A Japanese Multicenter Study on PET and Other Biomarkers for Subjects with Potential Preclinical and Prodromal Alzheimer's Disease.

BACKGROUND: PET (positron emission tomography) and CSF (cerebrospinal fluid) provide the "ATN" (Amyloid, Tau, Neurodegeneration) classification and play an essential role in early and differential diagnosis of Alzheimer's disease (AD). OBJECTIVE: Biomarkers were evaluated in a Japanese multicenter study on cognitively unimpaired subjects (CU) and early (E) and late (L) mild cognitive impairment (MCI) patients. MEASUREMENTS: A total of 38 (26 CU, 7 EMCI, 5 LMCI) subjects with the age of 65-84 were enrolled. Amyloid-PET and FDG-PET as well as structural MRI were acquired on all of them, with an additional tau-PET with 18F-flortaucipir on 15 and CSF measurement of Aß1-42, P-tau, and T-tau on 18 subjects. Positivity of amyloid and tau was determined based on the positive result of either PET or CSF. RESULTS: The amyloid positivity was 13/38, with discordance between PET and CSF in 6/18. Cortical tau deposition quantified with PET was significantly correlated with CSF P-tau, in spite of discordance in the binary positivity between visual PET interpretation and CSF P-tau in 5/8 (PET-/CSF+). Tau was positive in 7/9 amyloid positive and 8/16 amyloid negative subjects who underwent tau measurement, respectively. Overall, a large number of subjects presented quantitative measures and/or visual read that are close to the borderline of binary positivity, which caused, at least partly, the discordance between PET and CSF in amyloid and/or tau. Nine subjects presented either tau or FDG-PET positive while amyloid was negative, suggesting the possibility of non-AD disorders. CONCLUSION: Positivity rate of amyloid and tau, together with their relationship, was consistent with previous reports. Multicenter study on subjects with very mild or no cognitive impairment may need refining the positivity criteria and cutoff level as well as strict quality control of the measurements.

Patient perceptions of symptoms and concerns during cancer chemotherapy: 'affects my family' is the most important.

BACKGROUND: Cancer chemotherapy is associated with a variety of side effects/adverse events. It is very important that patients adhere to the planned chemotherapy regimen, which necessitates a minimum of side effects and that these side effects be kept under control. We have investigated patients' concerns and symptoms during chemotherapy with the aim to seek solutions that will improve patients' quality of life during chemotherapy. METHODS: Forty-nine patients with malignant diseases on parenteral antineoplastic agents were sequentially enrolled in this study. These patients completed a questionnaire consisting of 42 items related to non-physical concerns and 52 items of physical symptoms related to chemotherapy. Each patient was also asked to select the three items among these 94 items which affected him/her the most. RESULTS: The median age of the cancer patients was 62 years and the male-to-female ratio was 18:31. Among the non-physical concerns, the most frequently chosen concern was 'affects my family or partner,' followed by anxiety related to treatment. Regarding the physical symptoms, the most frequent complaints were fatigue, alopecia and constipation, while the most troublesome symptoms were nausea, poor taste and paresthesia. Overall, the most frequently expressed concerns were 'affects my family or partner' and anxiety related to treatment. Male patients suffered most from fever, fatigue and nausea, and female patients complained more of poor taste and gastrointestinal problems. CONCLUSION: Patient perceptions of adverse events associated with cancer chemotherapy apparently have changed from physical symptoms to non-physical concerns. In our patient cohort 'affects my family or partner' was the most important concern. One important point to note is that female patients often complained of poor taste because this meant they were unable to cook well.

Automated PET-only quantification of amyloid deposition with adaptive template and empirically pre-defined ROI.

