Association of Plasma Branched-Chain and Aromatic Amino Acids with Reduction in Kidney Function Evaluated in Apparently Healthy Adults.

The published literature on the association of circulatory branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) with reduced kidney function is inconsistent or conflicting. Clarification of it might help to better understand the underlying pathophysiology and to determine potential biomarkers for early detection and evaluation of kidney function decline. Our main purpose was to explore and clarify the potential relationships of individual BCAAs and AAAs with estimated glomerular filtration rate (eGFR) decline. We included the data from 2804 healthy subjects and categorized them into three groups based on eGFR tertiles. The associations between individual amino acids and eGFR were explored by covariate-adjusted logistic regression models. There was a progressive increase in the concentrations of BCAAs and AAAs from the upper to the lower tertiles. We revealed significant positive associations of isoleucine, leucine, and phenylalanine with lower tertiles of eGFR in the adjusted models (p < 0.01-0.001). The findings hold a promising potential of using plasma isoleucine, leucine, and phenylalanine levels for evaluation of kidney function decline. Future longitudinal studies should investigate the causal association between altered levels of these amino acids and impaired kidney function and also the utility of the former as potential biomarkers for evaluating the risk and early detection of the latter.

Plasma Branched-Chain and Aromatic Amino Acids in Relation to Hypertension.

Findings of the available studies regarding the roles of branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) in hypertension are inconsistent, conflicting and inconclusive. The purpose of this study was to explore and clarify the existence of any relationships of individual BCAAs and AAAs with hypertension with adjustments for potential relevant confounders. A total of 2805 healthy controls and 2736 hypertensive patients were included in the current analysis. The associations between individual amino acids and hypertension were explored by logistic regression analyses adjusted for potential confounding variables. Among the investigated amino acids, only the BCAAs showed consistently significant positive associations with hypertension in the adjusted models (p-trend < 0.05 to 0.001). However, compared with the corresponding lowest quartile of individual BCAAs, the positive association with hypertension remained significant only in the highest quartile (p < 0.01 to 0.001). We confirmed in a relatively large cohort of subjects that BCAAs, not AAAs, demonstrated consistent positive associations with hypertension. The results display the promising potential for the use of BCAAs as relevant and accessible biomarkers, and provide perspectives on interventions directed towards the reduction in plasma BCAA levels in the prevention and management of hypertension.

Association of plasma free amino acids with hyperuricemia in relation to diabetes mellitus, dyslipidemia, hypertension and metabolic syndrome.

Previous studies demonstrated independent contributions of plasma free amino acids (PFAAs) and high uric acid (UA) concentrations to increased risks of lifestyle-related diseases (LSRDs), but the important associations between these factors and LSRDs remain unknown. We quantified PFAAs and UA amongst Japanese subjects without LSRDs (no-LSRD, n = 2805), and with diabetes mellitus (DM, n = 415), dyslipidemia (n = 3207), hypertension (n = 2736) and metabolic syndrome (MetS, n = 717). The concentrations of most amino acids differed significantly between the subjects with and without hyperuricemia (HU) and also between the no-LSRD and LSRD groups (p < 0.05 to 0.001). After adjustment, the logistic regression analyses revealed that lysine in DM, alanine, proline and tyrosine in dyslipidemia, histidine, lysine and ornithine in hypertension, and lysine and tyrosine in MetS demonstrated significant positive associations with HU among the patients with LSRDs only (p < 0.05 to 0.005). By contrast, arginine, asparagine and threonine showed significant inverse associations with HU in the no-LSRD group only (p < 0.05 to 0.01). For the first time, we provide evidence for distinct patterns of association between PFAAs and HU in LSRDs, and postulate the possibility of interplay between PFAAs and UA in their pathophysiology.

Alteration in plasma free amino acid levels and its association with gout.

