Background: Knee osteoarthritis (OA) is the most common form of arthritis in older adults. Knee OA is associated with limitations in physical function. Functional limitations are also associated with another geriatric condition, frailty. Frailty is characterized by reduced strength, endurance and physiological function. Purpose: The primary purpose of this study is to determine if there is a difference in radiographic or symptomatic knee OA severity between non-frail and pre-frail women with knee OA. Secondary objectives include: a) the relationship between radiographic and symptomatic OA severity with serum inflammatory cytokines, and b) if there is a difference in inflammatory cytokines between non-frail and pre-frail women with knee OA. Methods: We included 21 community-dwelling women with knee OA. Frailty was assessed using the Fried Frailty Phenotype. Knee OA severity was characterized by the Kellgren and Lawrence (KL) score and the Knee Injury and Osteoarthritis Outcome Questionnaire (KOOS). Inflammatory cytokines included serum interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis alpha (TNF α) and C reactive protein (CRP). Results: Data from 20 participants (66.1 [9.6] years, BMI 29.7 [4.9] kg/m2, non-frail=55%; pre-frail=45%) were analyzed. Radiographic severity was not different between frailty groups (p= 0.11). There was no difference in symptomatic knee OA severity, measured using the KOOS subscales, between frailty groups (p>0.17). Radiographic OA severity and inflammatory markers were not associated (p>0.30). There was a negative relationship between TNF α and self-reported pain (r=0.26), no relationships between inflammatory cytokines with any other KOOS sub-scales. Lastly, there was no difference in any inflammatory cytokines between non-frail and pre-frail groups. Conclusion: Despite the relatively young age, nearly 50% of our participants were pre-frail. Pre-frailty was unrelated to the severity of the knee OA, or inflammatory cytokines. TNF α may be involved in the experience of pain in these women. While it appears women with knee OA frequently demonstrate pre-frail status, more work is necessary to examine the link between these diseases. / Thesis / Master of Science (MSc) / Arthritis is a chronic disease that has a debilitating effect on the lives of more than 4.6 million Canadians. In 2015, the cumulative economic burden of osteoarthritis was 195.2 billion dollars and is expected to increase significantly in the next two years. Knee osteoarthritis is the most common form of arthritis in older adults. Knee osteoarthritis is associated with increased pain, decreased physical function and decreased quality of life (QOL). In vulnerable older adults increased exhaustion, decreased physical function and muscle loss can increase the risk of developing frailty. Frail older adults are at higher risk of adverse health outcomes such as falls, hospitalization and death. Previous research has shown that older adults with knee OA are at higher risk of developing frailty however, it is not understood what underlying mechanisms increase this risk. This thesis provides fundamental information aimed at understanding potential mechanisms associated with knee osteoarthritis and frailty in women. Our study found that despite their relatively young age, nearly half of the women with knee OA are pre-frail. This data shows that inflammatory cytokines in particular, tumor necrosis factor alpha is related to symptomatic knee osteoarthritis severity in particular, self-reported pain. Overall, early detection of frailty is important when managing this condition. These data suggest that chronic knee pain associated with OA may be a useful trigger for early assessments of frailty in women.

Recently, C-reactive protein (CRP) was shown to affect intracellular calcium signaling and blood pressure in vitro and in vivo, respectively. The aim of the present study was to further investigate if a direct effect on G-protein coupled receptor (GPCR) signaling by CRP can be observed by using CRP in combination with different GPCR agonists on spontaneously beating cultured neonatal rat cardiomyocytes. All used agonists (isoprenaline, clenbuterol, phenylephrine, angiotensin II and endothelin 1) affected the beat rate of cardiomyocytes significantly and after washing them out and re-stimulation the cells developed a pronounced desensitization of the corresponding receptors. CRP did not affect the basal beating-rate nor the initial increase/decrease in beat-rate triggered by different agonists. However, CRP co-incubated cells did not exhibit desensitization of the respective GPCRs after the stimulation with the different agonists. This lack of desensitization was independent of the GPCR type, but it was dependent on the CRP concentration. Therefore, CRP interferes with the desensitization of GPCRs and has to be considered as a novel regulator of adrenergic, angiotensin-1 and endothelin receptors.

