Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: a phase II multicentre, randomized, double-blind, placebo-controlled trial.

AIM: Dapagliflozin is a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor under development as a treatment for type 2 diabetes mellitus (T2DM). This study assessed the efficacy and safety of dapagliflozin monotherapy in Japanese T2DM patients with inadequate glycaemic control. METHODS: Patients (n = 279) were randomized to receive dapagliflozin (1, 2.5, 5 or 10 mg/day) or placebo once daily for 12 weeks. The primary endpoint was change from baseline in haemoglobin A1c (HbA1c) at week 12. Secondary endpoints included change from baseline in fasting plasma glucose (FPG) and proportion of patients achieving HbA1c <7.0% at week 12. RESULTS: Significant reductions in HbA1c were seen with all dapagliflozin doses (-0.11 to -0.44%) versus placebo (+0.37%). Reductions were also observed in FPG with dapagliflozin (-0.87 to -1.77 mmol/l [-15.61 to -31.94 mg/dl]) versus placebo (+0.62 mmol/l [+11.17 mg/dl]). No significant difference in the proportion of patients achieving HbA1c levels <7.0% was noted with dapagliflozin versus placebo. Adverse events (AEs) were more frequent with dapagliflozin (40.7-53.8%) versus placebo (38.9%) and were mostly mild/moderate in intensity. Three hypoglycaemic events were reported (1 each with placebo, dapagliflozin 2.5 mg and 10 mg). The frequency of signs and symptoms suggestive of urinary tract or genital infections was 0-3.8 and 0-1.8% respectively with dapagliflozin and 1.9 and 0% with placebo. No AEs of pyelonephritis were observed. CONCLUSIONS: Compared with placebo, dapagliflozin significantly reduced hyperglycaemia over 12 weeks with a low risk of hypoglycaemia in Japanese T2DM patients with inadequate glycaemic control.

Depressive mood is independently related to stroke and cardiovascular events in a community.

By means of a multivariate Cox model, we investigated the predictive value of a depressive mood on vascular disease risk in middle-aged community-dwelling people. In 224 people (88 men and 136 women; mean age: 56.8 +/- 11.2 years) of U town, Hokkaido (latitude: 43.45 degrees N, longitude: 141.85 degrees E), a chronoecological health watch was started in April 2001. Consultations were repeated every 3 months. Results at the November 30, 2004 follow-up are presented herein. 7-day/24-h blood pressure (BP) and heart rate (HR) monitoring started on a Thursday, with readings taken at 30-min intervals between 07:00 h and 22:00 h and at 60-min intervals between 22:00 h and 07:00 h. Data stored in the memory of the monitor (TM-2430-15, A and D company, Japan) were retrieved and analyzed on a personal computer with a commercial software for this device. Subjects were asked to answer a self-administered questionnaire inquiring about 15 items of a depression scale, at the start of study and again after 1-2 years. Subjects with a score higher by at least two points at the second versus first screening were classified as having a depressive mood. The other subjects served as the control group. The mean follow-up time was 1064 days, during which four subjects suffered an adverse vascular outcome (myocardial infarction: one man and one woman; stroke: two men). Among the variables used in the Cox proportional hazard models, a depressive mood, assessed by the Geriatric Depression Scale (GDS), as well as the MESOR of diastolic (D) BP (DBP-MESOR) and the circadian amplitude of systolic (S) BP (SBP-Amplitude) showed a statistically significant association with the occurrence of adverse vascular outcomes. The GDS score during the second but not during the first session was statistically significantly associated with the adverse vascular outcome. In univariate analyses, the relative risk (RR) of developing outcomes was predicted by a three-point increase in the GDS scale (RR = 3.088, 95% CI: 1.375-6.935, P = 0.0063). Increases of 5 mmHg in DBP-MESOR and of 3 mmHg in SBP-Amplitude were associated with RRs of 2.143 (95% CI: 1.232-3.727, P = 0.0070) and 0.700 (95% CI: 0.495-0.989, P = 0.0430), respectively. In multivariate analyses, when both the second GDS score and the DBP-MESOR were used as continuous variables in the same model, GDS remained statistically significantly associated with the occurrence of cardiovascular death. After adjustment for DBP-MESOR, a three-point increase in GDS score was associated with a RR of 2.172 (95% CI: 1.123-4.200). Monday endpoints of the 7-day profile showed a statistically significant association with adverse vascular outcomes. A 5 mmHg increase in DBP on Monday was associated with a RR of 1.576 (95% CI: 1.011-2.457, P = 0.0446). The main result of the present study is that in middle-aged community-dwelling people, a depressive mood predicted the occurrence of vascular diseases beyond the prediction provided by age, gender, ABP, lifestyle and environmental conditions, as assessed by means of a multivariate Cox model. A depressive mood, especially enhanced for 1-2 years, was associated with adverse vascular outcomes. Results herein suggest the clinical importance of repetitive assessments of a depressive mood and the need to take sufficient care of depressed subjects. Another result herein is that circadian and circaseptan characteristics of BP variability measured 7-day/24-h predicted the occurrence of vascular disease beyond the prediction provided by age, gender, depressive mood and lifestyle, as assessed by means of a multivariate Cox model. Earlier, we showed that the morning surge in BP on Mondays was statistically significantly higher compared with other weekdays. Although a direct association between the Monday surge in BP and cardiovascular events could not be demonstrated herein, it is possible that the BP surge on Monday mornings may also trigger cardiovascular events. We have shown that depressive people exhibit a more prominent circaseptan variation in SBP, DBP and the double product (DP) compared to non-depressed subjects. In view of the strong relation between depression and adverse cardiac events, studies should be done to ascertain that depression is properly diagnosed and treated. Chronodiagnosis and chronotherapy can reduce an elevated blood pressure and improve the altered variability in BP and HR, thus reducing the incidence of adverse cardiac events. This recommendation stands at the basis of chronomics, focusing on prehabilitation in preference to rehabilitation, as a public service offered in several Japanese towns.

