Vessel Wall Enhancement on Black-Blood MRI Predicts Acute and Future Stroke in Cerebral Amyloid Angiopathy.

BACKGROUND AND PURPOSE: Cerebral amyloid angiopathy (CAA) is a known risk factor for ischemic stroke though angiographic imaging is often negative. Our goal was to determine the relationship between vessel wall enhancement (VWE) in acute and future ischemic stroke in CAA patients. MATERIALS AND METHODS: This was a retrospective study of patients with new-onset neurologic symptoms undergoing 3T vessel wall MR imaging from 2015 to 2019. Vessel wall enhancement was detected on pre- and postcontrast flow-suppressed 3D T1WI. Interrater agreement was evaluated in cerebral amyloid angiopathy-positive and age-matched negative participants using a prevalence- and bias-adjusted kappa analysis. In patients with cerebral amyloid angiopathy, multivariable Poisson and Cox regression were used to determine the association of vessel wall enhancement with acute and future ischemic stroke, respectively, using backward elimination of confounders to P < .20. RESULTS: Fifty patients with cerebral amyloid angiopathy underwent vessel wall MR imaging, including 35/50 (70.0%) with ischemic stroke and 29/50 (58.0%) with vessel wall enhancement. Prevalence- and bias-corrected kappa was 0.82 (95% CI, 0.71-0.93). The final regression model for acute ischemic stroke included vessel wall enhancement (prevalence ratio = 1.5; 95% CI, 1.1-2.2; P = .022), age (prevalence ratio = 1.02; 95% CI, 1.0-1.05; P = .036), time between symptoms and MR imaging (prevalence ratio = 0.9; 95% CI, 0.8-0.9; P < .001), and smoking (prevalence ratio = 0.7; 95% CI, 0.5-1.0; P = .042) with c-statistic = 0.92 (95% CI, 0.84-0.99). Future ischemic stroke incidence with cerebral amyloid angiopathy was 49.7% (95% CI, 34.5%-67.2%) per year over a total time at risk of 37.5 person-years. Vessel wall enhancement-positive patients with cerebral amyloid angiopathy demonstrated significantly shorter stroke-free survival with 63.9% (95% CI, 43.2%-84.0%) versus 32.2% (95% CI, 14.4%-62.3%) ischemic strokes per year, chi-square = 4.9, P = .027. The final model for future ischemic stroke had a c-statistic of 0.70 and included initial ischemic stroke (hazard ratio = 3.4; 95% CI, 1.0-12.0; P = .053) and vessel wall enhancement (hazard ratio = 2.5; 95% CI, 0.9-7.0; P = .080). CONCLUSIONS: Vessel wall enhancement is associated with both acute and future stroke in patients with cerebral amyloid angiopathy.

Addition of Amide Proton Transfer Imaging to FDG-PET/CT Improves Diagnostic Accuracy in Glioma Grading: A Preliminary Study Using the Continuous Net Reclassification Analysis.

BACKGROUND AND PURPOSE: Amide proton transfer imaging has been successfully applied to brain tumors, however, the relationships between amide proton transfer and other quantitative imaging values have yet to be investigated. The aim was to examine the additive value of amide proton transfer imaging alongside [18F] FDG-PET and DWI for preoperative grading of gliomas. MATERIALS AND METHODS: Forty-nine patients with newly diagnosed gliomas were included in this retrospective study. All patients had undergone MR imaging, including DWI and amide proton transfer imaging on 3T scanners, and [18F] FDG-PET. Logistic regression analyses were conducted to examine the relationship between each imaging parameter and the presence of high-grade (grade III and/or IV) glioma. These parameters included the tumor-to-normal ratio of FDG uptake, minimum ADC, mean amide proton transfer value, and their combinations. In each model, the overall discriminative power for the detection of high-grade glioma was assessed with receiver operating characteristic curve analysis. Additive information from minimum ADC and mean amide proton transfer was also evaluated by continuous net reclassification improvement. P < .05 was considered significant. RESULTS: Tumor-to-normal ratio, minimum ADC, and mean amide proton transfer demonstrated comparable diagnostic accuracy in differentiating high-grade from low-grade gliomas. When mean amide proton transfer was combined with the tumor-to-normal ratio, the continuous net reclassification improvement was 0.64 (95% CI, 0.036-1.24; P = .04) for diagnosing high-grade glioma and 0.95 (95% CI, 0.39-1.52; P = .001) for diagnosing glioblastoma. When minimum ADC was combined with the tumor-to-normal ratio, the continuous net reclassification improvement was 0.43 (95% CI, -0.17-1.04; P = .16) for diagnosing high-grade glioma, and 1.36 (95% CI, 0.79-1.92; P < .001) for diagnosing glioblastoma. CONCLUSIONS: Addition of amide proton transfer imaging to FDG-PET/CT may improve the ability to differentiate high-grade from low-grade gliomas.

Relationship between the retinacula cutis and sagging facial skin.

