Correction: Effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis.

In the above article, we noticed that one female patient in the positive group (plasma lyso-Gb3 7.6 ng/ml, α-galactosidase A activity 4.9 nmol/h/ml) who presented at the neurology clinic was already diagnosed with Fabry disease before the current study. We excluded patients with a confirmed diagnosis of Fabry disease and those with relatives known to have Fabry disease. To accurately describe the information in the current study, we must exclude this patient from the analysis. We have accurately revised this information as follows.

Correction: Effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis.

The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information.

Correction: Effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis.

The HTML version of this Article contained errors in Supplementary Figure S2 "Flowchart of the lyso-Gb3 screening and gene analysis in female patients", which have been detailed in the associated Correction.

Effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis.

PURPOSE: Plasma globotriaosylsphingosine (lyso-Gb3) is a promising secondary screening biomarker for Fabry disease. Here, we examined its applicability as a primary screening biomarker for classic and late-onset Fabry disease in males and females. METHODS: Between 1 July 2014 and 31 December 2015, we screened 2,359 patients (1,324 males) referred from 168 Japanese specialty clinics (cardiology, nephrology, neurology, and pediatrics), based on clinical symptoms suggestive of Fabry disease. We used the plasma lyso-Gb3 concentration, α-galactosidase A (α-Gal A) activity, and analysis of the α-Gal A gene (GLA) for primary and secondary screens, respectively. RESULTS: Of 8 males with elevated lyso-Gb3 levels (≥2.0 ng ml-1) and low α-Gal A activity (≤4.0 nmol h-1 ml-1), 7 presented a GLA mutation (2 classic and 5 late-onset). Of 14 females with elevated lyso-Gb3, 7 displayed low α-Gal A activity (5 with GLA mutations; 4 classic and 1 late-onset) and 7 exhibited normal α-Gal A activity (1 with a classic GLA mutation and 3 with genetic variants of uncertain significance). CONCLUSION: Plasma lyso-Gb3 is a potential primary screening biomarker for classic and late-onset Fabry disease probands.

Tenascin-C expression in renal biopsies from patients with tubulointerstitial nephritis and its relation to disease activity and prognosis.

Tenascin-C (TNC) is an extracellular matrix protein that is transiently expressed in close association with tissue remodeling in various organs. Expression of TNC in patients with tubulointerstitial nephritis (TIN) is not well-characterized. Using renal biopsy specimens from 25 patients with TIN and 8 patients with thin basement membrane disease (controls), we assessed immunohistochemical staining for TNC and investigated its relation with clinicopathologic data. TNC was undetectable in the controls, but TNC was observed in the interstitium of specimens from all patients with TIN, and strong TNC staining was detected within active tubulitis lesions. TNC was not principally expressed in glomeruli, and it was also absent from scar tissue. Comparison with Sirius red staining revealed that TNC was present where collagen fibers had not yet formed. The percent area of TNC within the interstitium (% TNC-positive area) showed a significant negative correlation with illness duration and significant positive correlations with the serum CRP level and eGFR aggravation, both of which reflect disease activity. On the other hand, no correlation was found between % TNC-positive area and eGFR recovery during 2 years of follow up. Examination of renal biopsy specimens from TIN patients revealed that TNC appears during the active stage of inflammation and then disappears with healing. This suggests that TNC expression reflects TIN disease activity, but not prognosis.

Long-Term Levocarnitine Ameliorates Left Ventricular Diastolic as Well as Systolic Dysfunction in Hemodialysis Patients　- Multi-Center Study.

