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Introduction: Colorectal cancer (CRC) survivors may experience functional deficits due to cancer-associated impairments. However, we do not understand their type and extent of functional deficits and how we could measure the associated cause of functional deficits, such as fatigue. As the survival of CRC survivors improves, the burden of living with functional deficits can be high. Purpose: My research program aims to understand (1) the functional changes and deficits that CRC survivors experience and (2) how to best measure fatigue in this population. Methods: To address the first aim, we used the data from the International Study of the Risk Factors for Gastrointestinal Bleeding and Cardiovascular Events after Gastrointestinal Bleeding to examine individuals’ functional abilities within 1 year of gastrointestinal cancer diagnosis (CRC being the most prevalent type). For the second aim, we conducted a systematic review on fatigue measures in adults with inflammatory bowel disease (IBD) because the causes, severity, and impact of IBD and CRC- related fatigue might be similar. We identified fatigue measures in the IBD population, appraised their psychometric properties, and recommended the most psychometrically robust and feasible measures for clinical and research use, indicating the optimal measures for CRC survivors. Results: After gastrointestinal cancer diagnosis, the majority (~70%) performed fewer functional tasks, mostly in the instrumental activities of daily living; and about 44% had more difficulty walking. Our review identified 16 measures, reviewed the content and psychometric properties, and recommended the Functional Assessment of Cancer Therapy Instrument-Fatigue and the IBD- Fatigue scale for research and clinical use in IBD and CRC populations. Conclusion: We provided a novel understanding of the functional deficits that CRC survivors experience and recommended the optimal measures for assessing CRC-related fatigue. As CRC survivors commonly experience fatigue, fatigue should be measured to understand its role in the functional abilities of CRC survivors. / Thesis / Master of Science Rehabilitation Science (MSc) / More people are living with colorectal cancer (CRC), but may have problems performing their daily activities (i.e. functional problems) due to cancer-associated impairments. However, we do not understand the extent of these impairments and functional problems. We used a sample of people with newly-diagnosed gastrointestinal cancer (CRC being the most common type) to understand their type and extent of functional problems. People were found to participate less in functional activities and particularly have more difficulty walking after a cancer diagnosis. Fatigue is common among those with CRC and may primarily cause functional problems. However, it is not commonly measured, and it is unclear how to best measure fatigue among them. Therefore, we reviewed key qualities of 16 fatigue measures in a similar population (inflammatory bowel disease, IBD) and recommended the Functional Assessment of Cancer Therapy Instrument-Fatigue and the IBD-Fatigue scale (English) as the most promising measures for those with CRC.

Microbial contaminants in water are a major public health concern. Pathogens have been identified as a primary threat to river water quality in the United States, potentially impacting drinking and irrigation water sources and recreational waters. Agricultural runoff, feedlot operations, wastewater effluents, swimming activities, domestic and wild animals are potential sources of microbial contamination. This thesis presents Massachusetts as a case study for linking public health data of waterborne gastrointestinal diseases with sources of drinking water, potential recreational exposures, as well as hydrologic, climatic, and land use data. Giardia sp. has been chosen as a model organism. Information of reported human Giardiasis cases has been synthesized. Using Geological Information system and statistical software (SPSS and SAS) relationships of confirmed Giardiasis have been compared with available climate and hydrologic data. In this thesis the research finding suggest that there is no visible difference in disease occurrence related with amount of precipitation or extreme rain event. However human giardiasis in Massachusetts has been found related with temperature thus shows a seasonal trend in disease occurrence. Seasonal water related human activity likely have played a role in disease occurrence.

Irritable bowel syndrome (IBS) is a functional bowel disorder with 6.5% worldwide prevalence that causes gas production, abdominal distension, and abdominal pain or discomfort. This systematic review describes efficacy of the Low-Fermentable Oligosaccharides, Disaccharides, Monosaccharides And Polyols (FODMAP) diet (Low-FODMAP diet or LFD) to alleviate IBS symptoms using the PRISMA guidelines. Nine randomized controlled trials (RCT) and one non-RCT consecutive controlled study published between 2015 to 2019 were identified using PubMed and CENTRAL. Included studies involved adult IBS participants with symptoms of abdominal pain, constipation, and/or diarrhea. A total of 530 participants completed the interventions from the 10 studies included in the final systematic review with participants ranging from mean ages of 40.31±12.83 years. The LFD can be recommended to patients for its use with alleviating abdominal pain severity and quality of life; however, more research is needed to verify the efficacy of the LFD concerning stool frequency and consistency.