BACKGROUND: Sagging skin is one of the most concerning esthetic issues for elderly individuals. Although reduced skin elasticity has been reported as the cause of sagging skin, a loss of skin elasticity alone is insufficient to explain sagging facial skin. This study investigated the mechanisms underlying sagging skin, with a focus on the subcutaneous network of collagenous fibers known as the retinacula cutis (RC). METHODS: To evaluate the structure of the RC noninvasively, tomographic images of the face were obtained using magnetic resonance imaging (MRI). The RC was identified by comparing MRI results with histological specimens of human skin. A descriptive scale was used to evaluate the degree of sagging, and a device equipped with a 6-mm-diameter probe was used to measure the elasticity of deeper skin layers and evaluate the physical properties of the skin. RESULTS: The density of RC in subcutaneous tissue correlated negatively with sagging scores and positively with elasticity. CONCLUSION: These results imply that a sparse RC structure contributes to a reduction in the elasticity of subcutaneous tissue, resulting in a greater degree of sagging facial skin. These findings are expected to contribute to the understanding of the mechanisms underlying sagging skin.

Spectrometer for cluster ion beam induced luminescence.

A spectrometer to detect the ultra-weak luminescence originated by the collision of cluster ions on the surfaces of solid materials was constructed. This spectrometer consists of 11 photomultipliers with band-pass interference filters that can detect the luminescence within the wavelength ranging from 300 to 700 nm and of a photomultiplier without filter. The calibration of the detection system was performed using the photons emitted from a strontium aluminate fluorescent tape and from a high temperature tungsten filament. Preliminary measurements show the ability of this spectrometer to detect the cluster ion beam induced luminescence.

Equipment to detect luminescence induced by cluster ion collision.

The possibility to analyze on-line the surface region of solid materials using the cluster ion beam luminescence spectroscopy has been examined. At this aim, the cluster ion beam apparatus for the processing of solid materials was modified. The neutral clusters were ionized by the electron impact ionization to obtain an intense cluster ion beam. The tungsten filament used in this ionization method was replaced with an oxide one to reduce the emission of the background light by decreasing the operating temperature of the filament. To further suppress this light, antireflection materials were used to cover the parts inside the vacuum chamber, such as walls and inner surfaces of the einzel lens. The signal to noise ratio was improved more than one order of magnitude. The emission of photons induced by the irradiation of cluster ion beams was detected.

Intra-articular injection of mesenchymal stem cells expressing coagulation factor ameliorates hemophilic arthropathy in factor VIII-deficient mice.

BACKGROUND: Transplantation of cells overexpressing a target protein represents a viable gene therapeutic approach for treating hemophilia. Here, we focused on the use of autologous mesenchymal stem cells (MSCs) expressing coagulation factor for the treatment of coagulation factor VIII (FVIII) deficiency in mice. METHODS AND RESULTS: Analysis of luciferase gene constructs driven by different promoters revealed that the plasminogen activator inhibitor-1 (PAI-1) gene promoter coupled with the cytomegalovirus promoter enhancer region was one of the most effective promoters for producing the target protein. MSCs transduced with the simian immunodeficiency virus (SIV) vector containing the FVIII gene driven by the PAI-1 promoter expressed FVIII for several months, and this expression was maintained after multiple mesenchymal lineage differentiation. Although intravenous injection of cell supernatant derived from MSCs transduced with an SIV vector containing the FVIII gene driven by the PAI-1 promoter significantly increased plasma FVIII levels, subcutaneous implantation of the MSCs resulted in a transient and weak increase in plasma FVIII levels in FVIII-deficient mice. Interestingly, intra-articular injection of the transduced MSCs significantly ameliorated the hemarthrosis and hemophilic arthropathy induced by knee joint needle puncture in FVIII-deficient mice. The therapeutic effects of a single intra-articular injection of transduced MSCs to inhibit joint bleeding persisted for at least 8 weeks after administration. CONCLUSIONS: MSCs provide a promising autologous cell source for the production of coagulation factor. Intra-articular injection of MSCs expressing coagulation factor may offer an attractive treatment approach for hemophilic arthropathy.

Immune response against serial infusion of factor VIII antigen through an implantable venous-access device system in haemophilia A mice.

Haemophilia A is a life long bleeding disorder caused by an inherited deficiency of factor VIII (FVIII). About 30% of haemophilia A patients develop neutralizing antibodies as a consequence of treatment with FVIII concentrates. Immune tolerance protocols for the eradication of inhibitors require daily delivery of intravenous FVIII. We evaluated the immune responses to serial intravenous administration of FVIII in preimmunized haemophilia A mice. We introduced an implantable venous-access device (iVAD) system into haemophilia A mice to facilitate sequential infusion of FVIII. After preimmunization with FVIII, the haemophilia A mice were subjected to serial intravenous administration of FVIII through the iVAD system. In all mice with serial infusion of FVIII, high titers of anti-FVIII inhibitory antibodies developed at 10 exposure days (EDs). However, the anti-FVIII IgG titers were decreased after 150 EDs of sequential low-dose infusion of FVIII [0.05 U g(-1) body weight (BW) five times per week]. Proliferative response to ex vivo FVIII stimulation was significantly suppressed in splenic CD4(+) T cells from mice with serial low-dose FVIII infusion compared with those from mice with high-dose FVIII infusion (0.5 U g(-1) BW five times per week) or preimmunized mice. Moreover, splenic CD4(+) T cells from mice with serial low-dose infusion of FVIII failed to produce interleukin-2 and interferon-γ. These data suggest that serial infusion of FVIII could induce T-cell anergy in haemophilia A mice with inhibitor antibodies.