Background: Levocarnitine has been reported to improve the left ventricular (LV) systolic function and decrease LV hypertrophy in hemodialysis (HD) patients. Its effect on LV diastolic dysfunction, however, has not yet been clarified. Methods and Results: HD patients (n=88) were given levocarnitine i.v. 1,000 mg for 12 months at the end of every dialysis session through the dialysis circuit of the venous site. LV ejection fraction (EF), E/A, E/e', left atrial volume index (LAVI) and LV mass index (LVMI) were measured before and 3, 6, 9, and 12 months after the start of levocarnitine on echocardiography. We regarded E/A≤0.8, E/e'>14 and LAVI>34 mL/m2 as LV diastolic dysfunction, and LVEF<55% as LV systolic dysfunction. We also investigated the effect of levocarnitine on HFpEF. Plasma brain natriuretic peptide, total carnitine, free carnitine, and acyl-carnitine and biochemistry parameters were measured. Levocarnitine significantly improved LV diastolic function in HD patients with LV diastolic dysfunction, but did not affect LV diastolic function in those with normal LV diastolic function. Levocarnitine significantly improved HFpEF. Levocarnitine significantly improved the LV systolic function in HD patients with LV systolic dysfunction but did not affect the LV systolic function in those with normal LV systolic function. Levocarnitine significantly decreased LVMI and increased plasma total, free, and acyl-carnitine. Conclusions: Levocarnitine ameliorates LV diastolic as well as LV systolic dysfunction in HD patients.

Application of an adenoviral vector encoding soluble transforming growth factor-beta type II receptor to the treatment of diabetic nephropathy in mice.

1. In the present study, we examined the effects of inhibiting transforming growth factor (TGF)-beta in a mouse model of diabetic nephropathy. 2. An adenovirus harbouring the gene encoding soluble TGF-beta type II receptor (Ad.CAG-sTbetaRII), a competitive inhibitor of TGF-beta, was injected into hindlimb muscles (systemic delivery) of mice 5 weeks after the induction of diabetes with streptozotocin. The control group was injected with an adenovirus encoding the LacZ gene (Ad-LacZ). 3. Five weeks after administration, anti-TGF-beta gene therapy was found to have had no effect on renal function, albuminuria or glucose metabolism in mice with diabetic nephropathy. Nonetheless, this gene therapy did significantly reduce fibrosis in both glomeruli and renal tubules. These effects were accompanied by attenuation of the increased expression of alpha-smooth muscle actin normally seen in kidneys of diabetic mice and better preservation of glomerular cell numbers, although the thickness of the glomerular capillary basement membrane was unchanged. The plasma concentration of soluble TGF-beta type II receptor peaked on Day 7 after treatment, but was undetectable by Day 14. Moreover, a second treatment with Ad.CAG-sTbetaRII failed to prolong the interval of gene product expression in the blood. 4. The present anti-TGF-beta gene therapy showed a significant antifibrotic effect in a model of diabetic nephropathy, but failed to improve renal function. The inadequacy of the observed effect is likely due to the relatively short interval of gene product expression. This problem will have to be overcome if gene therapies for slowly progressing diseases, like diabetic nephropathy, are to be realised.

Efficacy of Acupuncture Treatment for Improving the Respiratory Status in Patients Receiving Prolonged Mechanical Ventilation in Intensive Care Units: A Retrospective Observational Study.

BACKGROUND AND OBJECTIVE: Patients in critical care settings often require prolonged mechanical ventilation (MV) therapy and, occasionally, they cannot be weaned from MV. The authors evaluated the efficacy of acupuncture treatment for improving the respiratory status and promoting successful weaning from prolonged MV in patients at intensive care units (ICUs). DESIGN: Retrospective observational study. SETTING: Gifu University Hospital, Gifu, Japan. SUBJECTS: The authors included 16 tracheostomized patients receiving MV for >21 days at the ICU of Gifu University Hospital, who underwent acupuncture therapy for improving their respiratory status. INTERVENTION: Acupuncture treatment was conducted in four sessions per week. OUTCOME MEASURES: The data of tidal volume (VT), respiratory rate (RR), heart rate (HR), oxygen saturation as measured by pulse oximetry (SpO2), dynamic lung compliance (Cdyn), rapid shallow breath index (RSBI; RR/VT) values before and immediately after acupuncture were extracted from the medical records. RESULTS: The median number of days on MV before acupuncture initiation was 31 days. VT and Cdyn were significantly increased immediately after acupuncture (all p < 0.001), whereas RR, HR, and RSBI were significantly decreased (all p < 0.05). Eleven patients were successfully weaned from MV after acupuncture initiation. In the weaning success group, VT and Cdyn were significantly increased (all p < 0.01), whereas RR, HR, and RSBI were significantly decreased (all p < 0.05) after acupuncture. Conversely, in the weaning failure group, these values were not changed significantly. The increase in Cdyn after acupuncture was larger in the weaning success group than in the weaning failure group (p < 0.05). CONCLUSION: Acupuncture treatment might have beneficial effects on the respiratory status of ICU patients receiving MV and may help in weaning from prolonged MV. Further large prospective cohort studies are warranted.