Current practices support the use of probiotic and prebiotic supplementation to improve chronic gastrointestinal distress (GID). The aim of this study was to determine the tolerance and benefits of GlutenShield (GS), a prebiotic, probiotic, and enzyme supplement, on adults with GID. Subjects (n=20) took either GS or the placebo for 30 days and completed a pre-treatment FFQ as well as a pre- and post-treatment GID questionnaire, blood draw, and stool sample. Participants consumed more total and saturated fat, and less fiber and whole grains compared to the recommended intake. A significant reduction in IgG2 was observed in the GS group (p=0.008) as well as a significant reduction in self-reported bloating (p=0.038) with no change observed to cytokines or SCFAs (p>0.05). GS was well tolerated and perceived to be beneficial; however, further research is needed to identify the specific population of GID patients who could most benefit from GS supplementation.

Neonatal abstinence syndrome (NAS) is a syndrome of withdrawal symptoms in newborn infants that have a history of prenatal exposure to certain substances. Affected infants may have gastrointestinal (GI) issues, such as gassiness and diarrhea. Although infants with known exposures may be monitored in the first few days of life, it is unclear how long these symptoms persist. This poster will examine GI issues in the first six months of life across four groups of infants: those with prenatal opioid exposure, those with prenatal substance exposure that does not include opioids, those with polysubstance exposure, and those without substance exposure in a pediatric clinic in northeast TN. A retrospective chart review of 600 charts of infants born from 2017—2020 was conducted with IRB approval in a pediatric clinic in rural middle Appalachia. Of these, 300 charts were selected based on known prenatal substance exposure, and the other 300 charts were randomly selected. A REDCap extraction manual was created, research assistants were trained, and % agreement was determined. Data was collected about type of prenatal substance exposure, growth, and medical conditions in the first three years of life. Infants were divided into groups by type of prenatal substance exposure for analysis. The opioid-only group included exposure to buprenorphine, methadone, or other opiates. The other (non-opioid) exposure group included exposure to marijuana, cocaine, benzodiazepines, methamphetamines, and prescription ADHD medications. The polysubstance exposure group included exposure to both opiate and non-opiate substances. The control group had no prenatal substance exposure. Analyses were performed using SAS version 9.4. Descriptive statistics showed the demographics of the sample were representative of the population in rural middle Appalachia, with a predominantly Caucasian sample of 121 females and 123 males, mostly receiving TennCare. Chi-square results showed there was only a statistically significant difference between the prenatal substance exposure groups at 2 months, X2 (3, N = 176) = 8.03, p = 0.045, but not at hospital discharge, within the first few days of life, at 1 month, 4 months, or 6 months. Infants in the opioid-only exposure group were most likely to have GI issues. These findings suggest that GI issues are more likely to occur in infants with certain prenatal substance exposures. This poster also shows a longitudinal perspective of these issues, indicating that the symptoms may persist in the first few months of life. Thus, caregivers of infants at risk for NAS may benefit with information about the long-term effects. Because the retrospective chart review is still in progress, this poster only analyzes a preliminary number of charts. Future research should also take into consideration other factors that may be associated with GI issues in this population, such as nutrition.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24131号 / 医博第4871号 / 新制||医||1059(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 阪上 優, 教授 佐藤 俊哉, 教授 小杉 眞司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Bioactive compounds, such as curcumin, lutein, coenzyme Q10, β-carotene, cholecalciferol, astaxanthin, and β-sitosterol, have antioxidant and anti-inflammatory properties that promote health, but their low solubility, fast metabolism, and degradation have made it difficult to fully harness their potential. Encapsulation techniques, such as nano and microencapsulation using food-based biopolymers, have been employed to address these challenges. However, research efforts in protein-based delivery have mainly focused on encapsulation without considering structural, physicochemical, and matrix compatibility, which is tedious, unsustainable, and not cost-effective. Hence, this thesis reports the structural basis of guest-host interaction in the gastrointestinal delivery of lipophilic bioactive compounds using protein-based vehicles. This research employed fluorescence quenching techniques to estimate the influence of protein modification, fractionation and ionic strength on the nature and strength of interactions between protein and bioactive compounds. Morphological examination was carried out with transmission electron microscopy, confocal and widefield fluorescence microscopy whereas the sizes of the nano and micro-complexes was measured with dynamic light scattering techniques. Thermal stability was measured with differential scanning calorimetry and functional group characterization done with Fourier Transform infrared spectroscopy. Encapsulation efficiency was estimated by UV-Visible spectroscopy whereas in vitro bioactive compound release study was carried out in simulated salivary, gastric and intestinal fluids. Cytotoxicity assessment was estimated by calcein leakage assay. The study showed that protein modification affects the strength of protein-curcumin interaction and encapsulation efficiency. Pea protein succinylation increased electrostatic interaction with chitosan but decreased protein-curcumin interaction. Pea glutelin, albumin and globulin fractions showed different binding strengths with curcumin and the protein hydrophobicity and encapsulation efficiency correlated positively with the binding strength. The study also investigated the impact of bioactive compound lipophilicity and physiological ionic strength on the interaction between protein and bioactive compound. Lipophilicity influenced the strength of protein-bioactive compound interaction, while ionic strength changed the mode of interaction from static to static-dynamic quenching. The morphology of the nano and micro complexes formed with protein varied depending on the nature of encapsulated bioactive compound. Finally, bio-nano interaction involving giant unilamellar vesicles and curcumin-loaded pea protein of various surface functionalities as model biomembrane and nanoparticles respectively, was investigated. The result showed that while the protein/chitosan shell stabilizes bioactive compounds from degradation, the bioactive compound modulates their interaction with biomembrane. Overall, this work has demonstrated that for a rational design of protein-based nano/micro-encapsulation system, it is essential to consider the influence of the structural and physicochemical properties of proteins and bioactive compounds, stabilizing intermolecular forces, ionic strength of the environment, lipophilicity of the bioactive compounds, mechanism of release and modulation of cytotoxicity by bioactive compound. For instance, in high ionic strength solution, the stoichiometric ratio between protein carrier and bioactive compounds influences the stability of the complex. Balancing the intermolecular forces in the shell and core of bilayer complexes is essential for the stability of nanocomplexes and the presence of bioactive compound stabilizes the macromolecular carrier to minimal biomembrane disruption.

