京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19558号 / 医博第4065号 / 新制||医||1013(附属図書館) / 32594 / 京都大学大学院医学研究科医学専攻 / (主査)教授 平岡 眞寛, 教授 福原 俊一, 教授 一山 智 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Cognitive functioning is disrupted during a depressive episode and cognitive dysfunction persists when depression is in remission. A subtype of depressed individuals who exhibit elevated inflammatory biomarkers may be at particular risk for cognitive dysfunction. We examined whether an elevated inflammatory biomarker (C-reactive protein: CRP) in acute and/or remitted depression was associated with specific deficits in executive functioning, episodic memory, and verbal fluency. Data were drawn from a population-based sample of Dutch adolescents (N = 1,066; 46% male) recruited at the age of 11 and followed over the course of eight years. We tested whether adolescents with either, (i) a history of depression (Wave 1 – 3) or (ii) current depression (Wave 4), and elevated levels of C-reactive protein measured in blood at Wave 3 performed worse on cognitive assessments at Wave 4. Eight measures of cognitive functioning were hypothesized to load on to one of three dimensions of cognitive functioning (executive functioning, episodic memory, and verbal fluency) within a structural equation model framework. Higher levels of CRP were associated with worse future executive functioning in adolescents with and without current/prior depression. A current depression diagnosis also was associated with worse future executive functioning. There was consistent evidence linking low socioeconomic status and health-related covariates (high body mass index/sedentary behavior) with worse performance across multiple measures of cognitive functioning and, importantly, the association of depression/CRP and executive functioning was no longer significant when controlling for these covariates. Future studies may benefit from investigating whether specific depressogenic behaviors (e.g., sedentary behavior/substance use) mediate a relationship between depression and worse executive functioning, potentially via a prospective pathway through elevated inflammation. / Psychology

Iron depletion (ID) is the most common nutrient deficiency worldwide and is the leading cause of anemia. Chronic arsenic (As) exposure is a major public health problem in Bangladesh and triggers inflammatory responses that render iron status assessment challenging. We assessed the prevalence of ID and iron deficiency anemia (IDA) in 147 arsenic-exposed Bangladeshi women (75 skin lesion cases; 72 controls), ages 18-33 years, who were part of a skin lesion study. Hemoglobin (Hb) was measured in whole blood; ferritin and hs-c-reactive protein (CRP) were measured in serum. The prevalence of anemia (Hb<120g/L) was 18%. Although the prevalence of ID (ferritin≤12mcg/L) did not differ between cases and controls, anemia was more common among cases (25% vs. 10%; p=0.02). Of anemic women, 27% (N=7) also had ID (Hb<120g/L and ferritin≤12mcg/L), indicating IDA. Women with normal iron status had higher toenail arsenic compared to iron-depleted women (2.9 vs 1.4 µg As/g toenail; p=0.00), and their water arsenic concentration was higher than that of iron-depleted women (18.8 vs 6.2 µg As/L; p=0.03); every 1µg increase in toenail As was associated with a 45% lowered risk of ID (OR=0.55, 95%CI=0.33,0.94). Much of the anemia in this cohort appears unrelated to ID, but could be linked to other nutrients, such as folate and vitamin B12, which are involved in both hematopoiesis and arsenic metabolism. It is possible that arsenic exposure in this cohort compromised folate and vitamin B12 status.

Human C-reactive protein (CRP) increases survival of and decreases bacteremia in mice infected with Streptococcus pneumoniae. Such protection of mice against pneumococcal infection is seen only when CRP is administered into mice 6 hours before to 2 hours after the injection of pneumococci, but not when CRP is given to mice at a later time. Our first aim was to define the mechanism of CRP-mediated initial protection of mice against infection. It was proposed that CRP binds to phosphocholine (PCh) moieties present in the cell wall and activates the complement system on the pneumococcal surface that kills the pathogen. We generated a CRP mutant F66A/T76Y/E81A incapable of binding to PCh. Mutant CRP did not protect mice from pneumococcal infection. Thus, the proposed hypothesis was correct; the PCh-binding property of CRP contributes to the protection of mice against pneumococcal infection. Our second aim was to investigate why CRP was not protective during the late stages of infection. Pneumococci are known to recruit an inhibitor of complement activation, factor H, from the host to their surface to escape complement attack. We considered the ability of CRP, in its nonnative form, to bind to factor H, and generated a CRP mutant E42Q/F66A/T76Y/E81A capable of binding to factor H. In vivo experiments using the quadruple CRP mutant are in progress. We anticipate that the combination of wild-type and quadruple mutant CRP should be protective during the late stages of infection; wild-type CRP would bind to PCh and activate complement while mutant CRP would cover factor H to prevent its complement-inhibitory activity. Our long-term goal is to explore the possibility of developing a CRP-based strategy to treat pneumococcal infection.

