Prolonged sitting time links to subclinical atherosclerosis.

BACKGROUND: This study investigates the association between daily sitting time and subclinical atherosclerosis by using coronary computed tomography angiography (CCTA). METHODS: The study enrolled 203 subjects (age 57.6 ± 8.8 years) who underwent CCTA at annual medical checkups. Sitting time was categorized as < 5 hours/day (short), 5 to 9 hours/day (moderate) and ≥10 hours/d (long). We analyzed the coronary calcium score, plaque characteristics, and severity of coronary artery stenosis, including the segment involvement score (SIS) and segment stenosis score (SSS). RESULTS: Subjects with longer sitting times tended to be male gender and have lower levels of high-density lipoprotein cholesterol (p for trend < 0.05). In addition, those with longer sitting time had higher SIS (1.2 ± 1.5 vs. 1.6 ± 2.1 vs. 2.3 ± 2.0 for short, moderate, and long sitting time, respectively) (p for trend = 0.015) and SSS (1.4 ± 2.0 vs. 1.9 ± 2.7 vs. 2.7 ± 2.6) (p for trend = 0.015), suggesting longer sitting time-correlated with the severity of coronary atherosclerosis. When considering the coronary plaque patterns, subjects with shorter sitting time (<5 hours/d) tended to have more calcified plaque and subjects with longer sitting time (≥10 hours/d) had more mixed plaque (p for trend = 0.018). After adjusting for age, gender, comorbidities, body mass index, and lipid profiles, increased sitting time was independently associated with the presence of mixed plaque, suggesting longer sitting time may be associated with higher risk of the formation of vulnerable plaque. CONCLUSION: Longer sitting time was linked to the severity of subclinical atherosclerosis and the presence of high-risk vulnerable plaque in the general population.

The association of the steatosis severity in fatty liver disease with coronary plaque pattern in general population.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is commonly observed in patients with cardiovascular disease (CVD). However, whether the steatosis severity of NAFLD is independently associated with coronary artery atherosclerosis is still controversial. METHODS: Consecutive Taiwanese individuals (1502) who received coronary computed tomography angiography (CCTA) and abdominal sonography as part of a general routine health evaluation were enrolled. The association between steatosis severity, coronary atherosclerosis involvement and various plaque patterns were analysed. RESULTS: Compared with non-steatosis, NAFLD subjects had more cardiovascular risk factors that correlated with the severity of steatosis (P for the trend <.05). The presence of atherosclerotic plaques correlated with the severity of steatosis (none: 53%, mild: 64.1%, and moderate to severe: 66.9%; P for the trend <.001). Parameters of coronary atherosclerosis, including atheroma burden obstructive score (ABOS), segment involvement score (SIS) and segment stenosis score (SSS), were higher in the moderate to severe steatosis group. After adjusting for major confounding factors, the severity of steatosis still correlated with the mixed plaque pattern (P = .043). Subgroup analysis of the risk of the presence of overall coronary and mixed plaques showed a significant association with increasing severity of steatosis, especially among these who were <65 years old, male, without metabolic syndrome, and with lower low-density lipoprotein choleseterol values. CONCLUSION: In this general population, steatosis severity of NAFLD is associated with coronary artery atherosclerosis burden. Furthermore, steatosis severity correlated with the risk of the presence of coronary plaques, especially high-risk plaques, and was independent of traditional risk factors.

Factor analysis for the clustering of cardiometabolic risk factors and sedentary behavior, a cross-sectional study.

BACKGROUND: Few studies have reported on the clustering pattern of CVD risk factors, including sedentary behavior, systemic inflammation, and cadiometabolic components in the general population. OBJECTIVE: We aimed to explore the clustering pattern of CVD risk factors using exploratory factor analysis to investigate the underlying relationships between various CVD risk factors. METHODS: A total of 5606 subjects (3157 male, 51.5±11.7 y/o) were enrolled, and 14 cardiovascular risk factors were analyzed in an exploratory group (n = 3926) and a validation group (n = 1676), including sedentary behaviors. RESULTS: Five factor clusters were identified to explain 69.4% of the total variance, including adiposity (BMI, TG, HDL, UA, and HsCRP; 21.3%), lipids (total cholesterol and LDL-cholesterol; 14.0%), blood pressure (SBP and DBP; 13.3%), glucose (HbA1C, fasting glucose; 12.9%), and sedentary behavior (MET and sitting time; 8.0%). The inflammation biomarker HsCRP was clustered with only adiposity factors and not with other cardiometabolic risk factors, and the clustering pattern was verified in the validation group. CONCLUSION: This study confirmed the clustering structure of cardiometabolic risk factors in the general population, including sedentary behavior. HsCRP was clustered with adiposity factors, while physical inactivity and sedentary behavior were clustered with each other.

Cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA-4-Ig) suppresses Staphylococcus aureus-induced CD80, CD86, and pro-inflammatory cytokine expression in human B cells.

BACKGROUND: Cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA-4-Ig) competes with CD28 for binding CD80/CD86 on antigen-presenting cells (APCs) to limit T cell activation. B cells are believed to be important APCs in the pathogenesis of autoimmune diseases and express CD80/CD86 after activation; however, relatively little is known about the effect of CTLA-4-Ig on B cells. This study tested the impact of CTLA-4-Ig on human B cell responses. METHODS: Human blood B cells were purified from healthy donors and activated in the presence of CTLA-4-Ig or the L6-Ig control protein in vitro. RT-q-PCR and immunofluorescence staining were performed to detect activation marker expression. ELISA was conducted to measure cytokine secretion. The CD80/CD86 levels on the surface of the memory B cells in the blood of 18 patients with rheumatoid arthritis (RA) were detected using immunofluorescence staining. RESULTS: CTLA-4-Ig suppressed the expression of Staphylococcus aureus (SAC)-induced CD80, CD86, TNFA, and IL6 in human B cells at the transcriptional level. Furthermore, CTLA-4-Ig concomitantly decreased SAC-induced CD80/CD86 surface expression on and TNF-α and IL-6 secretion from B cells. On the other hand, T cell-dependent (TD) stimulation-induced B cell activation, proliferation, plasma cell differentiation, and antibody secretion were not affected by CTLA-4-Ig. As expected, TD stimulation-induced surface CD80 was hindered by CTLA-4-Ig. Notably, a blockade of CD80/CD86 on the surface of the memory B cells was observed in the patients with RA after abatacept (CTLA-4-Ig) treatment. In a portion of the RA patients, restoration of CD80/CD86 staining on the surface of the memory B was detected starting in the 3rd month of abatacept treatment. Interestingly, the surface levels of CD80/CD86 on the patients' memory B cells positively correlated with disease activity. CONCLUSIONS: We found that CTLA-4-Ig directly suppressed SAC-induced B cell activation in vitro. Obstruction of CD80 and CD86 on the surface of the memory B cells was detected in the RA patients after abatacept treatment. Blocking CD80/CD86 on B cells by CTLA-4-Ig may hinder T cell activation and associated with the disease activity of RA in vivo. Our findings indicate that CTLA-4-Ig may regulate humoral responses by modulating B cell activation and interfering T cell-B cell interaction.

Hemoglobin A1C Levels are Independently Associated with the Risk of Coronary Atherosclerotic Plaques in Patients without Diabetes: A Cross-Sectional Study.

AIM: Coronary atherosclerotic plaques can be detected in asymptomatic subjects and are related to low-density lipoprotein cholesterol (LDL) levels in patients with coronary artery disease. However, researchers have not yet determined the associations between various plaque characteristics and other lipid parameters, such as HDL-C and TG levels, in low-risk populations. METHODS: One thousand sixty-four non-diabetic subjects (age, 57.86±9.73 years; 752 males) who underwent coronary computed tomography angiography (CCTA) were enrolled and the severity and patterns of atherosclerotic plaques were analyzed. RESULTS: Statin use was reported by 25% of the study population, and subjects with greater coronary plaque involvement (segment involvement score, SIS) were older and had a higher body mass index (BMI), blood pressure, unfavorable lipid profiles and comorbidities. After adjusting for comorbidities, only age (ß=0.085, p＜0.001), the male gender (ß=1.384, p＜0.001), BMI (ß=0.055, p=0.019) and HbA1C levels (ß=0.894, p＜0.001) were independent factors predicting the greater coronary plaque involvement in non-diabetic subjects. In the analysis of significantly different (＞50%) stenosis plaque patterns, age (OR: 1.082, 95% CI: 10.47-1.118) and a former smoking status (OR: 2.061, 95% CI: 1.013-4.193) were independently associated with calcified plaques. For partial calcified (mixed type) plaques, only age (OR: 1.085, 95% CI: 1.052-1.119), the male gender (OR: 7.082, 95% CI: 2.638-19.018), HbA1C levels (OR: 2.074, 95% CI: 1.036-4.151), and current smoking status (OR: 1.848, 95% CI: 1.089-3.138) were independently associated with the risk of the presence of significant stenosis in mixed plaques. CONCLUSIONS: A higher HbA1c levels is independently associated with the presence and severity of coronary artery atherosclerosis in non-diabetic subjects, even when LDL-C levels are tightly controlled.

