A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Background Infertility, or impaired fecundity, affects 11.8% of women between the ages of 15 and 44, which translates to 7.3 million women. The use of assisted reproductive techniques has doubled over the past decade, with 148,055 cycles performed during 2008 resulting in 46,326 live births and the delivery of 61,426 infants. Acupuncture has been used in China to treat numerous and disparate medical conditions for thousands of years. Many anecdotal reports and non-randomized studies have claimed that acupuncture improves fertility, but the number of high-quality randomized controlled clinical trials and cohorts is much thinner. Objectives To determine whether the use of acupuncture results in higher pregnancy rates in patients undergoing in vitro fertilization compared with placebo acupuncture or no treatment. Search strategy All randomized controlled trials and prospective cohort reports of acupuncture and assisted reproductive technology were obtained through a systematic search of Medline and the MeSH database (1996 to February 2011). Selection criteria Prospective, randomized controlled trials comparing acupuncture treatment versus no treatment, placebo acupuncture, sham acupuncture at non-acupoints, and sham acupuncture at non-fertility-related acupoints during IVF treatment with or without intracytoplasmic sperm injection (ICSI). Inclusion criteria: - primary or secondary subfertility - undergoing IVF with or without ICSI - timing of acupuncture for before and after embryo transfer Exclusion criteria: - frozen embryo transfer - acupuncture used as adjunct to analgesia - electroacupuncture - donor oocytes - non-randomized trials, case-controls, case studies - studies included in the 2009 Cochrane review Data collection and analysis Thirteen randomized controlled trials were identified that involved acupuncture and in vitro fertilization with embryo transfer. Trials were analyzed for the following methodological details and quality criteria: study characteristics (randomization, blinding, power analysis, intention-to-treat analysis), patient characteristics (demographics, inclusion and exclusion criteria), interventions (IVF stimulation protocols, timing of acupuncture or control, acupoints chosen), and outcomes (ongoing pregnancy rates, live birth rates). Main results Only one of the trials demonstrated a result that achieved statistical significance. So 2009 showed that placebo acupuncture resulted in significantly higher overall birth rate when compared to true acupuncture. Even with adequate power, none of the other trials showed a difference that achieved statistical significance in pregnancy rate or live birth rates between acupuncture and control groups. Conclusions Acupuncture does not improve IVF outcomes and should not be offered routinely as an adjunct to fertility treatment. The evidence from the current literature suggests a positive effect of sham and placebo acupuncture on IVF outcomes, and therefore merits further study with adequately powered RCTs.

acase@tulane.edu / This dissertation models integrative strategies pertaining the Classic Period (AD 200-900), Copan polity of western Honduras on the frontier of the Maya world. Past scholarship on integrative strategies is largely based on comparative analyses of empires, the largest and most diverse political entities of the ancient world. However, as is argued on the basis of new fieldwork, integrative strategies can be successfully employed at smaller scale polities, such as Maya polities, since these strategies are not sensitive to either population size or heterogeneity. The unique location of the Copán polity on the southeastern frontier of the Maya world in a multi-ethnic area, makes it an attractive area to study Classic Maya integrative strategies. The surrounding populations were non-Maya at the time of Copán’s dynastic foundation making subsequent structural transformations to political systems and styles in those regions highly visible in the archaeological record. The Cucuyagua and Sensenti valleys on the southeastern frontier of the Copán polity were systematically surveyed and excavated as part of this research. A model was created to evaluate whether the Copán polity cultivated territorial relations, hegemonic or transactional relation with the respective valleys. Using this model, I discovered greater convergences in settlement patterns, artistic styles, and economic interaction between Late Classic settlement in the Cucuyagua and Copán valleys than with the more distant Sensenti valley. The construction of a Copán-style secondary center in the Early Classic with nucleated settlement, Copán-style sculpture, and Copán-style palace suggests that this valley was territorially integrated within the Copán polity. In contrast, elites from the Sensenti valley emulated Copán-style residential architecture and consumed Madrugada model-carved pottery that was produced in Copán for inter-elite gift-giving. However, its Late Classic settlement lacked a nucleated center or public imagery referencing the rulers of Copán. Due to that combination of factors, I conclude that this area was hegemonically integrated within the Copán polity. Furthermore, smaller polities, like the Copán polity used the same varied integrative strategies carried out by larger, better known empires. / 1 / Erlend M. Johnson