C-reactive protein (CRP) binds to Streptococcus pneumoniae through the phosphocholine groups present in the cell wall and subsequently activates the complement system to kill the pathogen. To escape the attack of complement, pneumococci recruit a complement inhibitory protein, factor H, on their surface. It has been shown that CRP protects mice against pneumococcal infection only when injected within 2 hours after administering pneumococci. We hypothesized that CRP is not protective when injected at later times because, by then, factor H is recruited by pneumococci. In the current study, we evaluated the protective effects of an engineered CRP molecule (E-CRP) which does not bind to factor H in fluid phase but binds to factor H-coated pneumococci. We found that E-CRP, unlike native CRP, protected mice regardless of the timing of administering E-CRP by drastically reducing bacteremia and increasing survival of mice. Next, we established another murine model of pneumococcal infection using the antibiotic clarithromycin. We found that the combination of E-CRP and clarithromycin was more protective against infection when compared to the protective effects of either E-CRP alone or clarithromycin alone. These findings suggest that the structure of native CRP has to be altered to display its full anti-pneumococcal activity and that CRP and antibiotic act synergistically to protect against pneumococcal infection by decreasing bacteremia. These data also have implications for infections with other bacterial species that use factor H to evade the attack of complement. Additionally, the administration of E-CRP may be therapeutically beneficial to treat infections with antibiotic-resistant bacteria.

Patients infected with the human immunodeficiency virus (HIV+) are living longer and at heightened risk for developing cardiovascular events (CVEs). Commonly used prediction tools appear to misrepresent their CVE risk to varying degrees and in varying directions. Inclusion of markers of cellular infection, chronic immune activation and/or systemic inflammation into risk models might provide better predictive accuracy. Observational studies assessing the relationship of high-sensitivity C-reactive protein (hs-CRP) to CVE in HIV+ patients have reported inconsistent findings. This review of published studies attempted to determine if the available evidence supports its potential use in new models for stable, treated HIV+ patients. We searched the PubMed database using keywords and combinations of "HIV" AND "cardiovascular risk" AND "CRP". Papers presenting original analyses, associating hs-CRP concentration as an independent variable to hard cardiovascular outcomes (myocardial infarction and cardiovascular death), or to hard CVE as part of a composite endpoint, were included. Five observational studies met inclusion/exclusion criteria for review. Three papers identified an association between elevated hs-CRP and CVE, while two others failed to find any significant association. All reports were heterogeneous in terms of independent variables, controls, and designs. The larger and more rigorous studies, employing higher rates of confounder controls and more objective endpoints in their composites, showed positive associations. Though not conclusive, the preponderance of the evidence at this time supports CRP as a potentially valuable factor to be studied in prospective cardiovascular risk prediction investigations in HIV+ patients.

Frailty is a well-established indicator of late-life decline and is accompanied by higher rates of comorbidity and disability. Meanwhile, an estimated 41% of adults over the age of 65 report consuming alcohol – an identified health risk and protective factor depending on dosage. Given that the demographic group of older Americans is projected to double by the year 2050, identification of frailty risk and protective factors is imperative. The goals of this thesis are to: (1) identify how varying levels of alcohol consumption relate to frailty, and (2) elucidate a possible mechanism that accounts for the relationship between alcohol consumption and frailty. A sample of stroke-free participants over the age of 65 was identified from the Health and Retirement Study. Study 1 utilized stepwise logistic regression models to identify predictors of prevalent frailty at baseline (2000), and of incident frailty 4, 8, and 12 years later. For both males and females, significant predictors of frailty at all years included age, depressive symptomatology, and medical burden score. In addition, BMI was a significant predictor of frailty for females at all years. With respect to alcohol use, results revealed that drinking 1-7 drinks per week had a protective effect for females at baseline (OR=0.50) and 12 years later (OR=0.75); however, no such protective effects were found for males. Given that extant research has identified CRP as a mediator between the relationship of moderate alcohol use and cardiovascular health benefits, Study 2 used a cross-sectional sample from the 2008 wave to examine the potential mediating role of CRP between moderate alcohol use and reduced frailty risk. Results from structural equation modeling support the hypothesized model that moderate alcohol is associated with less frailty, and that this relationship is partially mediated by CRP levels. Overall findings suggest that moderate alcohol use confers health benefits for females by reducing frailty risk and that CRP is one mechanism by which alcohol use may confer protective effects for frailty. These results provide a starting place in an effort to better understand the protective effects of moderate alcohol use and can assist in improving prevention and treatment efforts for older adults by preventing or prolonging the onset of age-related diseases. Future research should further examine the relationship between alcohol use and frailty and determine if CRP mediates the relationship between moderate alcohol use and other beneficial health outcomes.