Arterial stiffness independently predicts cardiovascular events in an elderly community -- Longitudinal Investigation for the Longevity and Aging in Hokkaido County (LILAC) study.

We investigated the predictive value of arterial stiffness to assess cardiovascular risk in elderly community-dwelling people by means of a multivariate Cox model. In 298 people older than 75 years (120 men and 178 women, average age: 79.6 years), brachial-ankle pulse wave velocity (baPWV) was measured between the right arm and ankle in a supine position. The LILAC study started on July 25, 2000, consultation was repeated yearly, and the last follow-up ended on November 30, 2004. During this follow-up span of 1227 days, there were nine cardiovascular deaths, the cause of death being myocardial infarction for two men and three women or stroke for two men and two women. In Cox proportional hazard models, baPWV as well as age, Mini-Mental State Examination (MMSE), Hasegawa Dementia Scale Revised (HDSR) and the low-frequency/high-frequency (LF/HF) ratio showed a statistically significant association with the occurrence of cardiovascular death. A two-point increase in MMSE and HDSR score significantly protected against cardiovascular death, the relative risk (RR) being 0.776 (P = 0.0369) and 0.753 (P = 0.0029), respectively. The LF/HF ratio also was significant (P = 0.025), but the other indices of HRV were not. After adjustment for age and HDSR, a 200 cm/s increase in baPWV was associated with a 30.2% increase in risk (RR = 1.302, 95% CI: 1.110-1.525), and a 500 cm/s increase in baPWV with a 93.3% increase in risk (RR = 1.933, 95% CI: 1.300-2.874, P = 0.0011), whereas the LF/HF ratio was no longer associated with a statistically significant increase in cardiovascular mortality. In elderly community-dwelling people, arterial stiffness measured by means of baPWV predicted the occurrence of cardiovascular death beyond the prediction provided by age, gender, blood pressure and cognitive functions. baPWV should be added to the cardiovascular assessment in various clinical settings, including field medical surveys and preventive screening. The early detection of risk by chronomics allows the timely institution of prophylactic measures, thereby shifting the focus from rehabilitation to prehabilitation medicine, as a public service to several Japanese towns.

Fractal analysis of heart rate variability and mortality in elderly community-dwelling people -- Longitudinal Investigation for the Longevity and Aging in Hokkaido County (LILAC) study.