Altered neuromuscular control due to compromised position sense may contribute to shoulder instability. The purpose of this study was to investigate whether unstable shoulder subjects exhibit larger errors than intact shoulder subjects in kinesthetically guided active positioning and reaching that are of greater functional significance than passive testing of shoulder position sense. Ten subjects with a history of anterior shoulder dislocation and 15 intact shoulder subjects participated in the study. Shoulder position sense was examined with three different protocols (imposed motion to remembered shoulder rotation angles and active shoulder abduction/rotation to verbally specified positions) with targets located in both the mid- and end-range of rotation. Three dimensional end-point accuracy of kinesthetically guided reaches to visually specified targets, along with the shoulder rotation angle and scapula orientations at the end-point, were also analyzed. In agreement with previous studies, unstable shoulder subjects exhibited significantly larger errors in perception of shoulder joint angles than healthy controls in a protocol involving imposed motion to remembered shoulder rotation angles. However, the clinical significance of the observed deficit is questionable because the averaged rms error differences between unstable and intact shoulders were relatively small (average: 1.8°). During tests of active positioning, unstable shoulder subjects were able to move the shoulder to verbally defined angles as accurately as healthy controls in both shoulder abduction and rotation. Unstable and intact shoulder subjects exhibited similar reaching accuracy and scapular orientations in the kinesthetically guided reaching test, but unstable shoulder subjects consistently used less shoulder rotation angle than healthy controls. However, they were able to point to a remembered target as accurately as intact shoulder subjects, suggesting that a different reaching strategy was adopted by unstable shoulder subjects to minimize shoulder rotation. Results of this study show that unstable shoulder subjects can perceive shoulder angles and reach to visually specified targets in space as accurately as healthy controls in functional activities with voluntarily arm movements. The results suggest that less sensitive joint receptors due to over-stretched shoulder stabilizers following shoulder injury have little impact on the neuromuscular control of the shoulder joint.

The following thesis is a two-part study, investigating the influences of biochar (charcoal) on arbuscular mycorrhizal fungi (AMF). The first part of this study is a critical examination and conceptual overview of the literature regarding biochar and AMF available before July 2007. In the second part, I present three experiments all designed to evaluate the influences of biochar applications on AMF abundance in primarily temperate, neutral pH soils. This course of research was selected through an exstensive review of the literature suggesting that biochar presence can strongly affect both soil microbial populations, including mycorrhizal fungi, and biogeochemistry. As both biochar and mycorrhizal associations are subject to management, and because both components are potentially important in various ecosystem services provided by soils (e.g., sustainable plant production) understanding and exploiting interactions between them could be advantageous. After reviewing the experimental evidence for such effects, four mechanisms are proposed by which biochar could influence mycorrhizal abundance and/ or functioning. These mechanisms are: a) alteration of soil physico-chemical properties; b) indirect effects on mycorrhizae through effects on other soil microbes; c) plant-fungus signaling interference and detoxification of allelochemicals; and d) provision of refugia from fungal grazers. Through this overview, a roadmap for research is provided, which is aimed at testing these mechanistic hypotheses. Using this proposed framework as a template, three experiments were designed and implemented, incorporating three different soils, five different biochars, and eight different biochar application rates. Through these experiments, it was illustrated that five different types of biochar are all capable of significantly altering soil orthophosphate availabilities, with four of these biochars not significantly affecting soil pH. Overall, our results indicate that AMF abundances were either unchanged or decreased with biochar amendment across multiple treatments. These results also indicate that biochar, depending on the nature of the feedstock, the temperature attained during pyrolysis and amounts applied can significantly alter soil properties including phosphate availability. These findings may have implications for soil management where the goal is to increase the services provided by AMF.

Membrane proteins function as important communication channels of the cell and its environment that aid in regulating the overall homeostasis of organisms. Understanding the pathways by which these proteins adopt their three-dimensional structures can provide us with key insights into their functions. Failure of a membrane protein to fold into its native structure can lead to disruption of their functions and cause diseases. Through an understanding of the folding mechanisms of membrane proteins it may be possible to identify avenues for the treatment of such diseases. Towards these goals, this thesis describes the biophysical characterization of denatured states of rhodopsin, a model system selected to study helical membrane protein folding. The first contribution of this thesis was to establish approaches that can be used to identify suitable conditions for studying membrane protein folding in vitro. This required screening different denaturing conditions to obtain maximum unfolding without causing aggregation of rhodopsin. 30% SDS and 3% SDS + 8 M urea were found to be the most suitable denaturing conditions. Next, structural features of largely unfolded states of rhodopsin under optimized denaturing conditions were systematically characterized focussing on three levels of structural resolution: global, local and site-specific. Global tertiary structure changes upon SDS denaturation were observed to correlate with SDS micellar structure changes and also hinted at formation of compact intermediate states. Local structural dynamics, probed by NMR spectroscopy, showed that the cytoplasmic domain is more flexible than extracellular and transmembrane domains taken together in spite of an overall increase in flexibility with denaturation. Mobility studies probing site-specific changes by EPR spectroscopy, showed that specific extracellular residues retain more rigidity than cytoplasmic residues in denatured states. These results indicate that the former domain is involved in more stable interactions forming a possible folding core like structure, the location of which correlates with that described by the long-range interaction model of folding. Finally, the importance of dynamics in understanding folding mechanisms of rhodopsin led us to contribute to the development of two novel methodologies: terahertz spectroscopy to detect global motions and 19F NMR using new monofluoro labels to quantify residue specific motions.