Aim: The purpose of this study was to investigate docosahexaenoic acid (DHA) ingestion on muscle damage and inflammation during the first two weeks of a novice resistance training (RT) program. Methods: This study was a placebo-controlled, double-blind design. Forty-one healthy untrained males between the ages of 18 and 28 years consumed 2,000 mg/d of either DHA or corn oil (PCB) for 44 days including a 28 day loading period. Serum fatty acids were analyzed to determine treatment efficacy. During the 17 day training period, an acute eccentric exercise bout was implemented followed by a full-body RT regimen thrice weekly. Six fasted blood draws (days 1, 2, 4, 7, 12, and 17) during this exercise period were analyzed for creatine kinase (CK) and C-reactive protein (CRP). Maximum isometric strength (ISO) of the elbow flexors, delayed onset muscle soreness (DOMS), and range of motion (ROM) were measured on day 1 prior to exercise and also on days 2, 3, 4, 7, 12, and 17. Results: The CK response and the area under the curve (AUC) analysis for DOMS trended to decrease in the DHA group in comparison to placebo (p=0.0925 and p=0.0536, respectively). Treatment showed no effect on CRP levels. DHA supplementation significantly increased serum DHA by 380% as a proportion of total fatty acids (p<0.0001). Conclusion: This study does not demonstrate convincing benefits of DHA ingestion to recovery from a new resistance exercise program but does suggest a need for further investigation. / Master of Science

The objectives of this two part prospective study were to evaluate the effects of statins on C-reactive protein (CRP), butyrylcholinesterase (BChE), lipids, and the relationships between these parameters. Subjects enrolled in this study were separated into two cohorts. The first group (study 1) consisted of 37 subjects converted from pravastatin to cerivastatin. The second group (study 2) consisted of 11 subjects with diabetes initiated on cerivastatin therapy. The subjects were followed for 12-weeks in the Lipid Clinic at David Grant Medical Center at Travis Air Force Base. CRP, BChE, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG) were measured at baseline, 6-weeks, and 12-weeks. In study 1, CRP (p = 0.704) and BChE (p = 0.746) remained relatively stable over 12-weeks. The lipid panel changed significantly with TC (p < 0.001) and LDL (p < 0.001) decreasing and HDL (p = 0.017) increasing. Although TG declined numerically, it was not statistically significant (p = 0.649). A significant negative correlation was detected at baseline (r = −0.353, p = 0.032), but lost at 6-weeks and 12-weeks. In study 2, CRP declined by 42.9%, but was not statistically significant (p = 0.178). BChE remained relatively stable over 12-weeks (p = 0.666). TC (p < 0.001) and LDL (p < 0.001) declined and TG (p = 0.035) fluctuated over the course of the study. HDL increased, but it was not statistically significant (p = 0.396). Significant positive correlations were seen between CRP and TG (r = 0.908, p < 0.001) and BChE and TC (r = 0.721, P = 0.012) at baseline and BChE and TG (r = 0.64, p = 0.034) at 12-weeks. These results suggest that statin effects on CRP are independent of the lipid-lowering effects and switching statins may not affect CRP disposition. Cerivastatin does not appear to have effects on BChE activity. Lastly, a possible competitive relationship may exist between CRP and BChE. This is suggested by the negative correlation seen in study 1 and with the gain in correlation between BChE and TG as the correlation was lost between CRP and TG in study 2.