Interleukin-6 (IL-6) and C-reactive protein (CRP) are being used for diagnosis of sepsis. However, studies have reported varying cut-off levels and diagnostic performance. This study aims to investigate the optimal cut-off levels and performance of IL-6 and CRP for the diagnosis of neonatal sepsis. The study was conducted at the University Hospital of Leipzig, Germany from November 2012 to June 2020. A total of 899 neonates: 104 culture proven sepsis, 160 clinical sepsis, and 625 controls were included. Blood culture was performed using BacT/ALERT 3D system. IL-6 and CRP were analyzed by electrochemiluminescent immunoassay and immunoturbidimetric assay, respectively. Data were analyzed using SPSS 20 statistical software. Among neonates with proven sepsis, the optimal cut-off value of IL-6 was 313.5 pg/mL. The optimal cut-off values for CRP in 5 days serial measurements (CRP1, CRP2, CRP3, CRP4, and CRP5) were 2.15 mg/L, 8.01 mg/L, 6.80 mg/L, 5.25 mg/L, and 3.72 mg/L, respectively. IL-6 showed 73.1% sensitivity, 80.2% specificity, 37.6% PPV, and 94.8% NPV. The highest performance of CRP was observed in the second day with 89.4% sensitivity, 97.3% specificity, 94.5% PPV, and 98.3% NPV. The combination of IL-6 and CRP showed increase in sensitivity with decrease in specificity. In conclusion, this study defines the optimal cut-off values for IL-6 and CRP. The combination of IL-6 and CRP demonstrated increased sensitivity. The CRP 2 at cut-off 8.01 mg/L showed the highest diagnostic performance for identification of culture negative clinical sepsis cases. We recommend the combination of IL-6 (≥313.5 pg/mL) and CRP1 (≥2.15 mg/L) or IL-6 (≥313.5 pg/mL) and CRP2 (≥8.01 mg/L) for early and accurate diagnosis of neonatal sepsis. The recommendation is based on increased sensitivity, that is, to minimize the risk of any missing cases of sepsis. The CRP2 alone at cut-off 8.01 mg/L might be used to identify clinical sepsis cases among culture negative sepsis suspected neonates in hospital settings.

C-reactive protein (CRP), a humoral component of the innate immune system with important functions in host-defense, is extensively used as a sensitive biomarker of systemic inflammation. During inflammation, hepatocyte-derived CRP rises dramatically in the blood due to increased interleukin-6 (IL-6) levels. Reliable detection of CRP in saliva, instead of blood, would offer advantages regarding sampling procedure and availability but using saliva as a diagnostic body fluid comes with challenges. The aims of this study were to evaluate associations between salivary CRP, total protein levels in saliva and serum CRP. Furthermore, we examined associations with plasma IL-6, body mass index (BMI), tobacco smoking and age. Salivary CRP was investigated by ELISA in 107 middle-aged participants from the general population. We employed spectrophotometric determination of total protein levels. Correlation analyses were used for associations of salivary CRP with serum CRP (turbidimetry), plasma IL-6 (Luminex®), BMI and smoking habits. Salivary median CRP was 68% higher (p=0.009), and total protein levels were 167% higher (p<0.0001), in morning compared to evening saliva. The correlation coefficients between serum and salivary CRP were low to moderate, but stronger for evening than morning saliva. Plasma IL-6 correlated significantly with serum CRP (rs=0.41, p<0.01), but not with morning or evening salivary CRP. Non-smokers showed 103% higher salivary CRP levels (p=0.015), whereas serum CRP was independent of smoking status. As opposed to CRP in serum, salivary CRP was not associated with BMI. Salivary CRP was 90% higher among the age interval 60–69 years compared to subjects aged 45–59 (p=0.02) while serum CRP levels did not differ between the age groups. In conclusion, CRP in saliva did not straightforwardly reflect serum concentrations. This raises questions regarding adequate reflection of biological events. The pronounced diurnal salivary CRP pattern accentuates the importance of standardizing the time-point of sampling.