Amyloid PET is useful for early and/or differential diagnosis of Alzheimer's disease (AD). Quantification of amyloid deposition using PET has been employed to improve diagnosis and to monitor AD therapy, particularly in research. Although MRI is often used for segmentation of gray matter and for spatial normalization into standard Montreal Neurological Institute (MNI) space where region-of-interest (ROI) template is defined, 3D MRI is not always available in clinical practice. The purpose of this study was to examine the feasibility of PET-only amyloid quantification with an adaptive template and a pre-defined standard ROI template that has been empirically generated from typical cases. A total of 68 subjects who underwent brain (11)C-PiB PET were examined. The (11)C-PiB images were non-linearly spatially normalized to the standard MNI T1 atlas using the same transformation parameters of MRI-based normalization. The automatic-anatomical-labeling-ROI (AAL-ROI) template was applied to the PET images. All voxel values were normalized by the mean value of cerebellar cortex to generate the SUVR-scaled images. Eleven typical positive images and eight typical negative images were normalized and averaged, respectively, and were used as the positive and negative template. Positive and negative masks which consist of voxels with SUVR ⩾1.7 were extracted from both templates. Empirical PiB-prone ROI (EPP-ROI) was generated by subtracting the negative mask from the positive mask. The (11)C-PiB image of each subject was non-rigidly normalized to the positive and negative template, respectively, and the one with higher cross-correlation was adopted. The EPP-ROI was then inversely transformed to individual PET images. We evaluated differences of SUVR between standard MRI-based method and PET-only method. We additionally evaluated whether the PET-only method would correctly categorize (11)C-PiB scans as positive or negative. Significant correlation was observed between the SUVRs obtained with AAL-ROI and those with EPP-ROI when MRI-based normalization was used, the latter providing higher SUVR. When EPP-ROI was used, MRI-based method and PET-only method provided almost identical SUVR. All (11)C-PiB scans were correctly categorized into positive and negative using a cutoff value of 1.7 as compared to visual interpretation. The (11)C-PiB SUVR were 2.30 ± 0.24 and 1.25 ± 0.11 for the positive and negative images. PET-only amyloid quantification method with adaptive templates and EPP-ROI can provide accurate, robust and simple amyloid quantification without MRI.

Comparison of sirolimus eluting stent with bioresorbable polymer to everolimus eluting stent with permanent polymer in bifurcation lesions: Results from CENTURY II trial.

OBJECTIVE: To demonstrate the safety and efficacy of a new sirolimus eluting stent with bioresorbable polymer, Ultimaster, (BP-SES) compared with everolimus-eluting, permanent polymer, Xience stent (PP-EES) in bifurcation lesions with respect to the freedom from Target Lesion Failure at 1-year. METHODS: Within 1,119 patients enrolled in the CENTURY II randomized controlled multicenter trial, 194 patients were treated for bifurcation lesions and randomized to either BP-SES (n = 95) or PP-EES (n = 99). The primary endpoint was freedom from target lesion failure (TLF) composite endpoint [cardiac death, MI not clearly attributable to a non-target vessel, and clinically driven target lesion revascularization (TLR)] at 1-year. RESULTS: Baseline patient demographic, angiographic, and stenting characteristics were similar in both study arms. A single stent technique with provisional or "cross over" stenting were the most widely used in both arms (93.2% BP-SES vs. 92.4% PP-EES). Freedom from TLF at 1-year was 94.7% for BP-SES and 91.9% for PP-EES (P for noninferiority 0.031). The rate of clinically driven target lesion revascularization (TLR) at 1-year was 3.2% for BP-SES and 3.0% for PP-EES (P = 0.95). There were no significant differences detected in any of the individual clinical endpoints or other secondary clinical endpoints between the study arms at 1-year follow up. CONCLUSIONS: The new bioresorbable polymer sirolimus-eluting stent showed safety and efficacy profiles similar to durable polymer everolimus-eluting in the treatment of patients with bifurcation lesions at 1-year follow up. © 2015 Wiley Periodicals, Inc.

Plasma phylloquinone, menaquinone-4 and menaquinone-7 levels and coronary artery calcification.

