Modulation of human lymphocyte proliferative response with aging.

Previously, we have demonstrated age-associated alterations in transmembrane signaling. One of the most reproducible alterations found in the immune response with aging is the decrease of lymphocyte proliferation on stimulation with various different mitogens. Here, we confirm that proliferative responses to stimulation with phytohaemagglutin (PHA), recombinant human IL-2, or anti-CD3 monoclonal antibody are all greater in the young (20-25 years) than old (60-87 years) population. We attempted to modulate the proliferative response using various agents acting at different levels of transmembrane signaling (pertussis toxin, cholera toxin, isoproterenol, PMA, Ca ionophore A23187), as well as at the level of the lymphocyte plasma membrane (methyl-beta-cyclodextrin, MBCD), or by using antioxidant vitamins (Vitamin E or C). None of these agents was able to restore effectively the proliferative response of lymphocytes from the aged to the level of young subjects. Even the combination of A23187 and PMA acting directly on calcium metabolism and protein kinase C activity was insufficient to restore the decreased mitogenic capacity of T cells from elderly subjects. Cyclodextrin, which decreases the cholesterol content of the membrane, increased the proliferative response of lymphocytes of elderly subjects, but not to the level of the young. Vitamin E had a very strong inhibitory effect on lymphocyte stimulation in both the age groups, except in combination with MBCD in T cells of the elderly, while Vitamin C had no significant modulatory effect. MAPK ERK and p38 activation was found to be decreased with aging in T cells after anti-CD3 mAb stimulation. Vitamin E but not Vitamin C strongly inhibited MAPK ERK or p38 activation. The direct activation of certain molecules or the modulation of the cholesterol content of the membrane seems to be effective immunomodulatory interventions with aging.     

Effects of age on relationship of alcohol drinking and obesity to atherosclerotic risks

Atherosclerosis is a chronic pathological process in the arteries, in which a variety of its risk factors, such as hypertension, dyslipidemia, smoking, diabetes mellitus and obesity, are involved. Atherosclerotic progress is also closely linked with aging. We investigated effects of age on the relationships of alcohol drinking and obesity to atherosclerotic risks. Elevating effects of light drinking on blood pressure were significant in middle-aged and relatively old subjects but not in young subjects. The decreasing effects of light drinking on blood LDL cholesterol were significant in relatively young and middle-aged subjects, but not in elderly subjects, while increasing effects of light drinking on blood HDL cholesterol were significant in young, middle-aged, and elderly groups. In patients with type 2 diabetes, light drinking significantly decreased aortic pulse-wave velocity, which reflects atherosclerotic progress, without significant changes in blood HDL and fibrinogen levels, and this tendency was also found in elderly diabetes patients. Body mass index (BMI) was significantly correlated with arterial pressure and serum tryglyceride, HDL cholesterol, uric acid, and sialic acid levels in elderly patients with type 2 diabetes. Thus, age may be an important factor that affects the relations of some atherosclerotic risk factors to atherosclerotic progress.     

Age-related impairment of p56lck and ZAP-70 activities in human T lymphocytes activated through the TcR/CD3 complex.

Cellular immune responses decrease with aging. Lymphocytes of aged individuals do not perform as well as cells from young subjects in a number of in vitro assays including cell proliferation, cytokine production, and protection against apoptosis. Here, we have tested the hypothesis that a decrease in T cell responses in tymphocytes from elderly subjects could parallel a decrease in the activity of protein tyrosine kinases (PTK) associated with signal transduction in T lymphocytes. We report that anti-CD3-triggered T lymphocyte proliferation was significantly decreased in T lymphocytes from elderly subjects, but the decrease was not due to an alteration of the percentage or mean fluorescence intensities of CD3, CD4, and CD45. Of significance, the activities of p56lck and ZAP-70 in vitro were significantly decreased in T lymphocytes from elderly subjects compared to young individuals. However, the level of expression of the two kinases did not change with aging. The activity of p59fyn did not show changes with aging, suggesting that p59fyn did not compensate for the decreased activity of p56lck. We also found that the extent of tyrosine phosphorylation of the adaptor protein p95vav was similar in activated T lymphocytes from elderly and young subjects. Our results suggest that the altered cellular immune responses observed in T lymphocytes with aging may be the result, at least in part, of an alteration in early events associated with signal transduction through the TcR/CD3 complex that translates into decreased activities of p56lck and ZAP-70. Impairment in the activities of these twokey components of T cell signaling may contribute to reduced immune functions associated with aging.     