Renoprotective effect of the addition of losartan to ongoing treatment with an angiotensin converting enzyme inhibitor in type-2 diabetic patients with nephropathy.

Angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) are frequently used for the treatment for glomerulonephritis and diabetic nephropathy because of their albuminuria- or proteinuria-reducing effects. To many patients who are nonresponsive to monotherapy with these agents, combination therapy appears to be a good treatment option. In the present study, we examined the effects of the addition of an ARB (losartan) followed by titration upon addition and at 3 and 6 months (n=14) and the addition of an ACE-I followed by titration upon addition and at 3 and 6 months (n=20) to the drug regimen treatment protocol in type 2 diabetic patients with nephropathy for whom more than 3-month administration of an ACE-I or the combination of an ACE-I plus a conventional antihypertensive was ineffective to achieve a blood pressure (BP) of 130/80 mmHg and to reduce urinary albumin to <30 mg/day. During the 12-month treatment, addition of losartan or addition of an ACE-I to the treatment protocol reduced systolic blood pressure (SBP) by 10% and 12%, diastolic blood pressure (DBP) by 7% and 4%, and urinary albumin excretion by 38% and 20% of the baseline value, respectively. However, the effects on both BP and urinary albumin were not significantly different between the two therapies. In conclusion, addition of losartan or an ACE-I to an ongoing treatment with an ACE-I, or addition of an ACE-I to ongoing treatment with a conventional antihypertensive were equally effective at reducing the urinary albumin excretion and BP, and provided renal protection in patients with type-2 diabetic nephropathy.

The metabolic profile of a rat model of chronic kidney disease.

BACKGROUND: The kidney is always subjected to high metabolic demand. The aim of this study was to characterize metabolic profiles of a rat model of chronic kidney disease (CKD) with cardiorenal syndrome (CRS) induced by prolonged hypertension. METHODS: We used inbred male Dahl salt-sensitive (DS) rats fed an 8% NaCl diet from six weeks of age (high-salt; HS group) or a 0.3% NaCl diet as controls (low-salt; LS group). We analyzed function, pathology, metabolome, and the gene expression related to energy metabolism of the kidney. RESULTS: DS rats with a high-salt diet showed hypertension at 11 weeks of age and elevated serum levels of creatinine and blood urea nitrogen with heart failure at 21 weeks of age. The fibrotic area in the kidneys increased at 21 weeks of age. In addition, gene expression related to mitochondrial function was largely decreased. The levels of citrate and isocitrate increased and the gene expression of alpha-ketoglutaratedehydrogenase and succinyl-CoA synthetase decreased; these are enzymes that metabolize citrate and isocitrate, respectively. In addition, the levels of succinate and acetyl Co-A, both of which are metabolites of the tricarboxylic acid (TCA) cycle, decreased. CONCLUSIONS: DS rats fed a high-salt diet were deemed a suitable model of CKD with CRS. Gene expression and metabolites related to energy metabolism and mitochondria in the kidney significantly changed in DS rats with hypertension in accordance with the progression of renal injury.

Volumetric quantitative analysis of tissue characteristics of coronary plaques after statin therapy using three-dimensional integrated backscatter intravascular ultrasound.

