acase@tulane.edu / Introduction: High-Intensity Focused Ultrasound (HIFU) is the only noninvasive method available today for thermal ablation of tumors. HIFU-induced rapid heating and mechanical disruption of tissue, not only has a direct destructive effect on tumors, but also provides a noninvasive way for targeted release of chemotherapeutic drugs from drug delivery vehicles such as temperature sensitive liposomes (SfTSLs). The objective of this work was to evaluate the synergistic treatment of Sorafenib-loaded TSLs (SfTSLs) and HIFU via in vitro analysis of cell viability and proliferation using an aggressive human liver cancer cell line and corresponding in vivo analysis of tumor growth and survival using a human xenograft mouse model. Materials and Methods: Liposomes were developed using 70% Dipalmitoylphosphatidylcholine, 20% L-a-Phosphatidylcholinehydrogenated Soy, and 10% Cholesterol using thin film hydration method to encapsulate Sorafenib at 10μM. Pellets of Hep3B human liver cancer cells (100 μl, 2.7 million cells/ml) were placed in a 0.2 ml thin-wall PCR tube to mimic dense tumor aggregation. Cell pellets were then inoculated with HIFU alone, SfTSLs, or exposed to a combination of HIFU and SfTSLs. The focused ultrasound signal was generated by a 1.1 MHz transducer with acoustic power ranging from 4.1 W to 12.0 W. Cell viability and proliferation experiments were conducted to measure cancer cell damage at 24, 48, 72, and 96 h post treatment via Annexin V/PI and WST-8 staining. In our in vivo study, 1.0×106 Hep3B cells in Matrigel were injected into left and right flanks of athymic nude mice. Tumors were allowed to grow to 8-10 mm size and then separated into the following treatment groups: HIFU alone, SfTSLs (50 μl) alone, SfTSLs + HIFU, and sham. Tumor sizes were measured by caliper every day and a diagnostic ultrasound system was used pre-treatment, 5 days, 14 days, and prior to sacrificing. Tumors were grouped and processed at 5 days, 14 days, or placed in a survival study to evaluate whether treatment facilitated longer lifespans. Tumor tissues were collected for H&E staining and evaluated by a blinded pathologist post euthanasia. Results and Discussion: Our in vitro data indicate that Hep3B cells exposed to both SfTSLs and HIFU have a significantly lower viability and proliferation rate than untreated cells or the cells treated with only SfTSLs or HIFU. According to our in vivo study, tumor growth in the SfTSLs + HIFU group was reduced as compared to Sham, SfTSLs only, or HIFU only groups. Conclusions: The results of our in vitro and in vivo experiments clearly indicate that chemotherapeutic drug-loaded SfTSLs and HIFU can be an effective therapy for locally aggressive liver cancer. This combination treatment leads to more cellular damage, reduction in tumor growth, and better survival. / 1 / Gray Halliburton