A chemical screen of approximately 2000 small molecules in zebrafish embryos identified a compound that generated pericardial edema, suggesting aberrant renal development. Treatment with this compound, 4-(phenylthio)butanoic acid (PTBA), increased the size of the pronephric kidney in zebrafish. Earlier in development, PTBA expanded the expression of renal progenitor cell markers, including lhx1a, pax2a, and pax8. Blocking DNA synthesis with hydroxyurea and aphidicolin before PTBA treatment decreased its efficacy, suggesting that PTBA-mediated renal progenitor expansion is proliferation dependent. Structure-activity analysis revealed that PTBA was an analog of the known histone deacetylase inhibitors (HDACis) 4-phenylbutanoic acid (PBA) and trichostatin A (TSA). Like PTBA, PBA and TSA both demonstrated the ability to expand lhx1a expression in treated embryos. PTBA was subsequently confirmed to function as an HDACi both in vitro and in vivo. HDACis are hypothesized to stimulate retinoic acid (RA) signaling by decreasing the concentration of RA necessary to activate RA receptors (RARs) on target genes. Indeed, treatment with PTBA affected the expression of the RA-responsive genes, cyp26a1 and cmlc2, in a manner consistent with increased RA signaling. Furthermore, blocking the RA pathway with a dominant-negative RAR alpha construct decreased PTBA efficiency. Therefore, PTBA appears to stimulate renal progenitor cell proliferation by activating the RA-signaling pathway. HDACis have been shown to improve renal recovery following acute kidney injury. Since PTBA increases renal progenitor cell proliferation, it may exert similar effects on the multipotent cells involved in regeneration. In an effort to improve PTBA efficacy for pharmacological applications, analogs were generated by modifying the key structural elements of the general HDACi pharmacophore. These were tested along with a panel of known HDACis for their ability to increase lhx1a expression in treated embryos. Several compounds were characterized that function at nanomolar concentrations and do not cause toxicity in kidney cell culture. These second generation PTBA analogs are excellent candidates for development as potential renal therapeutics.

Tuberculosis kills nearly 2 million people each year, and more than one-third of the world�s population is infected with the causative agent, Mycobacterium tuberculosis. Mycobacteriophages, or bacteriophages that infect Mycobacterium species including M. tuberculosis, are already being used as tools to study mycobacteria and diagnose tuberculosis. More than 60 mycobacteriophage genomes have been sequenced, revealing a vast genetic reservoir containing elements useful to the study and manipulation of mycobacteria. Mycobacteriophages also encode proteins capable of fast and efficient killing of the host cell. In most bacteriophages, lysis of the host cell to release progeny phage requires at minimum two proteins: a holin that mediates the timing of lysis and permeabilizes the cell membrane, and an endolysin (lysin) that degrades peptidoglycan. Accessory lysis proteins have also been discovered, often with functions specific to that phage�s host. Many lysins of phages infecting Gram-positive bacteria are proving to be potent antibacterials. Further, lysis proteins can provide insight into the properties and composition of the host cell wall. Given the complexity of the mycobacterial cell wall and its medical relevance in tuberculosis as an immunogenic barrier that complicates treatment, as well as the urgent need for new therapeutic options, the mycobacteriophage lysins clearly warrant further scientific investigation. This work focuses on the mycobacteriophage lysin LysA and the accessory lysis protein LysB. Bioinformatic characterizations show that LysA proteins posess a variety of domains arranged in modular organizations, reflecting extensive recombination within the mycobacteriophage population. In addition to known peptidoglycan-hydrolytic activities, novel cell wall-binding domains are identified, as well as several domains of unknown function found only in mycobacteriophages. LysB proteins are unique to mycobacteriophages and perform a singular role as mycolylarabinogalactan esterases that sever the connection between the mycobacterial outer membrane and the peptidoglycan cell wall complex to ensure efficient lysis and progeny phage release. There is also preliminary evidence of peptidoglycan hydrolytic ability, inducible cell lysis, and growth inhibition of Mycobacterium smegmatis by LysA and LysB proteins. These studies suggest that mycobacteriophage lysis proteins can be exploited as useful tools, both in the laboratory and clinical setting.