10,291 participants, aged 20 to 85 years of age, available from the 1999 through 2002 NHANES databases participated in this study. Only 8,485 (82%) of these participants were included in the data analysis. Participants who were pregnant (n = 603), not examined at a mobile examination center (n = 820), or had missing values for height (n = 164) and/or weight (n = 125) were eliminated. Individuals were classified into four groups (underweight, normal, overweight and obese) based on body mass index (BMI). Variables measured in the study included body mass index, physical fitness, dietary folic acid, c-reactive protein, homocysteine, folate, serum total cholesterol, serum triglycerides, HDL-C, and glucose. All data was collected at Mobile Examination Centers (MEC). The results of the present study showed that being overweight and obese were associated with a poor serum lipid profile, higher serum glucose levels, lower participation in physical activity and a lower physical fitness level. Being overweight and obese was also associated with higher serum levels of inflammatory markers for cardiovascular disease (CVD). Overweight and obese individuals are also being diagnosed with coronary heart disease (CHD) at a younger age.

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Indiana University-Purdue University Indianapolis (IUPUI) / While depression is a risk factor for type 2 diabetes, little is known about the effect of depression treatment on diabetes risk markers. Using data from the recently completed eIMPACT trial (NCT02458690, supported by R01 HL122245), I examined if depression intervention improves diabetes risk markers and if improvements in somatic depressive symptoms mediate potential intervention effects. 216 participants (primary care patients ≥50 years with depression and elevated cardiovascular disease risk from a safety net healthcare system) were randomized to 12 months of the eIMPACT intervention (modernized collaborative care intervention involving internet cognitive-behavioral therapy [CBT], telephonic CBT, and/or select antidepressants; n=107) or usual primary care for depression (primary care providers supported by embedded behavioral health clinicians and affiliated psychiatrists; n = 109). Given my focus on diabetes risk, I excluded participants who did not attend the post-treatment visit (n = 17) or who had a diabetes history at pre-treatment (n = 73), leaving a final sample of 126 (n=66 intervention, n=60 usual care; Mage = 58 years, 79% women, 50% Black, 47% with income <$10k/year). I computed depressive symptom severity variables from the Hopkins Symptom Checklist-20 (SCL-20) items: hyperphagia (“overeating” item), poor appetite (“poor appetite”), hypersomnia (“sleeping too much”), disturbed sleep (“sleep that is restless or disturbed”) and SCL-15 (mean of items not pertaining to appetite or sleep). I calculated insulin resistance from fasting plasma glucose and insulin using the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR)-2 calculator, body mass index (BMI) from measured height and weight, and plasma concentrations of high-sensitivity C-reactive protein (hsCRP), leptin, and ghrelin using ELISA kits. Parallel mediation analyses revealed that 12 months of modernized collaborative care for depression improved both directions of sleep symptoms but did not improve poor appetite or hyperphagia – the somatic symptom most consistently linked with increases in HOMA-IR, BMI, hsCRP, and leptin. Of the five cardiometabolic biomarkers examined, the eIMPACT intervention decreased only hsCRP and ghrelin. There were no intervention effects on HOMA-IR, BMI, or leptin. In addition, no somatic depressive symptoms mediated intervention effects on the cardiometabolic biomarkers, nor did race moderate any mediation effects. Further research is warranted to determine best practices for targeting hyperphagia and reducing cardiometabolic disease risk among people with depression.