Relationship between drinking alcohol and atherosclerotic risk factors in female Japanese workers of different ages

AIM: To determine whether age influences the relationships of drinking alcohol with blood pressure and lipids in women. METHODS: The subjects were 53,911 female Japanese workers (20-69 years old) receiving annual health checkups at each workplace. The subjects were divided into three groups by daily average amount of ethanol consumed (non-drinkers; light drinkers, less than 30g ethanol/day; heavy drinkers, 30g ethanol/day or more). Blood pressure, body mass index (BMI) and total and HDL cholesterol were measured. RESULTS: In the age groups from twenties to fifties, BMI was significantly lower in light drinkers than in non-drinkers. In the forties and fifties age groups, systolic blood pressure in heavy drinkers was higher than that in non-drinkers, while no significant difference was found between non- and heavy drinkers in the twenties and thirties age groups. Diastolic blood pressure was higher in heavy drinkers than in non-drinkers in all age groups. Blood total cholesterol tended to be lower in drinkers than in non-drinkers at ages less than 60 years, while this relation was not observed in the sixties age group. Blood HDL cholesterol and atherogenic index tended to become higher and lower, respectively, with an increase in the amount of alcohol drinking in all age groups. CONCLUSION: In elderly women, the elevating effect of drinking on systolic blood pressure is increased and the lowering effects on BMI and blood total cholesterol are decreased. These results imply that drinking alcohol has less beneficial and more harmful effects on atherosclerotic risk in elderly women.     

Study of factors influencing the decreased HDL associated PON1 activity with aging

Paraoxonase (PON1) is principally complexed to HDL and is responsible, at least in part, for its antioxidant properties. PON1 activity decreases in several pathologies associated with atherosclerosis. The aim of this study was to investigate the PON1 activity and factors influencing its activity as a function of age. One hundred and twenty nine healthy subjects aged between 22 and 89 years were recruited for the study. We found that serum PON1 activity significantly decreased with age (r=-0.38, p<0.0001) while its arylesterase activity as well as its concentration in the serum did not change significantly. HDL concentrations remained unchanged with age, however, Apo A1 concentration showed a slight negative but significant correlation with age (r=-0.19, p<0.027). Moreover, the total cholesterol concentration was positively and significantly correlated with age (r=0.40, p<0.001). Thus, our results suggest that the decrease in PON1 activity cannot be explained by the decrease in Apo A1 concentrations with age. HDL from elderly subjects was more susceptible to oxidation than HDL from young subjects measured by higher lipid peroxidation rate. Thus, the decrease in PON1 activity may contribute to this increased susceptibility of HDL to oxidation with aging. Altogether our results suggest that the decrease in PON1 activity may be related to the development of oxidative stress conditions with aging and the increased HDL susceptibility to oxidation in elderly subjects.     