Vitamin K is considered to be involved in the pathological mechanisms of coronary artery calcification (CAC). Correlation between CAC and plasma vitamin K levels was studied. A total of 103 patients, with at least one coronary risk factor, were studied. CAC was measured using 64-slice multislice computed tomography (MSCT) and divided into three groups: none (CAC score = 0; n 25), mild to moderate (0 < CAC score < 400; n 52) and severe (CAC score > 400; n 26). Phylloquinone (PK) and menaquinone (MK)-4 and MK-7 were measured by HPLC-tandem MS. Mean age of patients was 64 (sd 13) years, of which 57 % were male. Median CAC score was 57·2. Median levels of PK, MK-4 and MK-7 were 1·33, 0 and 6·99 ng/ml, showing that MK-7 was the dominant vitamin K in this population. MK-7 showed a significant inverse correlation with uncarboxylated osteocalcin (ucOC, P = 0·014), protein induced by vitamin K absence of antagonist-2 (PIVKA-2, P = 0·013), intact parathyroid hormone (P = 0·007) and bone-specific alkaline phosphatase (P = 0·018). CAC showed an inverse correlation with total circulating uncarboxylated matrix Gla protein (t-ucMGP, P = 0·018) and Hb (P = 0·05), and a positive correlation with age (P < 0·001), creatinine, collagen type 1 cross-linked N-terminal telopeptide (NTX, P = 0·03), pulse wave velocity (P < 0·001) and osteoprotegerin (P < 0·001). However, CAC did not have a significant correlation with plasma levels of PK, MK-4 or MK-7. In conclusion, plasma MK-7, MK-4 or PK level did not show significant correlation with CAC despite the association between plasma vitamin K levels and vitamin K-dependent proteins such as ucOC or PIVKA-2.

Visual-statistical interpretation of (18)F-FDG-PET images for characteristic Alzheimer patterns in a multicenter study: inter-rater concordance and relationship to automated quantitative evaluation.

BACKGROUND AND PURPOSE: The role of (18)F-FDG-PET in the diagnosis of Alzheimer disease is increasing and should be validated. The aim of this study was to assess the inter-rater variability in the interpretation of (18)F-FDG-PET images obtained in the Japanese Alzheimer's Disease Neuroimaging Initiative, a multicenter clinical research project. MATERIALS AND METHODS: This study analyzed 274 (18)F-FDG-PET scans (67 mild Alzheimer disease, 100 mild cognitive impairment, and 107 normal cognitive) as baseline scans for the Japanese Alzheimer's Disease Neuroimaging Initiative, which were acquired with various types of PET or PET/CT scanners in 23 facilities. Three independent raters interpreted all PET images by using a combined visual-statistical method. The images were classified into 7 (FDG-7) patterns by the criteria of Silverman et al and further into 2 (FDG-2) patterns. RESULTS: Agreement among the 7 visual-statistical categories by at least 2 of the 3 readers occurred in >94% of cases for all groups: Alzheimer disease, mild cognitive impairment, and normal cognitive. Perfect matches by all 3 raters were observed for 62% of the cases by FDG-7 and 76 by FDG-2. Inter-rater concordance was moderate by FDG-7 (κ = 0.57) and substantial in FDG-2 (κ = 0.67) on average. The FDG-PET score, an automated quantitative index developed by Herholz et al, increased as the number of raters who voted for the AD pattern increased (ρ = 0.59, P < .0001), and the FDG-PET score decreased as those for normal pattern increased (ρ = -0.64, P < .0001). CONCLUSIONS: Inter-rater agreement was moderate to substantial for the combined visual-statistical interpretation of (18)F-FDG-PET and was also significantly associated with automated quantitative assessment.

Serum osteoprotegerin levels and long-term prognosis in subjects with stable coronary artery disease.

BACKGROUND: Osteoprotegerin (OPG) is a secretory glycoprotein which belongs to the tumor necrosis factor receptor family. OPG immunoreactivity was demonstrated in normal blood vessels and in early atherosclerotic lesions. In a previous study, we showed that high serum OPG levels are associated with progression of coronary artery disease (CAD). OBJECTIVES: The present study was designed to assess the association between serum OPG level and long-term prognosis in patients with stable coronary artery disease. METHODS: We performed a prospective, observational cohort study in 225 subjects to examine whether serum OPG levels can predict cardiovascular mortality. The median OPG levels were 1.02 ng mL(-1) at baseline. RESULTS: During the follow-up (61 + or - 25 months), 27 deaths occurred including 13 cardiovascular deaths. When the subjects were divided into three groups according to serum OPG level, the group with high serum OPG showed a higher risk for cardiovascular mortality. A Multivariate Cox proportional hazards model indicated that the higher risk of cardiovascular death in the high OPG level group remained significant (hazards ratio of 7.44, 95%CI 0.92-60.30, highest vs. lowest OPG tertile). In contrast, serum OPG levels were not associated with non-cardiovascular mortality. CONCLUSIONS: Our data show that serum OPG levels are an independent predictor of cardiovascular mortality in patients with stable coronary artery disease.