Adaptation to the shortage of oxygen at altitude (hypoxia) promotes physiological changes which could enhance endurance performance. Consequently, altitude training has become a popular practice among competitive endurance athletes. Since its inception, the live-high train-low paradigm (LHTL) has been widely regarded as the most effective approach to altitude training. Over the past decade, brief intermittent simulation of LHTL via the use of hypoxic inhalers and re-breathing devices has gained increased popularity, but the evidence supporting their use is limited and conflicting. The experimental studies in this thesis investigated the response of sea level exercise performance and related physiological measures following adaptation to the usual and a novel protocol of brief intermittent hypoxia. I intended to perform all experimental studies on flat-water kayakers. Therefore, an initial requirement of this thesis was to establish the smallest worthwhile effect in performance for this sport. The final study utilising a meta-analytic approach was conducted to compare the effectiveness of brief intermittent hypoxia to other natural and simulated protocols, and to investigate the topical issue of what physiological responses mediate performance changes following hypoxic exposure. In Study 1, the typical variation in competitive performance of elite flat-water canoeists was investigated using a repeated-measures analysis of race times. For individual flat-water canoeing events, the smallest worthwhile change in performance time was ~0.5%. In two separate experimental studies, adaptation to 60 min per day of brief intermittent hypoxia consisting of alternating 5 min intervals of hypoxia and normoxia for 3 weeks (5 days per week) using a nitrogen filtration device resulted in clear enhancement of endurance performance (~5%) for kayakers (Study 2) and cyclists (Study 3). Clear enhancements in repeat sprint performance were observed for kayaking only. The physiological mechanisms underlying performance changes were unclear. Modification of the hypoxic and normoxic intervals (Study 3) did not result in any clear alterations in performance or physiological mechanisms. The meta-analysis (Study 4) revealed clear enhancements in endurance power output of 1-3% in sub-elites following adaptation to hypoxia with the natural altitude protocols, and with two of the artificial-altitude protocols (LHTL-long and LHTL-brief-intermittent). In elite athletes the enhancements tended to be smaller and were clear only for the natural protocols. These enhancements could be mediated by VO2max, although other mechanisms may be possible.

<p>Syftet med den här studien är att undersöka huruvida en stor andel av intensiva grenspecifika pass utvecklade den aeroba kapaciteten hos motionärer som tränar inför Vasaloppet. Två testmetoder användes; ett maximalt laktattest på rullskidor utomhus och ett maximalt cykeltest på en cykelergometer inomhus. En utav fp genomförde ett tidstest på rullskidor på en given sträcka istället för laktattestet. Båda testerna genomfördes före och efter en 11-veckors träningsperiod som bestod av 41 procent medel- och högintensiva pass som genomfördes grenspecifikt. Det betyder intervaller på rullskidor eller i skidgång samt snabbdistanspass på rullskidor. Övriga 59 procent av träningspassen genomfördes på en lågintensiv nivå, vilket är mindre än de 70-80 procent som normalt förespråkas för en uthållighetsidrottare. 4 försökspersoner (fp) på motionsnivå deltog (4 män och 1 kvinna). Fp 3 förbättrade prestationen markant med 20 procent genom en minskning av blodlaktatkoncentrationer vid givna hjärtfrekvenser (HR), sålunda en förbättring av dels den aeroba laktattröskeln (LT) som den anaeroba laktattröskeln (AT). Fp 4 förbättrade prestationen med 15 procent genom att åka den givna sträckan under tidstestet på en snabbare tid vid andra tillfället. Fp 2 avverkade en 500m längre sträcka under andra rullskidtestet och förbättrade på så sätt sin prestation med 10 procent, fp fick dock en försämring av AT och hade högre blodlaktatkoncentrationer vid andra testtillfället. Fp 1 förbättrade LT men försämrade AT. Sammanfattningsvis, visar studien att ett 11-veckors träningsprogram bestående av mycket grenspecifik träning på högre intensiteter ledde till en klar prestationsförbättring hos två av fp, gällande alla parametrar som testades. De övriga två fp uppvisade vissa förbättringar men högre laktatkoncentrationer vid några mättillfällen.</p>