Human milk contains ~ 25 µg/mL of soluble cluster of differentiation 14 (sCD14) protein, a pattern recognition receptor (PRR) that triggers the innate immune system to respond to bacterial lipopolysaccharide (LPS). To date, the role of CD14 in the digestive tract of breast fed infants has not been well characterized and is the subject of this thesis. To investigate the biodistribution of proteins such as CD14 in vivo, a novel method for 14C radiolabeling of proteins to high specific radioactivity was developed using in vacuo methylation. Bovine serum albumin (BSA) and casein were used as test proteins to determine the following: 1) The efficacy of the in vacuo radiolabeling procedure; 2) The extent of incorporation of the 14C-label into the organs of oro-gastric gavaged 10 day old Sprague Dawley rats. [14C]BSA, [14C]casein and [14C]CD14 were prepared with specific radioactivities of 10 400, 10 800 and 163 000 dpm/µg, respectively. After feeding 6.25 µg of 14C-labeled proteins, quantifiable levels of 14C were found in the stomach, jejunum, duodenum, ileum, large intestine, intestinal luminal flushes, blood, liver, spleen and kidneys of rats. The accumulation of radiolabel in the organs of [14C]CD14 fed rats was temporally and spatially distinct from [14C]BSA and [14C]casein. Most notably, the label persisted in the stomach 480 min post-gavage. To design a neonate animal model for biodistribution, the segmental and total gastrointestinal transit times (GItt) were measured in two litters of 10 and 15 day old Sprague Dawley rat pups using barium sulfate. Ten day old rat pups that remained with and without the dam had a total gastrointestinal transit time of 13.8 ± 0.9 hr and 9.3 ± 0.7 hr, respectively. This decrease (p<0.05) in total gastrointestinal transit time in the absence of the dam was age dependent, as it was not observed (p>0.05) in the 15 day old rat pup litter. The immunological impact of an exogenous sCD14 source was examined in human peripheral blood mononuclear cells (PBMC). Pre-treatment of CD14+ monocytes with sCD14 had a protective effect, one of reducing the production of proinflammatory cytokines (TNF-α, IL-6, IL-8, IL-1β) when challenged with LPS. 14C was absorbed by neonate rats upon ingestion of [14C]CD14 and exposure to relatively high concentrations of rCD14 led to a reduction in inflammation. This may be beneficial to initial gut colonization in breast-fed newborns. / Alexander Graham Bell NSERC CGS M scholarship. Japan Society for the Promotion of Sciences, Summer in Japan Fellowship. Funded by the Canadian Institutes of Health Research, Institute of Nutrition Metabolism and Diabetes Grant #82816 “Fate and function of breast milk and recombinant human CD14 at mammary and newborn gastrointestinal mucosal epithelia”.