Short-term outcome of stent implantation in saphenous vein grafts: predictors of distal embolization and restenosis.

The present study, which aimed to determine the predictors of distal embolization and restenosis after stenting for vein graft disease, retrospectively analyzed 51 consecutive patients who underwent stent implantation for diseased saphenous vein grafts. Follow-up angiography was performed 6 months after the procedure and the clinical and angiographic variables were analyzed by multivariate logistic regression to determine the predictors of distal embolization and restenosis. Initial clinical success was achieved in 49 patients, 44 of whom underwent follow-up angiography and were enrolled in the retrospective analysis. Distal embolization occurred in 6 grafts (13.6%). Multivariate analysis showed that the lesion length and the total cholesterol level were independent predictors of distal embolization. Angiographic restenosis occurred in 13 (26.5%) of 49 lesions. The minimum luminal diameter and the percent diameter stenosis after stenting were associated with the occurrence of restenosis. Multivariate analysis of lesions located in the graft body identified graft age as an independent predictor of restenosis. Distal embolization can occur after vein graft stenting, especially in patients with hypercholesterolemia and diffuse stenosis. The post-stenting minimum luminal diameter and the percent diameter stenosis are predictors of restenosis. In particular, graft age is associated with the restenosis of graft body lesions.

An update of the Grützbalg hypothesis: the role of thrombosis and coagulation in atherosclerotic progression.

The Grützbalg analogy has obviously held up and been greatly extended by current work implicating specific molecules in inflammation and proteolysis. Still, Virchow's explanation is only partly able to account for the chronic outcome of this disease. Many of the open questions center on fibrin. For example, we do not know why fibrin forms in Virmani's eroded lesions. If the source of tissue factor in erosion is Nemerson's "stealth" particles, we may also need to rethink the source of tissue factor in plaque rupture. At the other extreme, as we all know, atherosclerotic vascular disease is a chronic disease. While multiple episodes of plaque rupture are likely to be important in this chronic process, the critical events here--scarring, narrowing of the lumen--remain largely unexplained. The data reviewed here suggest that intramural coagulation could be a critical process underlying these chronic changes.

Effects of cilostazol on late lumen loss and repeat revascularization after Palmaz-Schatz coronary stent implantation.

BACKGROUND: Cilostazol is an antiplatelet agent that increases the intracellular concentration of cyclic adenosine monophosphate by inhibiting phosphodiesterase III; it has been shown to reduce neointimal hyperplasia in animal balloon injury models. METHODS: One hundred thirty patients who underwent elective stenting (Palmaz-Schatz stent) were randomly assigned to cilostazol treatment 200 mg/d (n = 65) or to ticlopidine treatment 200 mg/d (n = 65). Angiographic follow-up was performed at 6 months, and clinical follow-up was continued up to 1 year. RESULTS: One sudden death and one myocardial infarction resulting from subacute occlusion were observed in the ticlopidine group. Drug adverse effects were observed in 3 patients in the cilostazol group, as opposed to 6 patients in the ticlopidine group. In the intention-to-treat analysis, 56 patients (61 lesions) in the cilostazol group and 58 patients (58 lesions) in the ticlopidine group were assessed with quantitative coronary angiography. Late loss in the cilostazol group was smaller (0.58+/-0.52 mm vs. 1.09+/-0.65 mm, P<.0001) than in the ticlopidine group. The restenosis rate was lower in the cilostazol group than in the ticlopidine group (16% vs. 33%, P = .044). The target vessel revascularization rate at 1 year was 23% in the cilostazol group and 42% in the ticlopidine group (P =.03). CONCLUSIONS: The results of this study suggest that cilostazol may be a safe medication that is effective in preventing restenosis after stent implantation.

alpha 1-Proteinase inhibitor, alpha 1-antichymotrypsin, and alpha 2-macroglobulin are the antiapoptotic factors of vascular smooth muscle cells.