Natural killer activity and thyroid hormone levels in young and elderly persons

BACKGROUND: On the basis that (1) multiple interactions exist between the hormonal and immune systems, and (2) aging is accompanied by changes in thyroid hormone metabolism and responsiveness, we postulate that thyroid hormones may be involved in the observed decrease in natural killer (NK) activity in a population of apparently healthy elderly subjects. The purpose of the study is to compare NK cytotoxic activity and serum concentrations of TSH and thyroid hormones in healthy old and young people, and to assess in vitro the effects of triiodothyronine (T(3)) on NK activity. MATERIALS AND METHODS: Sixteen of the 47 healthy old people (mean age 64 +/- 5.2) were classified as optimally healthy, and the remainder as 'almost healthy' (according to the criteria of the Senieur protocol) [Ligthart et al., Mech Ageing Dev 1984;28:47-55]; the mean age of the healthy young people was 23.3 +/- 2.3 years. NK cytotoxic activity of peripheral blood mononuclear cells was assessed using (51)Cr release from K562 target cells. The cutoff level for defining low and high NK responses was set at a value of 20%. Serum concentrations of TSH, total thyroxine (T(4)) and total triiodothyronine (T(3)) were measured by radioimmunoassay. RESULTS: NK activity in the 'optimally healthy' elderly was high (mean 41 +/- 12%, SE), whereas 'almost healthy' subjects showed low NK activity (mean 6 +/- 5%). Serum T(4) and TSH levels, but not T(3) concentrations were similar in both the young and old. We observed a significant correlation (r = 0.53, n = 21, p < 0.05) between the serum total T(3) level and the NK activity in the elderly individuals. Under in vitro conditions exogenous T(3) significantly increased NK activity in the elderly subjects who had serum T(3) values at the lower end of the reference range. However, no effect of T(3) on NK activity was observed in peripheral blood mononuclear cells obtained from either old or young individuals who had serum T(3) levels at the midpoint of the range. CONCLUSION: Decreased serum concentrations of total T(3) may contribute to low NK activity in the 'almost healthy' subgroup of the elderly.     

过氧化体增殖物激活型受体γ和δ在高密度脂蛋白介导细胞胆固醇流出中的作用

为探讨过氧化体增殖物激活型受体γ和δ在高密度脂蛋白介导的细胞胆固醇流出中的作用。取新鲜抗凝血浆 ,用超速离心机进行密度梯度离心 ,收集密度为 1 .0 6 3～ 1 .2 1 0组分。U937细胞用 5 0～ 4 0 0nmol L反义过氧化体增殖物激活型受体γ和δ预处理细胞 1 2h。培养U937细胞与 0 .2 8mCi L [3H] 胆固醇乙醇液共孵育 2 4h ,15 0 0r min离心 1 0min ,收集细胞 ,PBS漂洗 2次 ,RPMI 1 6 4 0重悬细胞 ,加HDL继续培养 0～ 4 8h。液体闪烁计数仪测细胞相对放射活性。Westernblot检测过氧化体增殖物激活型受体γ和δ蛋白表达水平。不同浓度HDL处理后细胞胆固醇流出具有明显差异 ,呈剂量 -效应关系。用 1 0 0nmol L反义过氧化体增殖物激活型受体γ处理 2 4h后 ,HDL介导的细胞胆固醇流出减少 (4 5 78± 2 0 6 ) ,与对照组 (4 0 2 4± 385 )比较差别有显著性。过氧化体增殖物激活型受体γ激动剂ciglitizone预处理后 ,HDL介导的细胞胆固醇流出增加 ,用 0、2 5、5 0、1 0 0、2 0 0 μmol Lciglitizone处理的放射活性分别为 4 371± 2 4 3、386 9± 2 1 2、346 9± 2 0 9、31 5 6± 31 5和 30 2 0± 2 96。反义过氧化体增殖物激活型受体δ处理后 ,HDL介导的细胞胆固醇流出略有增加 ,处理浓度达 4 0 0nmol L时的放射活     

Effects of age on the relationship between drinking and atherosclerotic risk factors