Merkel cell polyomavirus (MCV) has been recently described as the cause for most human Merkel cell carcinomas. MCV is similar to simian virus 40 (SV40) and encodes a nuclear large T (LT) oncoprotein that is usually mutated to eliminate viral replication among tumor-derived MCV. In search of novel cellular interactors for MCV LT, we identified the hVam6p cytoplasmic protein involved in lysosomal processing as a binding partner with MCV LT but not SV40 LT. We have shown that hVam6p binds through its clathrin heavy chain homology domain to a unique region of MCV LT adjacent to the retinoblastoma protein (pRB) binding motif. hVam6p and pRB have discrete binding sites on LT. Intriguingly, MCV LT translocates hVam6p to the nucleus, sequestering it from involvement in lysosomal trafficking. A naturally occurring, tumor-derived mutant LT (MCV350) lacking a nuclear localization signal binds hVam6p but fails to inhibit hVam6p-induced lysosomal clustering, suggesting MCV has evolved a novel mechanism to target hVam6p that may contribute to viral uncoating or egress through lysosomal processing during virus replication. In addition, we have investigated the effect of LT-hVam6p interaction on MCV virion production and viral replication. Mutation of the MCV LT-hVam6p binding site enhances encapsidated virion production, which is confirmed by both elevated subgenomic DNA synthesis and viral particle production. Remarkably, overexpression of hVam6p reduces MCV virion production by >90%, suggesting a previously unrecognized role for this protein in regulating virus replication. Collectively, identification of novel binding partners for MCV LT has provided new insights into the mechanisms underlying the MCV lifecycle.

Psychotherapy has developed from four foundational schools of psychoanalytic, cognitive behavioural, humanistic, and transpersonal psychology, and it has been estimated (Karasu 1986; Corsini 1995) that over 400 systems of psychotherapy have evolved. However, empirical studies (Asay & Lambert 1999) suggest that the quality of the therapeutic relationship, regardless of system, is the major influence on therapeutic outcome. These professional factors, and other economic and social influences (Norcross & Newman 1992), engendered a psychotherapy integration movement and a burgeoning of integrative approaches and publications. This movement, formalised by SEPI in 1982, is described currently by three main routes to integration (Safran and Messer 1997), which offer little guidance and leave several issues unresolved (Hollanders 2000b). This PhD thesis presents a new organising framework by which psychotherapy integration can be understood, described and developed. It consists of three dimensions I call constructive, complicit and contiguous integration, and it forms the connecting principle for the published works. The works cover over six years of qualitative inquiry into psychotherapy integration using a heuristic research strategy (Moustakas 1990), which incorporated interpretative phenomenology, case studies, reflexive action and writing as component methods. The new organising framework redefines the current topography of psychotherapy integration and provides an innovative tool for aspiring integrationists. Constructive integration repositions the existing routes to integration and is illustrated by articles on games and projective identification, relationship in organisations, Jung and object relations, and countertransference. Complicit integration emphasises how higher-order integrative approaches simplify the current complexity of psychotherapy. This is exemplified by articles on Clarkson's relational framework in Kleinian psychotherapy and brief dynamic therapy. Contiguous integration reflects how psychotherapy relates to the world at large. Freud's anthropology, Bion's group theories and Jung's collective unconscious are examples of this dimension. I present four articles on organisational and social artefact to further illustrate this dimension. Finally, I present an article on psychotherapy integration itself, which describes these dimensions and the innovative framework they form. I then highlight why this PhD thesis represents a significant and original contribution to knowledge.

This study sought to understand how practitioners of the traditional systems of complementary medicine (CM) were responding to the adoption of their traditional medicine therapies by the mainstream health care practitioners. The occupational domain of traditional CMPs is undergoing significant changes as a result of the continuing popularity of CM with health consumers and the market environment of contemporary health care. Although CM itself has become popular as a topic of research in mainstream health and medical journals, little is known about the perspectives of traditional CMPs or their response to the changes taking place in their occupational domain. / In depth interviews were used as the principle source of data, 20 interviews were conducted with 19 participants who were defined as non-mainstream practitioners from five traditional systems of medicine. Field notes form participant observation at CMP association meetings and professional literature sourced from within the CM sector were also used in the study. This was supported with secondary data sourced from relevant academic literature, accessed after the identification of the main concern of the participants and the formation of the central categories from the interview data. / Thesis (PhD)--University of South Australia, 2006.