Serum depletion induces cell death. Whereas serum contains growth factors and adhesion molecules that are important for survival, serum is also likely to have antiapoptotic factor(s). We show here that the plasma proteinase inhibitors alpha1-proteinase inhibitor, alpha1-antichymotrypsin, and alpha2-macroglobulin function as critical antiapoptotic factors for human vascular smooth muscle cells. Cell survival was assured when serum-free medium was supplemented with any one or all of the above serine proteinase inhibitors. In contrast, the cells were sensitive to apoptosis when cultured in medium containing serum from which the proteinase inhibitors were removed. The antiapoptotic effect conferred by the proteinase inhibitors was proportional to proteinase inhibitory activity. Without proteinase inhibitors, the extracellular matrix was degraded, and cells could not attach to the matrix. Cell survival was dependent on the intact extracellular matrix. In the presence of the caspase inhibitor z-VAD, the cells detached but did not die. The activity of caspases was elevated without proteinase inhibitors; in contrast, caspases were not activated when medium was supplemented with one of the proteinase inhibitors. In conclusion, the plasma proteinase inhibitors prevent degradation of extracellular matrix by proteinases derived from cells. Presumably an intact cell-matrix interaction inhibits caspase activation and supports cell survival.

Role of alpha5beta1 and alphavbeta3 integrins on smooth muscle cell spreading and migration in fibrin gels.

Fibrin is found at sites of vascular injury and is one of the major matrix ligands for beta3 integrins. Blocking the beta3 integrin on smooth muscle cell is hypothesized as a potential target to prevent restenosis because it could inhibit cell attachment and migration into fibrin provisional matrix. Human aortic smooth muscle cells (HNB18E6E7) spread stably in plasma gels within 24 h. Cell spreading was dramatically blocked by simultaneous use of alpha5beta1 and alphavbeta3 integrin antibodies (P <0.0001), however, blocking of either integrin alone failed to inhibit spreading. GPenGRGDSPCA, which has been considered a specific alphavbeta3 antagonist, inhibited spreading at 500 microM, suggesting that the peptide blocked both alpha5beta1 and alphavbeta3. Similarly, invasive migration into fibrin gels was blocked by simultaneous use of both alpha5beta1 and alphavbeta3 antibodies, however, blocking of either integrin alone failed to effect cell migration. Another migration assay using transwell indicated similar results. In conclusion, both alpha5beta1 and alphavbeta3 integrins are responsible for smooth muscle cell spreading and migration into fibrin gels. These data suggest that blocking beta3 integrin alone would not affect smooth muscle cell interaction with fibrin.

Human carotid artery smooth muscle cells rarely express alpha(v)beta3 integrin at sites of recent plaque rupture.

Fibrin(ogen) is the major matrix ligand for beta3 integrins. If alpha(v)beta3 is the major receptor for fibrin(ogen) on intimal smooth muscle cells, we might expect to see this integrin associated with fibrin(ogen). Eighty-four specimens obtained from endarterectomies of 14 patients were studied. Fibrin was frequently observed in carotid intima even at the non-atherosclerotic areas. As for beta1 and beta3 integrins, beta1 was predominant in intima. The alpha(v)beta3 integrin expression was less frequent than alpha5beta1, another receptor for fibrin(ogen), in diffuse intimal thickening, fibrous cap and advanced plaques. Furthermore, alpha(v)beta3 was generally negative on smooth muscle cells in recent plaque ruptures. In conclusion, we suggest more attention should be paid on abundant fibrin matrix in intima. Histologically, the alpha5beta1 integrin rather than the alpha(v)beta3 is the major receptor for fibrin in intimal smooth muscle cells.

[Gamma-interferon-induced cardiomyopathy during treatment of renal cell carcinoma: a case report].