OBJECTIVES: The purpose of the present study was twofold: 1) to evaluate the usefulness of three-dimensional (3D) integrated backscatter (IB) intravascular ultrasound (IVUS) for quantitative tissue characterization of coronary plaques; and 2) to use this imaging technique to determine if six months of statin therapy alters the tissue characteristics of coronary plaques. BACKGROUND: Three-dimensional IVUS techniques for quantitative tissue characterization of plaque composition have not been developed. METHODS: Radiofrequency (RF) signals were obtained using an IVUS system with a 40-MHz catheter. The IB values of the RF signal were calculated and color-coded. The 3D reconstruction of the color-coded map was performed by computer software. A total of 18 IB IVUS images were captured at an interval of 1 mm in each plaque. A total of 52 patients with hyperlipidemia were randomized to treatment with pravastatin (20 mg/day, n = 17), atorvastatin (20 mg/day, n = 18), or diet (n = 17) for six months. The tissue characteristics of arterial plaque in each patient (one arterial segment per patient) were analyzed with 3D IB IVUS before and after treatment. RESULTS: Significant increases of fibrous volume (pravastatin: 25.4 +/- 6.5% to 28.1 +/- 6.1%; atorvastatin: 26.2 +/- 5.7% to 30.1 +/- 5.5%) and mixed lesion volume (atorvastatin: 25.5 +/- 6.6% to 28.7 +/- 5.1%) and a reduction of lipid volume (pravastatin: 25.5 +/- 5.7% to 21.9 +/- 5.3%; atorvastatin: 26.5 +/- 5.2% to 19.9 +/- 5.5%) were observed after statin therapy. CONCLUSIONS: Statin therapy reduced the lipid component in patients with stable angina without reducing the degree of stenosis. Three-dimensional IB IVUS offers the potential for quantitative volumetric tissue characterization of coronary atherosclerosis.

Hepatocyte growth factor gene therapy slows down the progression of diabetic nephropathy in db/db mice.

BACKGROUND: Effect of hepatocyte growth factor (HGF) has scarcely been determined on diabetic nephropathy. METHODS: Adenovirus encoding human HGF gene or LacZ gene (as the control) was injected into the hindlimb muscles of the C57BL/KsJ-db/db (db/db) mice at the age of 12 weeks, a model of genetic diabetes. Diabetic nephropathy was then evaluated at the age of 24 weeks. RESULTS: The urine volume and albumin excretion progressively decreased in the control, whereas they remained unchanged in the HGF-treated group during the 12-week follow-up. The HGF gene therapy did not affect glucose metabolism. However, it resulted in a better renal function as evaluated by creatinine clearance (Ccr) than the control; Ccr was progressively worsened in controls (0.14 +/- 0.02 liters/day) whereas unchanged in the HGF gene-treated group (0.38 +/- 0.09 liters/day, p < 0.05). Kidneys of the HGF gene-treated mice showed glomeruli with greater area and cell population, smaller glomerular sclerotic index, and less fibrosis in both glomeruli and renal tubules, where apoptotic rate of glomerular endothelial cells and that of tubular epithelial cells were significantly decreased. TGF-beta1 expression was significantly decreased in kidneys of the HGF gene-treated group. Finally, the HGF treatment significantly improved the long-term survival of db/db mice. CONCLUSIONS: The HGF gene delivery thus appeared to slow down the aggravation of diabetic nephropathy in db/db mice by attenuating progression from the hyperfiltration phase into the sclerotic phase through antiapoptotic and antifibrotic actions. The present findings suggest that the HGF gene delivery can be a novel therapeutic approach against diabetic nephropathy.

Traditional Thermal Therapy with Indirect Moxibustion Decreases Renal Arterial Resistive Index in Patients with Chronic Kidney Disease.