BACKGROUND: Drinking modulates the progress of atherosclerotic cardiovascular diseases by affecting atherosclerotic risk factors. However, age-dependent effects of drinking on atherosclerotic risk factors have not been clarified in detail. OBJECTIVE: In this cross-sectional study, we investigated whether the relationship between drinking and atherosclerotic risk factors is influenced by age in male workers (12,386 men aged from 20 to 69 years) in Yamagata, a district of Japan. METHODS: The subjects were divided into five age groups, and each group was further divided into three subgroups according to ethanol consumption. The mean levels of each atherosclerotic risk factor were compared among the groups. RESULTS: Neither body mass index nor fasting blood glucose levels were significantly affected by drinking at any age. In the heavy drinkers (ethanol consumption of 30 g per day or more) in all age groups, blood pressure, serum triglyceride and HDL cholesterol levels were significantly higher and serum LDL cholesterol level and the atherogenic index were significantly lower than in the nondrinkers. In the light drinkers (ethanol consumption of less than 30 g per day) in all age groups, serum HDL cholesterol level and the atherogenic index were also higher and lower, respectively, than in the nondrinkers. However, light drinking significantly increased blood pressure only in the middle aged and relatively elderly groups (40-49, 50-59, 60-69 years of age) and significantly decreased the serum LDL cholesterol level only in relatively young and middle aged groups (30-39, 40-49, 50-59 years of age). Thus, the effects of light drinking on blood pressure and serum LDL cholesterol are dependent on age. The serum triglyceride level was not significantly affected by light drinking in any age group. CONCLUSIONS: Our results suggest that light drinking increases blood pressure in the middle-aged and the elderly but not in the young, while its beneficial effects on serum HDL cholesterol and atherogenic index are not changed with age.     

Characterization of lipid parameters in diabetic and non-diabetic atherosclerotic patients

Background & Objective The relationship between lipid profile perturbation and diabetes associated complications has long been an area of interest. Dyslipidemia is a potent predictor of cardiovascular morbidity and mortality in diabetic patients. The aim of present study was to investigate relationship between aging and lipid profiles in diabetic and non-diabetic atherosclerotic patients. Methods Five hundred and seventy six individuals (45–75 year age) participated in this study. Among these, 192 were having history of diabetes mellitus and atherosclerosis. Individuals are categorized on the base of health (normal, non-diabetic atherosclerosis, diabetic atherosclerosis) and age (45–55 years, 56–65 years, and 66–75 years). All the participants were subjected to the procedures like a detailed history, biochemical analysis for fasting blood sugar, hemoglobin A1c, total cholesterol (TC), triglycerides (TG), low-density lipoprotein-(LDL), very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL). All these parameters were compared between diabetic and non-diabetic atherosclerotic patients of all three age groups. TC/HDL and LDL/HDL were also calculated. Results Diabetic atherosclerotic individuals (both males and females) had high level of TC, TG, LDL, VLDL and low level of HDL in comparison to non-diabetic atherosclerotic and normal control individuals. Among all three age groups, lipoprotein abnormality was observed to be more frequent in females than males. There was a significant increase in TC/HDL and LDL/HDL ratio in diabetic atherosclerotic subjects compared to age and sex matched non-diabetic atherosclerotic and normal control. Conclusions Degree of dyslipidemia increases with increase in age in both genders. Female are more prone to diabetic dyslipidemia and hence have more risk of developing atherosclerosis with increasing age.     

Valpha24+ NKT cells are decreased in elderly humans.

Natural killer T (NKT) cells represent a novel cell lineage characterized by the restricted expression of an invariant TCRalpha chain encoded by Valpha24/JalphaQ gene segments in humans and Valpha14/Jalpha281+ in mice. Different aspects of the immune response are severely affected by age. Thus, we have studied the effect of aging on NKT cells from healthy elderly individuals. Our results demonstrated a decreased percentage of CD3+Valpha24+ cells in peripheral blood from elderly donors, whereas mainstream T lymphocytes showed an age-associated decrease in the expression of CD28, the vast majority of CD3+Valpha24+ cells from old individuals were CD28+. A significant increase in the percentage of Valpha24+ cells with the CD4-CD8+ phenotype was also found in the elderly, indicating a redistribution of Valpha24+ subsets according to the CD4/CD8 phenotype. Given the important immunoregulatory role of these cells, the decrease of NKT cells will contribute to the deleterious immune response in the elderly.     