BACKGROUND: Studies on the association of plasma-free amino acids with gout are very limited and produced conflicting results. Therefore, we sought to explore and characterize the plasma-free amino acid (PFAA) profile in patients with gout and evaluate its association with the latter. METHODS: Data from a total of 819 subjects (including 34 patients with gout) undergoing an annual health examination program in Shimane, Japan were considered for this study. Venous blood samples were collected from the subjects and concentrations of 19 plasma amino acids were determined by high-performance liquid chromatography-electrospray ionization-mass spectrometry. Student's t-test was applied for comparison of variables between patient and control groups. The relationships between the presence or absence of gout and individual amino acids were investigated by logistic regression analysis controlling for the effects of potential demographic confounders. RESULTS: Among 19 amino acids, the levels of 10 amino acids (alanine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, tryptophan, valine) differed significantly (P < .001 to .05) between the patient and control groups. Univariate logistic regression analysis revealed that plasma levels of alanine, isoleucine, leucine, phenylalanine, tryptophan and valine had significant positive associations (P < .005 to .05) whereas glycine and serine had significant inverse association (P < .05) with gout. CONCLUSIONS: The observed significant changes in PFAA profiles may have important implications for improving our understanding of pathophysiology, diagnosis and prevention of gout. The findings of this study need further confirmation in future large-scale studies involving a larger number of patients with gout.

Plasma free amino acid profiles evaluate risk of metabolic syndrome, diabetes, dyslipidemia, and hypertension in a large Asian population.

BACKGROUND: Recently, the association of plasma free amino acid (PFAA) profile and lifestyle-related diseases has been reported. However, few studies have been reported in large Asian populations, about the usefulness of PFAAs for evaluating disease risks. We examined the ability of PFAA profiles to evaluate lifestyle-related diseases in so far the largest Asian population. METHODS: We examined plasma concentrations of 19 amino acids in 8589 Japanese subjects, and determined the association with variables associated with obesity, blood glucose, lipid, and blood pressure. We also evaluated the PFAA indexes that reflect visceral fat obesity and insulin resistance. The contribution of single PFAA level and relevant PFAA indexes was also examined in the risk assessment of lifestyle-related diseases. RESULTS: Of the 19 amino acids, branched-chain amino acids and aromatic amino acids showed association with obesity and lipid variables. The PFAA index related to visceral fat obesity showed relatively higher correlation with variables than that of any PFAA. In the evaluation of lifestyle-related disease risks, the odds ratios of the PFAA index related to visceral fat obesity or insulin resistance with the diseases were higher than most of those of individual amino acid levels even after adjusting for potential confounding factors. The association pattern of the indexes and PFAA with each lifestyle-related disease was distinct. CONCLUSIONS: We confirmed the usefulness of PFAA profiles and indexes as markers for evaluating the risks of lifestyle-related diseases, including diabetes mellitus, metabolic syndrome, dyslipidemia, and hypertension in a large Asian population.

The different roles of innate immune receptors in inflammation and carcinogenesis between races.

Innate immune factors exert widespread effects on cytokine secretion, cell survival, autophagy, and apoptosis. Nucleotide-binding and oligomerization domain-like receptors (NLRs) are members of the innate immune system in the cytosol that sense pathogens, endogenous danger molecules such as uric acid, and pollutants. Nucleotide-binding oligomerization domain-containing protein 1 and 2 (NOD1 and NOD2) are components of NLR family, and ligands of these factors are γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP) and muramyl dipeptide (MDP), respectively. Upon recognition of ligands, NOD1 and NOD2 induce the production of inflammatory cytokines and transcription factors including interleukin-6 (IL-6) and nuclear factor-κB (NF-κB). We examined the function of NOD1 and NOD2 in innate immunity, with a focus on their differing roles in disease pathogenesis between Japanese and Caucasian populations. Susceptibility to several immune-related diseases, including Crohn's disease, colorectal and breast cancers, and graft-versus-host-disease (GVHD) showed a correlation with genetic variants of NOD2 in Caucasian, but not in Japanese, populations. This difference may be primarily due to the fact that three major NOD2 SNPs (R702W, G908R, L1007insC) prevalent in Caucasians are rare or absent in Japanese populations. Because NLR has diverse effects on immune function, it is possible that many as yet uncharacterized immune-related diseases will also show different susceptibilities between races due to the different ratio of genetic variants in innate immune genes.

[Fact-finding survey on regional healthcare services for patients with epilepsy based on a questionnaire administered to public health centers in Japan].