Syftet med den här studien är att undersöka huruvida en stor andel av intensiva grenspecifika pass utvecklade den aeroba kapaciteten hos motionärer som tränar inför Vasaloppet. Två testmetoder användes; ett maximalt laktattest på rullskidor utomhus och ett maximalt cykeltest på en cykelergometer inomhus. En utav fp genomförde ett tidstest på rullskidor på en given sträcka istället för laktattestet. Båda testerna genomfördes före och efter en 11-veckors träningsperiod som bestod av 41 procent medel- och högintensiva pass som genomfördes grenspecifikt. Det betyder intervaller på rullskidor eller i skidgång samt snabbdistanspass på rullskidor. Övriga 59 procent av träningspassen genomfördes på en lågintensiv nivå, vilket är mindre än de 70-80 procent som normalt förespråkas för en uthållighetsidrottare. 4 försökspersoner (fp) på motionsnivå deltog (4 män och 1 kvinna). Fp 3 förbättrade prestationen markant med 20 procent genom en minskning av blodlaktatkoncentrationer vid givna hjärtfrekvenser (HR), sålunda en förbättring av dels den aeroba laktattröskeln (LT) som den anaeroba laktattröskeln (AT). Fp 4 förbättrade prestationen med 15 procent genom att åka den givna sträckan under tidstestet på en snabbare tid vid andra tillfället. Fp 2 avverkade en 500m längre sträcka under andra rullskidtestet och förbättrade på så sätt sin prestation med 10 procent, fp fick dock en försämring av AT och hade högre blodlaktatkoncentrationer vid andra testtillfället. Fp 1 förbättrade LT men försämrade AT. Sammanfattningsvis, visar studien att ett 11-veckors träningsprogram bestående av mycket grenspecifik träning på högre intensiteter ledde till en klar prestationsförbättring hos två av fp, gällande alla parametrar som testades. De övriga två fp uppvisade vissa förbättringar men högre laktatkoncentrationer vid några mättillfällen.

This work examined lentils as an optimal and acceptable pre-exercise meal for athletes of high intensity intermittent exercise. Thirteen male athletes participated in 4 simulated soccer trials with a repeated-measures crossover design. Along with a fasted control condition, isocaloric lentil, potato & egg white, or potato meals providing 1.5 g total carbohydrate/kg were consumed 2-h before the trials. Pre-exercise meal sensory acceptability and digestive tolerability were measured throughout testing with fixed-point scales: A sensory test meal analysis and gastrointestinal digestive symptom rating scale. Participant demographics, nutrition knowledge, and psychosocial perceptions towards lentils were assessed with a questionnaire. Distance covered on a 5 x 1 min repeated sprint test (2.5 min rest) at the end of the soccer trial assessed exercise performance. The Borg Scale (0-20) determined ratings of perceived exertion during exercise testing. Barriers toward pulse-based meal consumption negatively correlated with weekly pulse consumption (r=-0.902, p <0.05), while a positive correlation existed between beneficial beliefs of pulse-based meal consumption and weekly pulse consumption (r=0.620, p <0.05). Participants consumed an average of 79.5 ± 1.8% of each meal. The meals were perceived large in size and cumbersome to ingest by the participants, and no between meal differences were observed (p>0.05). The lentil meal was not as appealing in aroma, appearance, or flavour compared to the potato meal, but no different than the potato & egg meal (p>0.05). Lentil consumption resulted in a minimal increase in nausea compared to the other conditions (1.0, 0.54, 0.31 and 0.08, for lentil, potato & egg, potato, and control, respectively, p<0.05). Initially after consumption, all meals resulted in more bloating and fullness, and less hunger than control (p<0.05). Improved overall exercise performance was proportional with greater pre-exercise meal energy (r = 0.68, p <0.05) and carbohydrate intake (r = 0.67, p<0.05). Pre–exercise consumption of the low glycemic index lentil meal, as well as the two high glycemic pre-exercise meals, resulted in improved total sprint distances compared to the fasted control condition (p<0.05). The comparative sensory acceptability, digestive tolerability and similar performance outcomes of the lentil meal to the other pre-exercise meals indicates lentils may be a suitable pre-exercise meal for athletes of high intensity intermittent exercise.