AIM: Fractal analysis of heart rate (HR) variability (HRV) has been used as a new approach to evaluate the risk of mortality in various patient groups. Aim of this study is to examine the prognostic power of detrended fluctuation analysis (DFA) and traditional time- and frequency-domain analyses of HR dynamics as predictors of mortality among elderly people in a community. METHODS: We examined 298 people older than 75 years (average age: 79.6 years) and 1-h ambulatory ECG was monitored. During the last 10 min, deep respiration (6-s expiration and 4-s inspiration) was repeated six times in a supine position. Time-domain and frequency-domain measures were determined by the maximum entropy method. Scaling exponents of short-term (<11 beats, alpha 1) and longer-term (>11 beats, alpha 2) were determined by the DFA method. Six estimates, obtained from 10-min segments, were averaged to derive mean values for the entire recording span. These average values were denoted Alpha 1 and Alpha 2, estimates obtained during the first 10-min segment Alpha 1 S and Alpha 2 S, and those during the last 10-min segment Alpha 1E and Alpha 2E, respectively. The LILAC study started on July 25, 2000 and ended on November 30, 2004. We used Cox regression analysis to calculate relative risk (RR) and 95% confidence interval (CI) for all-cause mortality. Significance was considered at a value of P < 0.05. RESULTS: Gender, age and Alpha 2E showed a statistically significant association with all-cause mortality. In univariate analyses, gender was significantly associated with all-cause mortality, being associated with a RR of 3.59 (P = 0.00136). Age also significantly predicted all-cause mortality and a 5-year increase in age was associated with a RR of 1.49 (P = 0.01809). The RR of developing all-cause mortality predicted by a 0.2-unit increase in Alpha 2E was 0.58 (P = 0.00390). Other indices of fractal analysis of HRV did not have predictive value. In multivariate analyses, when both Alpha 2E and gender were used as continuous variables in the same model, Alpha 2E remained significantly associated with the occurrence of all-cause mortality (P = 0.02999). After adjustment for both gender and age, a 0.2-unit increase in Alpha 2E was associated with a RR of 0.61 (95% CI: 0.42-0.90, p = 0.01151). CONCLUSION: An intermediate-term fractal-like scaling exponent of RR intervals was a better predictor of death than the traditional measures of HR variability in elderly community-dwelling people. It is noteworthy that the longer-term (alpha 2) rather than the short-term fractal component (alpha 1) showed predictive value for all-cause mortality, which suggests that an increase in the randomness of intermediate-term HR behavior may be a specific marker of neurohumoral and sympathetic activation and therefore may also be associated with an increased risk of mortality.

Common carotid intima-media thickness is predictive of all-cause and cardiovascular mortality in elderly community-dwelling people: Longitudinal Investigation for the Longevity and Aging in Hokkaido County (LILAC) study.

Several cohort studies have examined the association of carotid intima-media thickness (IMT) with the risk of stroke or myocardial infarction in apparently healthy persons. We investigated the predictive value of IMT of cardiovascular mortality in elderly community-dwelling people, beyond the prediction provided by age and MMSE, assessed by means of a multivariate Cox model. Carotid IMT and plaque were evaluated bilaterally with ultrasonography in 298 people older than 75 years (120 men and 178 women, average age: 79.6 years). The LILAC study started on July 25, 2000. Consultations were repeated every year. The follow-up ended on November 30, 2004. During the mean follow-up span of 1152 days, 30 subjects (21 men and nine women) died. Nine deaths were attributable to cardiovascular causes (myocardial infarction: two men and three women; stroke: two men and two women). The age- and MMSE-adjusted relative risk (RR) and 95% confidence interval (95% CI) of developing all-cause mortality was assessed. A 0.3 mm increase in left IMT was associated with a RR of predicted 1.647 (1.075-2.524), and a similar increase in right IMT with a RR of 3.327 (1.429-7.746). For cardiovascular mortality, the corresponding RR values were 2.351 (1.029-5.372) and 2.890 (1.059-7.891), respectively. Carotid IMT assessed by ultrasonography is positively associated with an increased risk of all-cause and cardiovascular death in elderly community-dwelling people.

Assessment of vasoactive agents and vascular aging by the second derivative of photoplethysmogram waveform.