Spirometric reference values in heathy Chinese adults in Taiwan: The secular changes and comparison with other Asian populations.

BACKGROUND/PURPOSE: Although the lung function test has played an important role in respiratory care for a long time, valid spirometry reference values in the Chinese population in Taiwan remain to be elucidated. METHODS: 2963 healthy Taiwanese subjects aged 21 to 88 years (1765 males, 59.6%) from February 2015 to February 2017 were enrolled. The subjects attempted to meet the 2005 American Thoracic Society (ATS) and the European Respiratory Society (ERS) guidelines when performing forced expiratory spirograms. We would like to establish the spirometry predictive equations for forced expiratory volume (FEV1), forced vital capacity (FVC), FEV1/FVC, and lower limit of normal (LLN) in Taiwan and compare with other Asian populations. RESULTS: We established the spirometry predictive equations using a linear model for the entire population, using age and height as independent variables, which best predicted all spirometry parameters for sea level and highland subjects. We found that the values of FEV1 and FVC for the Taiwanese subjects in our study were systematically lower than those reported in South Korea, Japan, and China, but higher than the values in Yang's 1993 and Pan's 1997 Taiwan study. CONCLUSION: This study addressed the up-to-date spirometry reference equations and values for a healthy adult Chinese population in Taiwan.

InVestiGation of the Association of Physical Activity and Sedentary Behavior with tHe Occurrence of Future Cardiovascular Disease and Long Term Outcome in General Population Using the HEALTHCARE Database (VGH-HEALTHCARE).

BACKGROUND: Current evidence supports the beneficial effect of physical activity in reducing adverse events, however studies on Asian populations are limited and have reported inconsistent findings. The aim of this study was to investigate the association between physical activity and the development of cardiovascular disease, diabetes, hypertension and malignancy in a large Asian cohort. We also investigated interactions between the intensity of physical activity, environmental exposure and biochemical markers. METHODS: Subjects who received annual checkups at Taipei Veterans General Hospital were invited to join this study. Information on physical activity was evaluated using the International Physical Activity Questionnaire Short Form (IPAQ-SF). Associations between the occurrence of clinical events including cardiovascular events, diabetes and malignancies and the intensity of physical activity, biochemical markers, imaging findings, personality trait evaluations and nutrition were evaluated. RESULTS: In the initial stage of this study, a total of 1010 patients enrolled, 626 (62%) were male, 74 (7.4%) had diabetes, 183 (18.3%) had hypertension, and 220 (21.8%) were smokers. The total cholesterol was 202.1 ± 36.2 mg/dL and low-density lipoprotein-cholesterol was 125.7 ± 32.9 mg/dL, including 49.3 ± 13.1 mg/dL for serum high-density lipoprotein-cholesterol and 120.7 ± 70.7 mg/dL for triglycerides. The fasting glucose level was 93.8 ± 21.9 mg/dL, and HbA1c was 5.7 ± 0.7%. All information collected will be incorporated with future events to analyze the relationship between biochemical parameters, physical activity and future adverse events. CONCLUSIONS: These findings will contribute to the understanding of the value of physical activity in determining future cardiovascular and non-cardiovascular events in Asian populations.

Serum bilirubin improves the risk predictions of cardiovascular and total death in diabetic patients.