OBJECTIVES: Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures. The prevalence of epilepsy is about 1%, and its incidence is increasing with the aging population. In addition to their medical problems, epilepsy patients face many social problems, including schooling, working, and maintaining their driver's licenses. However, these problems are not fully recognized by the regional healthcare centers (HCCs), and the inadequacy of collaboration between medical services, healthcare, and welfare is sometimes pointed out. Under these circumstances, this fact-finding survey was administered in the form of a questionnaire to HCCs across the nation for the purpose of improving the support system and educational activities for epilepsy in Japan. METHODS: A mail-back survey on regional healthcare services for epilepsy patients was sent out to 490 HCCs across the nation. Public health nurses (PHNs) responded to the self-completed questionnaire on behalf of each HCC. The questionnaire was comprised of the presence or absence of consultations on epilepsy, content of the consultations, and holding of workshops, lectures, or conferences in the community covered by the HCC. RESULTS: We obtained responses from 347 HCCs (response rate 71%). Seventy-three percent of the PHNs had experience with consultations regarding the medical and healthcare issues associated with epilepsy. However, only 10% of the PHNs responded that they could provide appropriate consultation for these issues. The content of the consultations mainly included medical services, clinical symptoms of epilepsy, and anxieties about their social life and their future. Workshops, lectures, or conferences on epilepsy were held for residents or health and welfare professionals in only 8% of the communities. This percentage is lower than those (21-70%) for other intractable or mental disorders that are mainly managed by HCCs (P<0.01). On the other hand, 76% of PHNs in the HCCs felt the need for knowledge about epilepsy, and 60% wanted to join the epilepsy educational programs. CONCLUSION: Although many PHNs belonging to HCCs conduct consultations regarding epilepsy-related issues, many feel they cannot adequately respond to these issues. Furthermore, they feel the need for further knowledge about epilepsy but are not able to gain such knowledge because of financial and geographical restrictions. To improve these situations, regional education programs for epilepsy should be established in each local municipality in the future with support provided by medical facilities, regional medical associations, the Japan Epilepsy Society, and the Government.

[Immune System Reaction against Environmental Pollutants].

Environmental pollutants (such as diesel exhaust particles and silica) cause disorders ranging from bronchial asthma to malignant tumors. In recent years, it has been reported that some of the signaling pathways in which environmental contaminants act in vivo are associated with innate immunity. Innate immunity recognizes ligands and induces inflammation. Those ligands are pathogen-associated molecular patterns (PAMPs: e.g., lipopolysaccharide) and danger-associated molecular patterns (DAMPs: e.g., cholesterol crystallization or uric acid crystal). Activation of innate immunity stimulates the acquired immunity system. Therefore, innate immunity regulates the strength of the general immune system. Furthermore, crystal silica, which is an environmental pollutant, activates innate immunity as a ligand. Innate immunity involves the membrane-bound Toll-like receptors (TLR) and cytoplasm-localized nucleotide-binding oligomerization domain (NOD)-like receptors (NLR). We reported the innate immunity-system-related diseases such as Crohn's disease, Blau syndrome, myelogenous leukemia, and sarcoidosis. An inflammasome complex containing NLR has attracted attention owing to its correlation with the onset of several diseases. It is reported that the inflammasome activation is related to the development of lifestyle-related diseases such as myocardial infarction and fatty liver. It is also reported that the mechanism by which crystal silica and asbestos cause inflammation involves the inflammasome activation. Analyzing the genes of innate immunity contributes to the clarification of the mechanism of disease onset caused by environmental pollutants.

Risk factors for silent cerebral infarction in the elderly.

BACKGROUND: A silent cerebral infarction (SCI) is often found in the elderly. However, studies on SCIs focusing on an elderly population are sparse. Our objective was to evaluate risk factors of SCIs in healthy elderly individuals. METHODS: One hundred seventy-five neurologically normal community-dwelling Japanese people aged >/=65 years (128 men and 47 women; 77.5 +/- 8.7 years) were studied. Among them we assessed the demographic data and detected SCIs on brain magnetic resonance imaging scans. RESULTS: Eighty four subjects had at least one SCI. Hypertension and low body mass index (BMI) were the significant risks for SCIs in multivariate analysis adjusted for age, sex and other risk factors. Mean BMI in subjects with SCIs was significantly lower than those without SCIs (20.8 +/- 3.2 kg/m(2) vs. 22.1 +/- 3.2 kg/m(2)). In the subgroup analysis by age stratum regarding hypertension and BMI, hypertension was a significant risk factor in subjects aged 65-75 years. Lower BMI had a significant risk in subjects aged >/=81 years. CONCLUSIONS: Hypertension and increasing age have been recognized as risk factors for SCIs, and low BMI might be a significant risk especially in superelderly subjects. Further data with a larger sample size is needed to confirm the relationship between BMI and SCIs among the elderly.