To evaluate the clinical application of the second derivative of the fingertip photoplethysmogram waveform, we performed drug administration studies (study 1) and epidemiological studies (study 2). In study 1, ascending aortic pressure was recorded simultaneously with the fingertip photoplethysmogram and its second derivative in 39 patients with a mean+/-SD age of 54+/-11 years. The augmentation index was defined as the ratio of the height of the late systolic peak to that of the early systolic peak in the pulse. The second derivative consists of an a, b, c, and d wave in systole and an e wave in diastole. Ascending aortic pressure increased after injection of 2.5 microg angiotensin from 126/74 to 160/91 mm Hg and decreased after 0.3 mg sublingual nitroglycerin to 111/73 mm Hg. The d/a, the ratio of the height of the d wave to that of the a wave, decreased after angiotensin from -0.40+/-0.13 to -0.62+/-0.19 and increased after nitroglycerin to -0.25+/-0.12 (P<0.001 and P<0.001, respectively). The negative d/a increased with increases in plethysmographic and ascending aortic augmentation indices (r=0.79, P<0.001, and r=0.80, P<0.001, respectively). The negative d/a reflects the late systolic pressure augmentation in the ascending aorta and may be useful for noninvasive evaluation of the effects of vasoactive agents. In study 2, the second derivative of the plethysmogram waveform was measured in a total of 600 subjects (50 men and 50 women in each decade from the 3rd to the 8th) in our health assessment center. The b/a ratio increased with age, and c/a, d/a, and e/a ratios decreased with age. Thus, the second derivative aging index was defined as b-c-d-e/a. The second derivative wave aging index (y) increased with age (x) (r=0.80, P<0.001, y=0.023x-1.515). The second derivative aging index was higher in 126 subjects with any history of diabetes mellitus, hypertension, hypercholesterolemia, and ischemic heart disease than in age-matched subjects without such a history (-0.06+/-0.36 versus -0.22+/-0.41, P<0.01). Women had a higher aging index than men (P<0.01). The b-c-d-e/a ratio may be useful for evaluation of vascular aging and for screening of arteriosclerotic disease.

Lysine malabsorption syndrome: a new type of transport defect.

A 21-month-old girl with physical and mental retardation is described. She excreted an increased amount of lysine in urine but no excessive quantities of arginine, ornithine, or cystine. Serum level of lysine was found to be low but the levels of the other amino acids were within normal limits. The endogenous renal clearance rates of amino acids showed a marked high value of lysine and normal values of the other dibasic amino acids. Oral loading test of amino acids revealed an imparied absorption of lysine and normal absorption of arginine, ornithine, and cystine in the intestine. These results indicate a specific defect in transport of lysine in the intestine as well as in the renal tubule.

MR imaging of the brain in patients with mucopolysaccharidosis.

MR imaging of the brain was performed in eight patients with mucopolysaccharidosis (MPS). Two had MPS I S, one had MPS IIA, two had MPS IIB, two had MPS IIIB, and one had MPS VI. In the patients with MPS IIA and MPS VI, T1 and T2 were prolonged in various areas of the cerebral white matter. These findings seemed to correspond with the development of pathologic changes in MPS, such as perivascular pits in the white matter observed on slices of the fixed brain. In the patients with MPS IIA and MPS IIIB, the white matter did not show the proper signal intensity, which suggested that myelination was insufficient and that infiltration or deposition of glycosaminoglycan had occurred; this was consistent with the association of these two types with mental retardation. In the patients with MPS I S, no intracranial abnormalities were detected on MR images. MR imaging of the brain may be used to obtain a differential diagnosis of the various types of MPS, to estimate the extent of mental retardation, and to monitor the progress of this disease.

Adrenoleukodystrophy: new CT findings.

Three cases of adrenoleukodystrophy are presented with sequential findings by computed tomography (CT). In two cases, CT confirmed not only the findings of several previous reports of a caudocranial direction of low-density white matter and contrast enhancement at the periphery of affected regions during the active demyelinating process, but also two other unusual features: (1) calcification in the affected white matter along the trigones of the lateral ventricles and (2) development of a mass effect during the active demyelinating period. Calcification alone without low-density white matter was the initial CT presentation in one case. Periventricular calcification may be specific for adrenoleukodystrophy in the appropriate clinical setting.

Graded response of heart rate variability, associated with an alteration of geomagnetic activity in a subarctic area.