BACKGROUND: Bilirubin is a potential endogenous inhibitor of atherosclerosis. We investigated the association of bilirubin and cardiovascular (CV) and all-cause mortality including potential improvements in bilirubin risk reclassification in asymptomatic diabetic patients. METHODS: We enrolled 2936 asymptomatic diabetic subjects. The serum bilirubin was measured, and future CV and all-cause death were the primary endpoints. RESULTS: The follow-up period was 5.4 ±â€¯3.0 y. There were 218 deaths including 95 cardiovascular deaths. The occurrence of CV death and all-cause death were negatively correlated with increasing serum bilirubin quintiles and actual bilirubin values. Serum bilirubin was negatively associated with incident cardiovascular death (hazard ratio: 0.26, 95% CI, 0.11-0.61, p = .01) and all-cause death (hazard ratio: 0.30, 95% CI, 0.17-0.51, p ≤.001). The addition of bilirubin for cardiovascular death increased the C-statistic from 0.713 (95% CI, 0.664-0.762) to 0.729 (95% CI, 0.681-0.776) (P = .008) and showed an integrated discrimination improvement (IDI) of 0.012 (P < .0171) with 8.57% improvement in net reclassification analysis (P = .0224). These results suggest additional predictive value is possible via total bilirubin levels for future CV deaths in diabetic patients. In terms of all-death, the addition of bilirubin significantly increased the C-statistic (from 0.769 to 0.78, P = .0064)-a 3.52% net reclassification improvement (P = .0307). It did not improve the IDI (p = .1505). CONCLUSIONS: Higher serum concentrations of bilirubin are associated with a decreased risk of developing CV and all-cause death in diabetic patients. Bilirubin improved the risk prediction of cardiovascular death but provided only a slightly better prediction of all-cause death than conventional risk factors.

High health literacy is associated with less obesity and lower Framingham risk score: Sub-study of the VGH-HEALTHCARE trial.

BACKGROUNDS: Lower health literacy (HL) is associated with several cardiovascular disease (CVD) risk factors such as diabetes, hypertension, and metabolic syndrome (MS). The aim of our study was to investigate the association between HL and the Framingham 10-year risk score of CVD. METHODS: From 2015-2016, 1010 subjects aged 23 to 88 years receiving health check-up in Taipei Veterans General Hospital had complete clinical evaluations and laboratory examinations. Fatty liver was diagnosed by ultrasonography. The short form questionnaire adapted from the Mandarin Health Literacy Scale was used to assess HL. The Framingham risk score was calculated by patient characteristics. RESULTS: Subjects with higher BMIs were associated with lower HL scores. The proportion of subjects with MS was higher in the lower health literacy score group (≤ 9) at 28.8%; further analysis found that lower HL was significantly associated with MS in women but not in men. The Spearman's rho demonstrated that the HL score was significantly associated with the BMI-based (rho = -0.11; P < 0.001) or lipid-based (rho = -0.09; P < 0.004) Framingham risk score. CONCLUSIONS: Higher HL scores were associated with less CVD risk such as lower BMIs, less MS in women, and less fatty liver disease. Furthermore, HL had an inverse association with the Framingham risk score as expected. Therefore, HL in patients with CVD risk should be improved and considered as an important issue in terms of CVD reduction.

Use of HLA-B*58:01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study.

OBJECTIVE: To evaluate the use of prospective screening for the HLA-B*58:01 allele to identify Taiwanese individuals at risk of severe cutaneous adverse reactions (SCARs) induced by allopurinol treatment. DESIGN: National prospective cohort study. SETTING: 15 medical centres in different regions of Taiwan, from July 2009 to August 2014. PARTICIPANTS: 2926 people who had an indication for allopurinol treatment but had not taken allopurinol previously. Participants were excluded if they had undergone a bone marrow transplant, were not of Han Chinese descent, and had a history of allopurinol induced hypersensitivity. DNA purified from 2910 participants' peripheral blood was used to assess the presence of HLA-B*58:01. MAIN OUTCOME MEASURES: Incidence of allopurinol induced SCARs with and without screening. RESULTS: Participants who tested positive for HLA-B*58:01 (19.6%, n=571) were advised to avoid allopurinol, and were referred to an alternate drug treatment or advised to continue with their prestudy treatment. Participants who tested negative (80.4%, n=2339) were given allopurinol. Participants were interviewed once a week for two months to monitor symptoms. The historical incidence of allopurinol induced SCARs, estimated by the National Health Insurance research database of Taiwan, was used for comparison. Mild, transient rash without blisters developed in 97 (3%) participants during follow-up. None of the participants was admitted to hospital owing to adverse drug reactions. SCARs did not develop in any of the participants receiving allopurinol who screened negative for HLA-B*58:01. By contrast, seven cases of SCARs were expected, based on the estimated historical incidence of allopurinol induced SCARs nationwide (0.30% per year, 95% confidence interval 0.28% to 0.31%; P=0.0026; two side one sample binomial test). CONCLUSIONS: Prospective screening of the HLA-B*58:01 allele, coupled with an alternative drug treatment for carriers, significantly decreased the incidence of allopurinol induced SCARs in Taiwanese medical centres.