Basic considerations in the reversal of atherosclerosis: significance of high-density lipoprotein in stimulating reverse cholesterol transport

Atherosclerotic cardiovascular disease in the elderly is the result of several decades of cholesterol accretion. Advanced lesions may not be amenable to treatment, but a reversal of cholesterol accumulation may be possible. High-density lipoproteins (HDL) could serve an important function in this reversal through their role in the process of reverse cholesterol transport, which removes cholesterol from the body. Reverse cholesterol transport could be stimulated by raising plasma HDL level, but the efficacy of the process may be determined by the way in which HDL level is elevated. The increase of HDL synthesis rate may be the best approach. The antiatherosclerotic effects of gemfibrozil, a lipid-lowering agent that appears to raise HDL synthesis rate, may be mediated through this mechanism.     

Decrease of cholesterol concentration in human erythrocyte ghosts in old age

The lipid composition of the erythrocyte membrane ghosts of 95 relatively healthy elderly subjects was compared between four age groups: 70 to below 75 years (I), 75 to below 80 (II), 80 to below 85 (III) and 85 to below 90 years of age (IV). The molar ratio of phospholipid to cholesterol (PL/CH) in the erythrocyte ghosts increased with advancing age. Whilst PL levels did not change significantly, a decrease of membrane cholesterol was found. Therefore, the red cell membrane cholesterol seems to parallel the well-known pattern of variation of mean plasma total cholesterol and LDL cholesterol concentrations with age: an increase to a maximum in the sixth decade of life, and a decline thereafter. The processes which are responsible for these changes in cholesterol level with age have not been delineated. However, the findings suggest that one might get different results in studies of age-dependent membrane lipid alterations if rough age group divisions are made (below 30 years of age vs. over 70 years) or to subdivide the group of the elderly.     

Changes in serum lipid levels during a 10 year period in a large Japanese population. A cross-sectional and longitudinal study

To determine the recent secular trends in serum lipid levels and characterize their influence on the aging process, we examined a large cohort of Japanese cross-sectionally and longitudinally. The participants included 80331 Japanese men and women 20-79 years of age, who had received annual health examinations from 1989 to 1998. In cross-sectional analysis, an increase in total and LDL cholesterol as well as triglyceride levels was observed in the population during the period of 1989-1998. The longitudinal changes showed that total and LDL cholesterol increased with age in men between the birth cohorts of the 1920s and 1960s. In women, these cholesterol levels increased in the 1930s and younger cohorts. HDL cholesterol decreased in men of all birth cohorts. However, HDL cholesterol increased in women of the 1940s and younger cohorts. Triglyceride levels increased in men of the 1940s and younger cohorts but decreased in the 1930s and older. Triglyceride levels increased in women of the 1930s and younger. Longitudinal analysis also suggested a birth cohort effect except for the triglyceride level for women. These results suggest that Japanese serum lipid levels continue to increase and that there exist birth cohort effects regarding serum lipid levels in the Japanese population.     

Effect of endogenous estrogen on plasma high density lipoprotein and total hydrosulfuryl group in membrane of erythrocyte in cholesterol-fed rats]

Under a cholesterol load, the effects of endogenous estrogen on plasma high density lipoprotein cholesterol (HDL-C), total hydrosulfuryl (T-SH) group in the membrane of erythrocyte and plasma total cholesterol were observed in female rats with a ovariectomized control group. The results indicate that endogenous estrogen might prevent the rats of atherosclerosis formation by keeping plasma HDL at higher level and increasing in T-SH group in the membrane of erythrocyte, and preventing the increase in total plasma cholesterol.     

Increased cellular cholesterol upregulates high density lipoprotein binding to rat luteal cells.