OBJECTIVE: To evaluate the immediate effects of traditional local thermal therapy with indirect moxibustion on renal hemodynamics in patients with chronic kidney disease (CKD) by using Doppler ultrasonography (US). DESIGN: Examiner-blinded crossover study. PARTICIPANTS: Forty-three participants with CKD (mean age ± standard deviation [SD], 44 ± 15 years; estimated glomerular filtration rate, 69.5 ± 25.5 mL/min per 1.73 m(2); 20 men and 23 women). INTERVENTION: Participants received three successive treatment sessions of indirect moxibustion bilaterally at BL 23, a crucial acupuncture point, in the session. In the control session, the examiner was blinded by using smoke and aroma produced by moxibustion performed in an ashtray placed near the patient's body. OUTCOME MEASURES: The main outcome measure was resistive index (RI) in the renal segmental arteries. Blood flow parameters, including RI, were measured for six renal segmental arteries by using Doppler US at rest (baseline), immediately after completion of moxibustion (post 1), and 10 minutes later (post 2). Adverse events were monitored during intervention. RESULTS: In the control session, RI at post 1 (median [first, third quartile]: 0.587 [0.562, 0.626]) and post 2 (0.583 [0.567, 0.629]) did not change significantly compared with baseline (0.592 [0.563, 0.636]), while in the treatment session, RI at post 1 (0.565 [0.530, 0.618]) and post 2 (0.561 [0.533, 0.614]) decreased significantly compared with baseline (0.590 [0.550, 0.652]) (p < 0.001 and p < 0.001, respectively). The reduction in RI from baseline to post 2 in treatment session was significantly greater than in control session (mean ± SD, -0.026 ± 0.028 versus -0.003 ± 0.028; mean difference, -0.023 [95% confidence interval, -0.036 to -0.010]; p = 0.001]. No adverse events, such as burns, were observed during the study period. CONCLUSION: Renal vascular resistance was decreased after indirect moxibustion therapy in patients with CKD.

Water extract of the root of Lindera strychnifolia slows down the progression of diabetic nephropathy in db/db mice.

We examined a possible preventive effect of Linderae radix (LR), the root of Lindera strychnifolia, on the progression of diabetic nephropathy. Water extract of Linderae radix (LR extract) was orally administered to the C57BL/KsJ-db/db (db/db) mice, a model of genetic diabetes, at a dose of 730 mg/kg/day for 12 week. The LR extract treatment did not affect glucose metabolism and systolic pressure. However, it resulted in a better renal function as evaluated by creatinine clearance (Ccr) and serum creatinine than the control; Ccr and serum creatinine were progressively worsened in controls (0.13+/-0.01 (l/day) and 0.69+/-0.04 (mg/dl), respectively) whereas unchanged in the treated group (0.24+/-0.03 (l/day), p<0.05 and 0.53+/-0.04 (mg/dl), p<0.05, respectively). Kidneys of the LR extract-treated group showed glomeruli with greater area and cell population, smaller glomerular sclerotic index, and less fibrosis in glomeruli, where apoptotic rate of glomerular cells were decreased compared with the control kidneys. Furthermore, renal TGF-beta(1) expression was decreased in the LR extract-treated group. These findings suggest that the LR therapy can be a novel therapeutic approach against diabetic nephropathy.

Higher plasma prorenin concentration plays a role in the development of coronary artery disease.

BACKGROUND: Prorenin and renin are both involved in atherosclerosis. However, the role of plasma prorenin and renin in the development and progression of coronary artery disease (CAD) is still not clear. Thus, we aimed to examine the relationships among plasma prorenin concentration, CAD and clinical parameters. METHODS: We measured plasma prorenin and renin concentrations and other parameters in 85 patients who underwent coronary angiography. Patients were divided into a CAD group (≥75 % stenosis in one or more coronary arteries) and a non-CAD group. RESULTS: There was a weak correlation between prorenin and plasma renin concentration (r =0.35, p =0.001), and plasma renin activity (r =0.34, p =0.001). There was no significant difference in the plasma prorenin concentration between the CAD group and non-CAD group. However, patients with a high plasma prorenin concentration frequently suffered CAD. Receiver-operating-characteristic curve analysis showed that the optimal cutoff value of plasma prorenin concentration to detect CAD was 1,100 pg/ml, with a positive predictive value of 94 % and a negative predictive value of 36 %. CONCLUSION: The plasma prorenin concentration increases with increases in plasma renin concentration. Higher plasma prorenin concentration (>1,100 pg/ml) plays a role in the development of CAD.