Clinical and biochemical indicators of homeostasis model assessment-estimated insulin resistance in postmenopausal women.

BACKGROUND: Homeostasis model assessment of insulin resistance (HOMA-IR) is a surrogate estimate of directly measured insulin resistance that been robustly proven to be associated with diabetes and cardiovascular disease. The purpose of this study was to evaluate the use of several simple indicators to identify postmenopausal women with insulin resistance estimated by HOMA-IR. METHODS: We recruited 262 naturally postmenopausal women without overt diabetes for the study. HOMA-IR values were calculated from fasting glucose and insulin levels. Multiple linear regression analyses were carried out to detect determinants of HOMA-IR. Insulin resistance was conventionally defined as the upper quartile of the HOMA-IR values. The diagnostic power of clinical and biochemical markers for insulin resistance was assessed using receiver operating characteristic curves. RESULTS: Some 90% of the women with HOMA-IR ≥ 2.8 (75th percentile as cutoff) showed abnormal glucose metabolism and 45% of them had silent diabetes (odds ratio 6.09, 95% CI 3.17 - 11.73 vs. those with HOMA-IR < 2.8). Results revealed that uric acid, body mass index, waist circumference, alanine aminotransferase, triglycerides, and high-density lipoprotein cholesterol were important determinants of HOMA-IR in these women. Using uric acid ≥ 5.0 mg/dL as a cutoff point, we could diagnose insulin resistance with 75.4% sensitivity and 73.1% specificity. CONCLUSION: Postmenopausal women with HOMA-IR-estimated insulin resistance were at high risk of glucose abnormalities in this study. High HOMA-IR values were significantly associated with six clinical and biochemical indicators. Among these, high serum uric acid levels seemed to be a useful marker identifying postmenopausal women with insulin resistance. This study was registered at clinicaltrials.gov as NCT00945271.

Human SA gene polymorphisms are associated with non-high-density lipoprotein cholesterol in postmenopausal women: a pilot study.

OBJECTIVE: The purpose of the study is to evaluate the associations between polymorphisms of the human SA (SAH) gene, an acyl-CoA synthetase gene, with dyslipidemia and phenotypes of the insulin resistance syndrome in postmenopausal women. METHODS: One hundred and forty-two postmenopausal women were recruited for the study. Each subject received anthropometric and blood pressure measurements, fasting sampling for lipids, and a 75-g oral glucose tolerance test for insulin resistance. Genotypes of two polymorphisms in the promoter region (c.-962ins/del, c.-451G>A), one missense variant (c.1077G>C, p.K359N) in exon 8, and one in intron 12 (A>G) of the SAH gene, were determined. RESULTS: There were significant differences in genetic distribution of the SAH gene promoter I/D polymorphism between the two groups of subjects by non-high-density lipoprotein cholesterol (non-HDL-C) levels (p=0.004). The subjects with the DD genotype was associated with high levels of non-HDL-C (>160 mg/dL) as compared with the ID or II genotypes (p=0.002). Furthermore, three haplotypes were constructed based on the promoter I/D and the exon 8 G/C polymorphisms. Homozygosity for SAH haplotype 3 was associated with increased adiposity, insulin resistance, and elevated levels of non-HDL-C in the post menopausal women. The subjects with haplotype 3 had double the risk to have higher non-HDL-C levels than those with haplotype 1. CONCLUSION: Our results suggest that the polymorphisms of the SAH gene are associated with non-HDL-C levels in postmenopausal women. Further studies with larger sample sizes or different populations are warranted to confirm our preliminary findings.

Fasting triglyceride is a major determinant of postprandial triglyceride response in postmenopausal women.