Spiking representing a periodic melting and solidification in the depth of fusion zone during high-intensity beam welding is experimentally and theorectically investigated in this work . A spike is a sudden increase in penetration beyond what might be called the average penetration line. Many spikes have voids in their lower portions because molten metal does not fuse to the sides of the hole, producing a condition similar to a cold shut in a casting. These defects seriously reduce the strength of the joint. Due to the significant role of specular reflection on absorption, an investigation of the beam characteristics, especially the focal location, on spiking is important. Furthermore, as the cavity base oscillates upward and downward relatively from the focal location, a central region subject to direct irradiation changes instantaneously from maximum to zero and vice versa. This leads to several hundred time difference in energy absorption and strongly periodic melting at the cavity base. Physical phenomenon of spiking is obtained by comparing between the measured and predicted data based on scale anlaysis of transport process near the cavity base and energy absorption as a function of focal location.

The aim of this series of studies was to investigate the effects of oral caffeine ingestion (5 mg . kg-1) on whole-body, short-term, high-intensity exercise (ST; representing an exercise intensity of between 100% -150% V02 max), an area that has received scant attention in the past. It was found that, in common with other 'open-ended' tests, one ST assessment, the maximal accumulated oxygen deficit (MAOD), appeared to lack both validity and reliability. Although traditional reliability markers of MAOD were favourable, the 95% limits of agreement were unacceptably large. In addition, the validity of MAOD was also found to be questionable because a study of elite runners revealed that a large proportion were unable to accomplish a plateau in the V02 -exercise intensity relationship. A follow-up study developed an original bespoke 'preloaded' ST cycling protocol that combined constant-rate exercise with an 'all-out' effort. This protocol appears to have several features that make it a more appropriate assessment to use in ergogenic studies than the MAOD. The work also considered the original, and as yet, undeveloped potential, for the assessment of rating of perceived exertion (RPE) during ST. It was shown for the first time that RPE (Borg scale; 6-20) could be used reliably during constant-rate ST. Three of the ten studies demonstrated that caffeine can be ergogenic during ST, with improvements averaging 11 % (95% GI, 7.4% -14.5%) above placebo treatment. In addition, the caffeine studies contributed to a meta-analysis of the effects of caffeine on test outcome that resulted in an effect size greater than zero, with 95% confidence intervals not crossing zero. The studies have examined potential physiological and metabolic mechanisms of action that may help explain caffeine's impact on ST. These suggest that there is some evidence that caffeine both stimulates anaerobic glycolysis and reduces electrolyte disturbance during ST. Finally this work has demonstrated for the first time that the perceptual response during constant-rate ST, as measured by RPE, is blunted following caffeine ingestion. It is concluded that caffeine is ergogenic during ST, and that while the exact mechanism(s) of action remains unknown, one consistent test outcome is a reduction in RPE during constant-rate ST.

Adaptation to the shortage of oxygen at altitude (hypoxia) promotes physiological changes which could enhance endurance performance. Consequently, altitude training has become a popular practice among competitive endurance athletes. Since its inception, the live-high train-low paradigm (LHTL) has been widely regarded as the most effective approach to altitude training. Over the past decade, brief intermittent simulation of LHTL via the use of hypoxic inhalers and re-breathing devices has gained increased popularity, but the evidence supporting their use is limited and conflicting. The experimental studies in this thesis investigated the response of sea level exercise performance and related physiological measures following adaptation to the usual and a novel protocol of brief intermittent hypoxia. I intended to perform all experimental studies on flat-water kayakers. Therefore, an initial requirement of this thesis was to establish the smallest worthwhile effect in performance for this sport. The final study utilising a meta-analytic approach was conducted to compare the effectiveness of brief intermittent hypoxia to other natural and simulated protocols, and to investigate the topical issue of what physiological responses mediate performance changes following hypoxic exposure. In Study 1, the typical variation in competitive performance of elite flat-water canoeists was investigated using a repeated-measures analysis of race times. For individual flat-water canoeing events, the smallest worthwhile change in performance time was ~0.5%. In two separate experimental studies, adaptation to 60 min per day of brief intermittent hypoxia consisting of alternating 5 min intervals of hypoxia and normoxia for 3 weeks (5 days per week) using a nitrogen filtration device resulted in clear enhancement of endurance performance (~5%) for kayakers (Study 2) and cyclists (Study 3). Clear enhancements in repeat sprint performance were observed for kayaking only. The physiological mechanisms underlying performance changes were unclear. Modification of the hypoxic and normoxic intervals (Study 3) did not result in any clear alterations in performance or physiological mechanisms. The meta-analysis (Study 4) revealed clear enhancements in endurance power output of 1-3% in sub-elites following adaptation to hypoxia with the natural altitude protocols, and with two of the artificial-altitude protocols (LHTL-long and LHTL-brief-intermittent). In elite athletes the enhancements tended to be smaller and were clear only for the natural protocols. These enhancements could be mediated by VO2max, although other mechanisms may be possible.