It is becoming recognized that geomagnetic activity may influence biological processes, including the incidence of various human diseases. There is evidence that heart rate variability (HRV) may serve not only as an index of autonomic coordination of the circulation, but also as a powerful predictor of risk in apparently healthy subjects. This study focuses on the effects of geomagnetic disturbance on HRV, by comparing different indices of HRV of young, healthy men living in a subarctic area on days of low (Ap; 0-7), middle (Ap; 7-20), and high (Ap; 20-45) geomagnetic activity. The effect of geomagnetic disturbance on HRV is examined on the basis of 7-day records by Holter ECG, obtained longitudinally on 5 clinically healthy men, 21-31 years of age, in Alta, Norway (70 degree N). Frequency- and time-domain measures of HRV were analyzed for each subject on separate 24-hour spans. A graded alteration of HRV endpoints was found in association with increased geomagnetic activity. As time-domain measures of HRV, SDNNIDX and the 90% length of the Lorenz plot decreased statistically significantly on days with increased geomagnetic disturbance (p = 0.0144 and p = 0.0102, respectively). A graded decrease in frequency-domain HRV measures was also validated statistically for the total spectral power (decrease of 18.1% and 31.6% on days when 7 < Ap < 20 and 20 < Ap < 45 versus days when Ap < 7; p = 0.0013). The decrease in spectral power was mainly found at frequencies below 0.04 Hz, in the "ultra-low-frequency" (0.0001-0.003 Hz; 18.1% and 27.5% decrease, respectively; p = 0.0102) and "very-low-frequency" (0.003-0.04 Hz; 12.9% and 28.6% decrease, respectively; p = 0.0209) regions of the spectrum. The decrease in spectral power was much less pronounced around 10.5 sec ("low frequency"; N.S.) and around 3.6 sec ("high frequency"; N.S.). Evidence is provided here that HRV decreases on magnetically disturbed days, and that it does so in a dose-dependent fashion, HRV being depressed more on days when 20 < Ap < 45 than on days when 7 < Ap < 20, by comparison with days when Ap < 7. This graded response of HRV to geomagnetic activity should encourage us to search for human magnetoreceptors and for a better understanding of putative mechanisms of magnetoreception.

Positive impact of social intervention on disturbed neurobehavioral function in an elderly community-dwelling population: longitudinal investigation for longevity and aging in Hokkaido County (LILAC).

Several kinds of health consultation and rehabilitation for functional disorders aimed at stroke prevention and maintenance of cognitive function in an elderly population in Hokkaido county, Japan. Changes in cardiovascular and neurobehavioral endpoints between 2000 and 2002 were assessed in 72 of 115 subjects over 75 years of age. Direct social intervention, including lifestyle modification can have a positive impact, notably on subjects with cardiovascular disorders.

Ferritin, creatine kinase, and neopterin in subacute sclerosing panencephalitis.

To study the disease process in the brain in subacute sclerosing panencephalitis (SSPE), sequential changes in ferritin, creatine kinase (CK), and neopterin in the cerebrospinal fluid (CSF) of two patients with SSPE were compared with the changes in the clinical signs and symptoms and the findings by magnetic resonance imaging (MRI). On the basis of changes in various substances in the CSF, especially ferritin, CK and neopterin, we concluded that the high-intensity area in MRI might be evidence of local inflammation and the resulting cell damage. Ferritin, CK and neopterin seemed to be biochemical markers in patients with SSPE for detection of the extent of lesions, and their measurement may provide information useful for evaluation of the therapeutic response.

A case of cerebral aneurysm associated with complex partial seizures.

We report a 20-month-old girl with an unruptured aneurysm of the middle cerebral artery. The initial sign was complex partial seizures. Magnetic resonance angiography showed an aneurysm of the right middle cerebral artery. Cerebral angiography confirmed the presence of a saccular aneurysm. After 3 months, the aneurysm spontaneously thrombosed without neurological deficit. The seizures were controlled by anti-convulsants. The aneurysm was probably near the focus of the complex partial seizures. This is a rare case of a childhood cerebral artery aneurysm that first manifested itself by complex partial seizures.

CT and MR imaging of cerebral tuberous sclerosis.

Tuberous sclerosis is a heredofamilial neurocutaneous syndrome, or phakomatosis, with multisystem involvement including the brain, kidney, skin, retina, heart, lung, and bone. The brain is the most frequently affected organ in tuberous sclerosis. Brain lesions in tuberous sclerosis are of three kinds; cortical tubers, white matter abnormalities, and subependymal nodules. We review the computed tomography (CT) and magnetic resonance (MR) features of the brain lesions in patients with tuberous sclerosis. CT clearly demonstrates calcified subependymal nodules. MR imaging demonstrates more clearly cortical, and white matter lesions than CT, since MR imaging shows excellent image contrast between various normal structures and high sensitivity in detecting pathological states due to intrinsic differences in proton density and in particular, in proton relaxation times of tissues. Possible pathogenesis of this disorder is also discussed.

Clearance of intravenously injected colloidal carbon from peripheral blood in mice, rats, rabbits and dogs.

The clearance of intravenously injected colloidal carbon from the peripheral blood was investigated in mice, rats, rabbits and dogs. The blood clearance of carbon was more rapid in the young than in the old for all the species examined. A biphasic clearance curve was observed in the dogs of all age groups tested, and in the rabbits of 8 and 16 weeks old. The rate of colloidal carbon clearance was slower in the rabbits than in other three species.