OBJECTIVE: The purpose of the study was to examine the relative influences of fasting lipids, insulin resistance, and waist circumference (WC) on postprandial lipemia in postmenopausal women. DESIGN: Forty-nine naturally postmenopausal women were recruited for the study. Each woman underwent a 75-g oral glucose tolerance test to measure insulin resistance and a 1,000-kcal high-fat mixed meal test for postprandial triglyceride (TG) response. RESULTS: The participants were divided into three groups by tertiles of incremental TG response in the mixed meal test. The three groups were comparable in weight, WC, and fasting high-density lipoprotein cholesterol (HDL-C) levels. There were significant differences in fasting TG and non-HDL-C concentrations among the three groups. The women in the high-tertile group were more insulin resistant than those in the low-tertile group, indicated by higher homeostasis model assessment for insulin resistance (HOMA-IR) values. The postprandial TG response was significantly correlated with Log(fasting TG), fasting non-HDL-C and Log(HOMA-IR), but not with WC, in univariate regression analyses. Log(fasting TG) was the only variable that remained significantly related to incremental TG response when all the above were entered into multiple regression models. Subsequently, we found that Log(HOMA-IR) and fasting non-HDL-C independently predicted the variance of Log(fasting TG) in stepwise multiple regression. CONCLUSIONS: Our data demonstrated that the fasting TG level is a major determinant of postprandial TG response in postmenopausal women. Insulin resistance and non-HDL-C may contribute independently to the fasting TG level. The influences of WC on postprandial lipemia seemed to be insignificant.

Is hyperuricemia another facet of the metabolic syndrome?

BACKGROUND: Hyperuricemia is commonly associated with obesity, glucose intolerance, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. The resemblance of the metabolic syndrome and hyperuricemia has led to the suggestion that hyperuricemia is a part of the metabolic syndrome. The purpose of this study is to examine the contribution of uric acid (UA) as an additional component of the metabolic syndrome in middle-aged men. METHODS: In total, 393 male participants, aged 45-60 years, were recruited from a professional health evaluation program. Anthropometric measurements and blood pressure (BP) were taken after an overnight fast. Fasting blood samples were collected for the measurements of glucose, UA, and lipid profile. Logistic regression models were fitted to examine the relationship between UA and the diagnosis of metabolic syndrome. Factor analysis was performed to explore the relationship between UA and the components of the metabolic syndrome. RESULTS: The diagnosis of the metabolic syndrome was significantly associated with waist circumference (WC), glucose, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), systolic BP, and liver enzyme levels, but not associated with UA levels. The sensitivity of hyperuricemia (serum UA > or = 7.0 mg/dL) for the diagnosis of the metabolic syndrome was 58.0% and the specificity was 55.3%. In factor analysis, UA aggregated with body mass index, WC, glucose, log TG, and HDL-C as a metabolic factor. Systolic and diastolic BP were loaded on a second factor separately. The model loaded with UA explained a similar proportion of the total variance (56.9%), as did the model loaded without UA (62.5%). CONCLUSION: Our results suggest that the contribution of UA as an additional component of the syndrome seems to be insignificant. We propose that hyperuricemia might not be an important facet for the understanding of the underlying structure of the metabolic syndrome.

Inducible nitric oxide synthase expression and plasma bilirubin changes in rats under intermittent hypoxia treatment.

It has been reported that intermittent hypoxia treatment prevents oxidative injuries to the brain and protects the heart against ischemia-reperfusion injury. Both anti-oxidative defensive systems and prevention of free intracellular calcium overload might be the result of intermittent hypoxia. Thus, the purpose of this study was to explore the effects of intermittent hypoxia (8 h at 12 % O2 per day) for 0, 7 or 14 days on inducible nitric oxide synthase (iNOS) expression in the spleen and on splenic calcium response to the mitogen phytohemagglutinin (PHA). The results demonstrated that administration of intermittent hypoxia for 7 days caused severe hemolysis of erythrocytes in the spleen and the hemolytic condition was ameliorated by intermittent hypoxia for 14 days. However, a significant decline in splenic weight and an increase in plasma total bilirubin levels appeared in rats after hypoxia for 14 days. No calcium response to PHA was observed in splenocytes obtained from rats after intermittent hypoxia for 7 days. After intermittent hypoxia for 14 days, the calcium response to PHA was restored to the level of the controls. Intermittent hypoxia for 7 days was able to induce higher iNOS expression in splenic tissues than hypoxia for 14 days. These results suggested that intermittent hypoxia for 14 days appeared to involve acclimatization that protects the rats from oxidative injury through less hemolysis and iNOS expression in splenic tissues and by the presence of more bilirubin in the plasma. The increase in plasma total bilirubin levels might be the cause of induced adaptation to chronic intermittent hypoxia.