Rat luteal cells preferentially utilize cholesterol derived from high density lipoproteins (HDL) as a substrate for steroid hormone synthesis. The uptake of cholesterol from HDL by these cells is in contrast to nonsteroidogenic cells, which export cholesterol to HDL. A previous study demonstrated that HDL binding to luteal cell membranes was increased in conjunction with in vivo cholesterol depletion or cholesterol loading of the ovary induced by pharmacological agents. These results suggest a biphasic regulation of the HDL receptor in luteinized rat ovaries. In the present studies, the in vitro regulation of HDL binding in rat luteal cells by increased intracellular cholesterol was examined. Cultured luteal cells were incubated with increasing doses of low density lipoproteins (LDL) for 2 days after which the cellular sterol content and the effects on progesterone production and HDL binding were measured. As expected, the LDL treatment increased total cellular sterol content in a dose-dependent manner, resulting in a 2.1-fold increase over control at a dose of 1 mg LDL/ml. Increased cellular cholesterol was accompanied by a comparable increase in progesterone secretion. These results suggest that exogenous cholesterol was utilized by these cells. The LDL treatment also increased the binding of HDL to the cells in a dose-dependent manner to a maximum of 2.2-fold over control. The effect of increased cellular sterol on HDL binding was also examined using a more polar cholesterol derivative, 25-hydroxycholesterol. Cells were cultured for 2 days in media containing 0.3-40 micrograms/ml 25-hydroxycholesterol in the presence of 100 micrograms/ml aminoglutethimide, an inhibitor of cholesterol metabolism. The HDL binding to luteal cells exhibited dose-dependent up-regulation by 25-hydroxycholesterol with a 5.8-fold increase in binding at the maximum dose tested. Equilibrium binding studies using cells treated with 10 micrograms/ml 25-hydroxycholesterol revealed a 2.1-fold increase in the number of HDL binding sites on the luteal cells without affecting the binding affinity. From the results of this study, it is concluded that HDL binding in rat luteal cells is up-regulated by an increase in the intracellular cholesterol level.     

Genetic-epidemiological evidence on genes associated with HDL cholesterol levels: A systematic in-depth review

High-density lipoprotein (HDL) particles exhibit multiple antiatherogenic effects. They are key players in the reverse cholesterol transport which shuttles cholesterol from peripheral cells (e.g. macrophages) to the liver or other tissues. This complex process is thought to represent the basis for the antiatherogenic properties of HDL particles. The amount of cholesterol transported in HDL particles is measured as HDL cholesterol (HDLC) and is inversely correlated with the risk for coronary artery disease: an increase of 1 mg/dL of HDLC levels is associated with a 2% and 3% decrease of the risk for coronary artery disease in men and women, respectively. Genetically determined conditions with high HDLC levels (e.g. familial hyperalphalipoproteinemia) often coexist with longevity, and higher HDLC levels were found among healthy elderly individuals.     

Factors affecting low-density lipoprotein and high-density lipoprotein cholesterol response to pravastatin in the West Of Scotland Coronary Prevention Study (WOSCOPS)

Statins are regarded as efficacious in general but there is a wide variation in individual response. We sought demographic and lifestyle factors that influenced the response to pravastatin 40 mg/day in moderately hypercholesterolemic men in the West Of Scotland Coronary Prevention Study (WOSCOPS). Changes in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol after 6 months of treatment were examined in 1,604 highly compliant subjects. LDL cholesterol decreased by a mean of 30.4%. The magnitude of the change was influenced, albeit to a small extent, by baseline plasma triglyceride levels and alcohol intake and age; subjects with low plasma triglyceride levels, older subjects, and subjects with low alcohol intake had the greatest reductions. The mean response in HDL cholesterol in the group was an 8.3% increase (0.09 mmol/L). The percent increase in HDL cholesterol was affected by baseline HDL level, plasma triglyceride levels, decrease in plasma triglyceride levels during the administration of pravastatin, and body mass index. The absolute increase in HDL cholesterol was influenced by the decrease in plasma triglyceride levels, body mass index, and alcohol intake. All of these associations were weak (r <0.2) although highly significant. In conclusion, plasma lipid phenotype, obesity, and alcohol consumption appear to influence the response of LDL and HDL cholesterol to statin treatment. The absolute increment in HDL cholesterol is relatively constant across a range of baseline values, hence the percent change is largely a function of the starting value.     