A 78-year-old woman with renal cell carcinoma and pulmonary metastasis presented with reversible cardiomyopathy induced by gamma(gamma)-interferon. She was treated with gamma-interferon twice a week since November 1996. She presented with severe acute congestive heart failure and gamma-interferon was immediately discontinued in December 1997. Left ventricular fractional shortening was 38% before admission, 12% on admission, and improved to 31% by 40 days after discontinuation of interferon together with administration of diuretics and angiotensin converting enzyme inhibitor. We restarted the same gamma-interferon regimen because it was effective against renal cell carcinoma after 47 days. She has remained well with no significant changes of cardiac function or renal cell carcinoma for almost one year.

Alpha(1)-proteinase inhibitor, alpha(1)-antichymotrypsin, or alpha(2)-macroglobulin is required for vascular smooth muscle cell spreading in three-dimensional fibrin gel.

It is assumed that vitronectin and other adhesion molecules induce cell spreading. We found that vascular smooth muscle cells require unidentified plasma components besides adhesion molecules to spread in fibrin gel, a likely provisional matrix at wound sites. By purification, the plasma components were found to be alpha(1)-proteinase inhibitor, alpha(1)-antichymotrypsin, and alpha(2)-macroglobulin. The chemically inactivated alpha(1)-proteinase inhibitor and alpha(2)-macroglobulin lose the spreading activity, indicating that these proteins function as proteinase inhibitors but not as adhesion molecules. Not only anti-integrin (alpha(v)beta(3) and alpha(5)beta(1)) antibodies but also anti-fibronectin antibodies inhibit the cell spreading. The spreading occurs without the addition of fibronectin and integrins, suggesting that cells produce these molecules. In the absence of the proteinase inhibitors, Western blot analysis shows that the fibronectin is degraded in fibrin gel, while it is intact in the presence of the inhibitors. Thus, the proteinase inhibitors prevent adhesion molecules such as fibronectin from being degraded by a cell-derived proteinase(s) and thus play a role in cell spreading.

Kistrin inhibits human smooth muscle cell interaction with fibrin.

Because of the lack of function-blocking anti-integrin antibodies that react with nonprimate species, the study of the role of integrins in in vivo animal models of atherosclerosis has been limited. In contrast, peptides or small molecules have shown less species specificity and thus may be better tools to use. In an attempt to identify integrin antagonists of potential use against smooth muscle response to injury, we investigated the role of human smooth muscle cell interactions with fibrin by using a panel of integrin antagonists consisting of the snake venom disintegrin, Kistrin, as well as cyclic peptides with well-defined integrin antagonists activities. We demonstrate that Kistrin, a disintegrin that inhibits beta1, beta2, beta3, and beta5 integrin interactions, had the most potent inhibitory effect. Based on our results, Kistrin or peptides with similar pan-integrin selectivity patterns are prime candidates for use as anti-integrin antagonists in further studies of atherosclerosis and restenosis.

New long-tip guiding catheters designed for right transradial coronary intervention.

New long-tip catheters, one for the left and the other for the right coronary artery, were designed specifically for right transradial intervention. We utilized the overbending principle to achieve more precise control of the catheters. We also analyzed principal factors involved to determine guiding catheter support considering the anatomy of the innominate artery, ascending aorta, left and right coronary arteries. Catheter shapes were designed to exploit favorable factors to compensate for mechanically disadvantageous anatomy. The catheter for the left coronary artery has an initial loop to make use of the angle between the innominate artery and the ascending aorta to introduce the catheter to the correct position to provide strong backup support. The catheter for the right coronary artery has a unique three-dimensional curve that provides sufficient backup support and compensates for the angles between the innominate artery and the proximal portion of right coronary artery to achieve coaxial engagement. The distal portions of these catheters include long tips aiming to minimize the loss of transmitted force. The performance of these catheters was studied in 143 patients with 161 lesions. Successful engagement was achieved in 138 patients with 156 lesions (97%) and coronary intervention was successful in 136 patients with 154 lesions (99%). No major complications or coronary artery dissection occurred due to use of these catheters. This study showed the present long-tip catheters to be safe and highly effective for right transradial coronary intervention. Cathet. Cardiovasc. Intervent. 49:218-224, 2000.