof of concept, we demonstrate that pharmacologic TβRI kinase inhibition can rescue bone mass defects and prevent tibial fracture non-union in Nf1flox/-;Col2.3Cre mice, suggesting that targeting TGF-β1 signaling in myeloid lineages may provide therapeutic benefit for treating NF1 skeletal defects.

Indiana University-Purdue University Indianapolis (IUPUI) / An excess of bone resorption over bone formation leads to osteoporosis, resulting in a reduction of bone mass and an increase in the risk of bone fracture. Anabolic and anti-resorptive drugs are currently available for treatment, however, none of these drugs are able to both promote osteoblastogenesis and reduce osteoclastogenesis. This thesis focused on the role of eukaryotic translation initiation factor 2 alpha (eIF2alpha), which regulates efficiency of translational initiation. The elevation of phosphorylated eIF2alpha was reported to stimulate osteoblastogenesis, but its effects on osteoclastogenesis have not been well understood. Using synthetic chemical agents such as salubrinal and guanabenz that are known to inhibit the de-phosphorylation of eIF2alpha, the role of phosphorylation of eIF2alpha in osteoclastogenesis was investigated in this thesis. The questions addressed herein were: Does the elevation of phosphorylated eIF2alpha (p-eIF2alpha) by salubrinal and guanabenz alter osteoclastogenesis? If so, what regulatory mechanism mediates the process? It was hypothesized that p-eIF2alpha could attenuate the development of osteoclast by regulating the transcription factor(s) amd microRNA(s) involved in osteoclastogenesis. To test this hypothesis, we conducted in vitro and in silico analysis of the responses of RAW 264.7 pre-osteoclast cells to salubrinal and guanabenz. First, the in vitro results revealed that the elevated level of phosphorylated eIF2alpha inhibited the proliferation, differentiation, and maturation of RAW264.7 cells and downregulated the expression of NFATc1, a master transcription factor of osteoclastogenesis. Silencing eIF2alpha by RNA interference suppressed the downregulation of NFATc1, suggesting the involvement of eIF2alpha in regulation of NFATc1. Second, the in silico results using genome-wide expression data and custom-made Matlab programs predicted a set of stimulatory and inhibitory regulator genes as well as microRNAs, which were potentially involved in the regulation of NFATc1. RNA interference experiments indicated that the genes such as Zfyve21 and Ddit4 were primary candidates as an inhibitor of NFATc1. In summary, the results showed that the elevation of p-eIF2alpha by salubrinal and guanabenz leads to attenuation of osteoclastogenesis through the downregulation of NFATc1. The regulatory mechanism is mediated by eIF2alpha signaling, but other signaling pathways are likely to be involved. Together with the previous data showing the stimulatory role of p-eIF2alpha in osteoblastogenesis, the results herein suggest that eIF2alpha-mediated signaling could provide a novel therapeutic target for treatment of osteoporosis by promoting bone formation and reducing bone resorption.