Obesity increases the risk of development of atherosclerosis in elderly type 2 diabetic patients*

Background: Obesity has been suggested to have no effect on the rates of mortality from cerebro‐ and cardiovascular diseases in the elderly. The purpose of the present study was to determine whether obesity influences atherosclerotic risk factors in elderly diabetic patients. Methods: The relationships between body mass index (BMI) and representative atherosclerotic risk factors were investigated using data from patients with type 2 diabetes who were aged from 65 to 91 years (mean ± standard deviation, 72.3 ± 5.2 years). Results: BMI significantly correlated with systolic and diastolic arterial pressures and serum triglyceride, uric acid and sialic acid levels. BMI also showed significant negative correlations with duration of diabetes and serum HDL cholesterol levels. Multiple regression analysis using BMI as a target variable and age, sex, duration of diabetes, mean arterial pressure, serum uric acid and triglyceride as explanatory variables showed that BMI significantly correlated with arterial pressure and serum triglyceride level (R = 0.459). After adjustment for history of drug therapy for each disease (hypertension, dyslipidemia or hyperuricemia), BMI also significantly correlated with arterial pressure, serum triglyceride, HDL cholesterol and uric acid levels. In the subjects with BMI of 25 or over, the mean levels of systolic and diastolic arterial pressures, serum triglyceride and sialic acid were higher and the mean level of serum HDL cholesterol was lower, after adjustment for age and sex, than those in the subjects with BMI below 22. Conclusion: These results suggest that obesity is related to arterial pressure, blood lipid and uric acid levels and increases the risk of development of atheroclerosis in elderly diabetic patients.     

The characterization of bronchoalveolar lavage fluid in very elderly patients with cerebrovascular disease.

BACKGROUND: Elderly patients with cerebrovascular disease have a high frequency of pneumonia due to impaired immune function and the occurrence of micro-aspiration. METHODS: We performed bronchoalveolar lavage in 11 very elderly subjects with cerebrovascular disease and 9 healthy volunteers to investigate whether there were changes of local immunity in the lungs of the elderly subjects. The total cell count, the cell characteristics, and the lymphocyte subsets in bronchoalveolar lavage fluid were compared between the two groups. RESULTS: A significant increase in the total cell count as well as in the number of neutrophils and CD8(+) T cells was observed in the elderly group. In addition, the mean CD4/CD8 lymphocyte ratio was lower in the elderly patients than in the healthy volunteers. CONCLUSIONS: These observations suggest that silent micro-aspiration occurs in many elderly individuals with cerebrovascular disease and that pulmonary defenses decrease with age.     

高密度脂蛋白靶向防治动脉粥样硬化新进展

许多随机临床试验已经明确,他汀类药物因为可以降低低密度脂蛋白胆固醇水平并轻度增加高密度脂蛋白胆固醇(HDLC)水平,已经成为防治动脉粥样硬化(As)疾病的主要标准疗法。高密度脂蛋白(HDL)颗粒介导的胆固醇逆转运(RCT)途径具有抗As的作用。目前HDL靶向治疗的重要途径已经不是升高HDLC水平,更多的是通过改善HDL功能,增强血浆胆固醇的清除,以及预防和减轻与As有关的炎症。胆固醇酯转移蛋白抑制剂可增加正常或低HDLC患者的HDLC水平;肝X受体激动剂可通过增加RCT减少As;使用重组HDL的HDL治疗在动物模型中显著有效;在细胞以及动物模型中研究发现,通过干预某些基因靶点,可使HDLC的水平和HDL功能得到改善。回顾相关文献,我们认为:HDL靶向治疗有防治As的潜力,可能对心血管疾病患者有效。