Chan Fat-Yiu. / Thesis (M.Sc.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 85-93). / Abstracts in English and Chinese. / ACKNOWLEDGEMENTS --- p.4 / SUMMARY --- p.5 / ABBREVIATIONS --- p.9 / LIST OF TABLES --- p.11 / LIST OF FIGURES --- p.13 / Chapter CHAPTER I --- INTRODUCTION --- p.14 / Chapter 1.1 --- The Historical Aspects of C-Reaction Protein --- p.15 / Chapter 1.2 --- Biochemistry of CRP --- p.16 / Chapter 1.3 --- Physiology of CRP --- p.18 / Chapter 1.4 --- Current Clinical Applications of Serum CRP Assay --- p.19 / Chapter 1.5 --- Recent Findings of CRP --- p.21 / Chapter 1.5.1 --- Pathophysiology of atherosclerosis --- p.22 / Chapter 1.5.2 --- A nother atherogenic risk factor: hs- CRP --- p.26 / Chapter 1.5.3 --- Can hs-CRP replace other risk factors? --- p.30 / Chapter 1.5.4 --- Altering hs-CRP result in medication --- p.32 / Chapter 1.6 --- Methods of Measurement of CRP Concentration --- p.33 / Chapter 1.7 --- Analytical Considerations in the Measurement of hs-CRP --- p.34 / Chapter CHAPTER II --- OBJECTIVES AND SIGNIFICANCE --- p.36 / Chapter 2.1 --- Objectives --- p.37 / Chapter 2.2 --- Issues and Problems --- p.37 / Chapter 2.3 --- Significance and Value of this Study --- p.38 / Chapter CHAPTER III --- MA TERIALS AND METHODS I Setting up the serum hs-CRP assay on the Hitachi 911 Analyzer --- p.39 / Chapter 3.1 --- Materials --- p.40 / Chapter 3.1.1 --- Reagents from Roche Diagnostics --- p.40 / Chapter 3.1.2 --- Reagents for the Beckman Coulter Array ® Analyzer --- p.40 / Chapter 3.1.3 --- In-house reagents --- p.41 / Chapter 3.2. --- Apparatus and Equipment --- p.41 / Chapter 3.2.1 --- Hitachi 911 Analyzer --- p.41 / Chapter 3.2.2 --- Beckman Coulter Array ® 360 Analyzer --- p.42 / Chapter 3.3 --- The Tina-quant a C-Reactive Protein (Latex) Ultrasensitive Assay --- p.42 / Chapter 3.3.1 --- Priniciple of the Dual-Radius Enhanced Latex (DuREL´ёØ) technology --- p.42 / Chapter 3.3.2 --- Assessment of Analytical Performance --- p.45 / Chapter CHAPTER IV --- MA TERIALS AND METHODS II Serum hs-CRP in Chinese chronic-renal-failure patients with atherosclerotic vascular disease or cardiac valve calcification --- p.48 / Chapter 4.1 --- Patient Recruitment --- p.49 / Chapter 4.2. --- Blood Specimens --- p.49 / Chapter 4.3 --- Assay Methods --- p.50 / Chapter 4.3.1 --- hs-CRP --- p.50 / Chapter 4.3.2 --- TC --- p.50 / Chapter 4.3.3 --- TG --- p.51 / Chapter 4.3.4 --- HDL-C --- p.51 / Chapter 4.3.5 --- LDL-C --- p.52 / Chapter 4.3.6 --- Apo A-1 --- p.52 / Chapter 4.3.7 --- Apo B --- p.53 / Chapter 4.3.8 --- Lp(a) --- p.53 / Chapter 4.4 --- Ultrasound measurement of carotid artery inter-media thickness --- p.53 / Chapter 4.5 --- Statistical analysis --- p.54 / Chapter CHAPTER V --- RESUTLSI Setting up the serum hs-CRP assay on the Hitachi 911 Analyzer --- p.55 / Chapter 5.1 --- Imprecision --- p.56 / Chapter 5.2 --- Linearity --- p.56 / Chapter 5.3 --- Recovery --- p.56 / Chapter 5.4 --- Detection Limit --- p.57 / Chapter 5.5 --- Carry-over --- p.57 / Chapter CHAPTER VI --- RESULTS II Serum hs-CRP in Chinese chronic-renal-failure patients with atherosclerotic vascular disease or cardiac valve calcification --- p.63 / Chapter 6.1 --- Patient Recruitment --- p.64 / Chapter 6.2 --- Chinese chronic-renal-failure patients with AVD --- p.64 / Chapter 6.3 --- Chinese chronic-renal-failure patients with CVC --- p.65 / Chapter CHAPTER VII --- DISCUSSION I Performance of the serum hs-CRP assay on the Hitachi 911 Analyzer --- p.75 / Chapter 7.1 --- "Imprecision, Detection Limit, Linearity, and Recovery of hs-CRP Assay" --- p.76 / Chapter 7.1.1 --- Imprecision --- p.76 / Chapter 7.1.2 --- Detection Limit --- p.76 / Chapter 7.1.3 --- Linearity --- p.76 / Chapter 7.1.4 --- Recovery --- p.77 / Chapter 7.2 --- Overall Performance --- p.77 / Chapter CHAPTER VIII --- DISCUSSION II Serum hs-CRP in Chinese chronic-renal-failure patients with atherosclerotic vascular disease or cardiac valve calcification --- p.79 / Chapter 8.1 --- CAPD Patients --- p.80 / Chapter 8.2 --- Serum hs-CRP Concentration of AVD and CVC Patients --- p.81 / Chapter 8.3 --- Other risk factors in AVD and CVC Patients --- p.82 / Chapter 8.4 --- Conclusion --- p.83 / REFERENCES --- p.85