Traditional thermal therapy with indirect moxibustion decreases renal arterial resistive index.

OBJECTIVE: To evaluate the immediate effects of indirect moxibustion, a traditional local thermal therapy, on renal hemodynamics by using Doppler ultrasonography (US). DESIGN: Prospective observational study of postintervention changes in several variables. SETTING: Gifu University Hospital, Gifu, Japan. PARTICIPANTS: Eleven healthy persons (7 men and 4 women; mean age±standard deviation, 32.6±5.7 years) were enrolled. INTERVENTION: Indirect moxibustion was applied for 4 minutes to bilateral lower back acupuncture points (BL23). Each participant received 3 successive treatments. OUTCOME MEASURES: The main outcome measurement was resistive index (RI) in the renal segmental arteries. Blood flow variables, including RI, were measured for 6 renal segmental arteries by Doppler US at rest (baseline), immediately after completion of moxibustion (post 1), and 10 minutes later (post 2). Participants were monitored for adverse events during the intervention. RESULTS: The mean RI was 0.578±0.037 at baseline, 0.546±0.027 at post 1, and 0.547±0.032 at post 2. RI decreased significantly between post 1 and baseline (95% confidence interval [CI], -0.053 to -0.011; p=0.003) and between post 2 and baseline (95% CI, -0.052 to -0.009; p=0.005). No adverse events, such as burns, were observed. CONCLUSION: This study of the short-term effects of indirect moxibustion on renal hemodynamics in healthy persons showed that renal vascular resistance was reduced after the therapy.

Expression of prorenin receptor in renal biopsies from patients with IgA nephropathy.

Prorenin receptor (PRR) has been implicated in the onset and progression of various renal diseases, though its possible association with immunoglobulin A (IgA) nephropathy remains unclear. In the present study, we tried to clarify expression and pathophysiological significance of PRR in IgA nephropathy. We immunohistochemically assessed PRR levels in renal biopsy specimens from 48 patients with IgA nephropathy and evaluated its relevance to the clinical and pathological features of the disease. PRR was detected mainly in renal tubular cells, which was confirmed at the subcellular level using immunoelectron microscopy. The PRR-positive area (%PRR area) correlated with daily urinary protein, which is known to reflect disease severity (r=0.286, P=0.049). PRR levels were weaker in tubular cells bordering areas of severe interstitial fibrosis, where α-smooth muscle actin-positive myofibroblasts were present. We also used immunohistochemical detection of microtubule-associated protein-1 light chain 3 (LC3) and electron microscopy to assess autophagy, a cytoprotective mechanism downstream of PRR. We noted an apparent coincidence between autophagy activation in tubular cells and PRR expression in the same cells. Taken together, our findings suggest that renal expression of PRR in IgA nephropathy may be a compensatory response slowing disease progression by preventing tubular cell death and subsequent fibrosis through activation of cytoprotective autophagic machinery. Further studies using different type of kidney diseases could draw conclusion if the present finding is a generalized observation beyond IgA nephropathy.

Treatment with Lindera strychnifolia reduces blood pressure by decreasing sympathetic nerve activity in spontaneously hypertensive rats.