Time-dependent changes of microscopic localization of intravenously administered colloidal carbon particles in mouse lymph nodes.

Time-dependent changes of microscopic localization of intravenously administered colloidal carbon particles were studied in mouse lymph nodes. Carbon particles were preferentially trapped by postcapillary venules (PCV) immediately after injection, and migrated easily outside of PCV either through intercellular space of the PCV endothelium or by phagocytic process during the 1 hr after injection. Particles were thereafter up-taken by pericytes and macrophages around PCV during the 24 hr, and consequently distributed throughout the cortex and medulla. Finally, they migrated to the medullary lymphatic sinuses, and phagocytosed by endothelial cells. Redistribution process of particles via the lymphatic sinuses from the regional lymph was observed during 30 minutes or 10 to 14 days after injection in different lymph nodes.

Age and sex differences in the clearance of intravenously injected colloidal carbon from peripheral blood in rats.

Age and sex differences of carbon clearance from the peripheral blood of the rat were investigated. The clearance of carbon was more rapid in the young rats than in the old. Sex difference was significant in the rats of 10 and 14 weeks old, but not significant in the rats of 3 weeks old. Liver blood flow, extraction rate of carbon by the liver and whole circulating blood volume may be the factors involved in the sex and age differences of the blood clearance of carbon.

Dependence on particle size in the phagocytosis of latex particles by rabbit alveolar macrophages cultured in vitro.

The dependence of the phagocytosis of particulate materials on their size was studied. Rabbit alveolar macrophages (AMs) obtained by lung lavage were cultured in suspensions or monolayers with Latex particles of 1 micron or 2 microns in diameter. After culturing AMs with 10(7)(-5) X 10(9) Latex particles per ml for 15 to 360 minutes, the number of phagocytized particles in each of 100 individual cells was counted by light microscopy. In suspension culture, there was no significant difference in the average number of particles phagocytized per AM between 1 micron and 2 microns particles in the identical conditions as to the particle concentration (particle number/ml) and the incubation time. In monolayer culture, it was difficult to compare the average number of 1 micron particles phagocytized by AM with that of 2 microns ones in the identical condition as to the particle concentration, since the sedimentation velocities at which particles sank to the bottom of culture chamber were different between both particles, resulting in the difference of particle concentration around AMs. The sign of saturation was observed when the average number of phagocytized particles reached approximately 10 particles per AM in either case of suspension culture with 1 micron or 2 microns particles and approximately 45 of 1 micron and 10 of 2 microns particles in monolayer culture.

Phagocytosis of colloidal carbon in perfused liver of rats and rabbits.

A constant-flow, nonrecirculating system was used to study the extraction efficiency of colloidal carbon in the perfused liver of rats and rabbits. In both species, a diminution in perfusate flow produced an increased extraction efficiency. The extraction efficiency also increased with a decrease in the carbon concentration of the perfusate. In identical conditions regarding the flow rate and carbon concentration, the perfused liver of the rabbits showed a relatively lower phagocytic efficiency than that of the rats.

Pulmonary deposition and effects of inhaled silica particles after short-term exposures in the rat.

The present study was designed to evaluate the pulmonary deposition and the effects of inhaled silica particles in the rat model. Wistar (W/M strain) rats were exposed to silica aerosols generated from a fluidized bed dust generator for 1 hr a day, intermittently for 6 days, using a "nose-only" inhalation chamber. After the cessation of the exposures, analysis of lavaged bronchoalveolar cells (BAC) and histological examinations of lungs and tracheobronchial lymph nodes (TBLN) were performed during a period of 6 months. Total cell yields and the proportions of alveolar macrophages (AM) in BAC were not altered, whereas the proportions of lymphocytes in BAC were significantly increased in the exposed animals. Although the proportions of silica-laden AM in BAC were gradually decreased during the 6 months, particle-laden AM were predominantly and persistently observed in the alveoli under light microscopy. Silica particles were also identified in macrophages of granulomatous nodules in pulmonary peribronchial lymphoid tissues(PBLT) and TBLN, indicating the translocation of particles via the lymph. Associated with pulmonary particle deposition, some characteristic histopathological features were evident, including thickening of alveolar duct bifurcations and lymphocyte infiltrations both in the alveolar sacs and around the interstitial blood vessels. At later months after the exposures, the alveolar interstitium was thickened with the increase of fibroblasts and collagen. These results implicate that short-term exposures of silica particles in the rat can evoke histopathologic changes in the lungs and lymphatic tissues, associated with their deposition and translocation.