In recent years there has been a surge in interest concerning high intensity intermittent exercise training (HIT) due to its ability to confer rapid notable cardio-metabolic health benefits. Specifically, HIT has been shown to improve insulin sensitivity and glycaemic control as well as other cardiovascular health factors after just 2 weeks of training (typically 6 training sessions). This thesis investigated the potential therapeutic role of HIT training within obese cohorts specifically addressing metabolic health, inclusive of inflammatory profiles and glycaemic control.

The aim of this thesis was to develop and validate squash-specific fitness tests to identify physiological determinants of repeat-sprint ability and performance in sub-elite and elite-standard squash players. Study one examined the validity of a squash-specific test of endurance capability and VO[2max]. Trained squash players and runners completed squash-specific and treadmill incremental tests to exhaustion. Squash players achieved greater VO[2max] on the squash-specific than the treadmill test while runners did not differ. Squash players exercised longer than runners on the squash-specific test despite similar VO2max. The squash test discriminated endurance capability between squash and non-squash players of similar fitness and elicited higher VO[2max] in squash players. The results suggest that it is a valid test of aerobic fitness in squash players. Study two assessed the reproducibility of physiological and performance measures from the squash specific test in county-standard players. Test-retest variability was low for all measures (Typical error < 5%) though the magnitude varied depending on the metric used. Studies three and four examined the validity and reproducibility of squash-specific tests of change-of-direction speed and multiple-sprint ability. County-standard squash players and footballers completed squash-specific and equivalent non-specific tests on separate days. Performance time was recorded. Participants repeated the tests seven days later to assess reproducibility. Squash outperformed non-squash players on the squash-specific tests despite similar non-specific capabilities. Squash-specific tests discriminated squash player rank while non-specific tests did not. Test-retest variability was low (Typical Error < 3%) for both tests. Squash-specific tests predicted ability in squash players and discriminated between squash and non-squash players of equal nonspecific fitness. The findings suggest that the squash-specific tests are valid for the assessment of high-intensity exercise capabilities in squash players. Studies five and six explored correlates of multiple-sprint ability and performance in sub-elite and elite squash players. Squash-specific and general tests were performed by regional league players ranging from division three to premier standard and elite players on three tiers of a national performance program. In sub-elites, multiple-sprint ability and endurance capability discriminated performance and multiple-sprint ability was related to change-of-direction-speed, VO[2max] and endurance capability. In world-ranked men and women, the ability to perform and sustain rapid changes of direction correlated with multiple-sprint ability and together with multiple-sprint ability discriminated performance. Aerobic fitness was not related to performance or multiple-sprint ability in elite players. Senior elites performed better than players on the talented athlete scholarship scheme (TASS) on all tests except VO[2max] and counter-movement jump. Drop-jump power and reactive strength discriminated senior and transition level from TASS players and indices from the multiple-sprint test discriminated seniors from transition and TASS players. This thesis has validated squash-specific tests of endurance and high-intensity exercise capabilities. These tests have shown that high-intensity exercise capabilities determine performance in elites while sub-elite performance is determined by multiple-sprint ability and endurance capability. The findings can be used to improve assessment of training effects and to inform the design of effective training methods.