Lindera strychnifolia (Tendai-Uyaku), a medicinal plant, has long been used for the treatment of cardiac, renal and rheumatic diseases in Japan. We investigated the effect of Lindera strychnifolia on systolic blood pressure, cardiac function, and plasma noradrenaline levels in rats. Spontaneously hypertensive rats (SHR) were given free access to water or extract solution of Lindera strychnifolia, which was extracted with a ratio of 10 g Lindera strychnifolia roots/20 ml water. Systolic blood pressure was measured by using a tail-cuf sphygmomanometer twice a week from 10 to 30 weeks of age, and compared to the age-matched Wistar Kyoto rats (WKY) as a control group. At 30 weeks of age, heart function was measured by echocardiography and blood samples were taken for detection of plasma noradrenaline levels, and rats were then sacrificed. Systolic blood pressure gradually increased from 10 to 30 weeks of age in the SHR group, while it did not change in the WKY group. In the Lindera-treated SHR group, the increase in systolic blood pressure was significantly attenuated from 21 to 30 weeks of age. Echocardiography showed a significant increase in ejection fraction in the Lindera-treated SHR group (60.4 +/- 7.8%) as compared to the SHR group (39.7 +/- 23.4%). Plasma noradrenaline levels were significantly decreased in Lindera-treated SHR group compared to the SHR group. These results suggest that Lindera strychnifolia has an anti-hypertensive effect and improves cardiac function in spontaneous hypertensive rats. These effects may be related to the decrease in plasma noradrenaline levels by Lindera strychnifolia.

In vivo quantitative tissue characterization of angiographically normal coronary lesions and the relation with risk factors: a study using integrated backscatter intravascular ultrasound.

BACKGROUND: Autopsy studies have shown atherosclerotic changes in angiographically normal coronary lesions (ANCL), and conventional intravascular ultrasound shows intimal thickening in these lesions, but cannot differentiate the lipid core. Accurate characterization of ANCL is essential to prevent progression to coronary artery disease. METHODS AND RESULTS: ANCL (n=120) were analyzed by integrated backscatter intravascular ultrasound (IB-IVUS) in 30 patients with stable angina pectoris. Of the 120 arterial segments analyzed by IB-IVUS, 78 (65%) showed lipid cores of 0.69+/-0.35 mm2 with fibrous caps of 200+/-100 microm thick, 44 (37%) had intimal hyperplasia with a thickness of 350+/-100 microm, and 65 (54%) showed fibrosis in the intimal wall without lipid core with a thickness of 450+/-150 microm. The diabetes mellitus (DM) group (n=14) had significantly (p<0.05) bigger lipid cores (0.62+/-0.38 mm2) and thinner intimal hyperplasia (100+/-100 microm) compared with the non-DM group (0.31+/-0.33 mm2, 150+/-150 microm, respectively). The hypertension (HT) group (n=23) had significantly more intimal hyperplasia (150+/-150 microm) compared with the non-HT group (50+/-100 microm). Hyperlipidemia (n=16) or smoking (n=6) did not significantly affect tissue characteristics. CONCLUSION: IB-IVUS showed various types of plaque in ANCL and the plaque characteristics were affected by DM and HT. The results provide new clinical insight into the early stage of human coronary atherosclerosis.

Apoptotic cell loss following cell proliferation in renal glomeruli of Otsuka Long-Evans Tokushima Fatty rats, a model of human type 2 diabetes.

BACKGROUND: The mechanism of glomerular cell loss during the late stage of diabetic nephropathy is unknown. METHODS: We examined cell population, proliferation, apoptosis, and immunohistochemical expression of apoptosis-related proteins, Bcl-2 and Bax, in renal glomeruli of the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model of human type 2 diabetes. 10-, 30-, 50-, and 70-week-old rats were used (n = 5-8). Control was the Long-Evans Tokushima Otsuka (LETO) rat. RESULTS: The cell population in renal glomeruli of OLETF rats progressively increased with age, but decreased at 70 weeks old. High cell proliferative activity based on proliferating cell nuclear antigen (PCNA) expression was limited during the early stage, whereas by in situ nick end-labeling (TUNEL), Taq polymerase based in situ ligation, and electron microscopy, apoptosis was detected during the late stage (50 and 70 weeks old). Augmented expression of Bax, but not of Bcl-2, was evident in glomeruli of OLETF rats during the late stage, which contributed to an increased Bax/Bcl-2 ratio. CONCLUSION: It appears that high cell proliferative activity and the subsequent cell loss via apoptosis counterbalance each other and determine glomerular cell population of OLETF rats. Augmented Bax expression may be one of the important regulators of this apoptosis.