Does migraine-associated vertigo share a common pathophysiology with Meniere's disease? Study with vestibular-evoked myogenic potential.

To clarify if migraine-associated vertigo (MAV) and Meniere's disease (MD) share a common pathophysiology, vestibular-evoked myogenic potentials (VEMP) were measured in 11 patients with MAV, 11 with unilateral MD and eight healthy subjects. As acoustic stimuli, tone bursts (TB; 250, 500, 1000 and 2000 Hz) were presented. In healthy subjects, 500-Hz TB evoked the largest amplitude. To quantify this tendency, 500-1000 VEMP slope was calculated, and 500-1000 VEMP slope was the smallest on the affected side of MD patients. Among the 11 MD patients, five had significantly decreased 500-1000 VEMP asymmetry (shift of the tuning to 1000 Hz). Three of the 11 MAV patients also showed a significantly decreased 500-1000 VEMP slope. This finding suggests that MAV might share a common pathophysiology with MD. In addition to this finding, four of the other eight MAV patients showed prolonged p13 latencies. This suggests that MAV could consist of patients with different lesion sites.

Endometrial stromal sarcoma with smooth muscle and glandular differentiation of the feline uterus.

The intra-abdominal tumor developing in the uterus and lung of a domestic Shorthair cat was examined histopathologically and immunohistochemically. The tumor showed a proliferation of both endometrial stromal and smooth muscle cells accompanied by prominent vasculature. There were well-differentiated endometrial glands, and tubuli made up a monolayer of eosinophilic cuboidal epithelium. Immunohistochemically, the spindle-shaped cells and half of the stromal-like cells reacted to caldesmon and desmin antibodies. The neoplastic epithelium expressed AE1/AE3 cytokeratin. Feline endometrial stromal tumor has, to the best of our knowledge, not been reported previously and has smooth muscle and glandular components that are a unique variant to the human counterpart.

Increased intensity of acute graft-versus-host disease after reduced-intensity bone marrow transplantation compared to conventional transplantation from an HLA-matched sibling in children.

Eight children underwent reduced-intensity stem cell transplantation (RIST) from an HLA-matched sibling. They received a fludarabine-melphalan based preparative regimen. Stem cell source was bone marrow, and GVHD prophylaxis consisted of cyclosporine A alone. Acute GVHD grade II-IV and grade III-IV were observed in four (50%) and three (37.5%), respectively, out of these eight patients. This incidence was significantly higher than that after conventional bone marrow transplantation, without severe tissue damage, in the same setting of stem cell source and GVHD prophylaxis. Although the number of patients is small, our results suggest that incidence of acute GVHD after RIST for children is significant. It should be remembered that RIST for children does not seem to be an easy transplant procedure from the viewpoint of acute GVHD, although RIST is less toxic.

Cytotoxic chemotherapy successfully induces durable complete remission in 2 patients with mosquito allergy resulting from Epstein-Barr virus-associated T-/natural killer cell lymphoproliferative disease.

Recent findings indicate that Epstein-Barr virus (EBV)-infected T-/natural killer (NK) cells play an important role in the pathogenesis of mosquito allergy, and most patients with mosquito allergy die early in life if not properly treated. Over the last 7 years, we have been using combination chemotherapy and allogeneic stem cell transplantation for the treatment of EBV-associated T-/NK cell lymphoproliferative disease (LPD) in which chronic active EBV infection and mosquito allergy were included. As of this writing, we have successfully treated 2 patients with mosquito allergy with chemotherapy in which EBV-infected T-/NK cells were eradicated. The findings suggest the possible role of chemotherapy in the treatment of EBV-associated T-/NK cell LPD.

Vibratory coherence as an alternative to radiography in assessing bone healing after osteodistraction.

Distraction osteogenesis is used in orthopedics to lengthen bones by cutting or breaking the bone and gradually separating the two pieces as new bone fills the intervening space. There is a need for early assessment of the degree of bone healing that allows for normal functioning without unwanted side effects. This study compared different techniques used to evaluate the degree of bone healing during mandibular osteodistraction in 21 rabbits. For each rabbit, the mandible was cut in a surgical procedure and then 72 h later distraction began at a rate of 3 mm per day. Bone formation at the distraction site was assessed by in vivo photodensitometry on head radiographs, an in vivo (nondestructive) vibratory coherence test across the distraction site, a postmortem, ex vivo (destructive) three-point bending mechanical test, and by postmortem, ex vivo (destructive) histological examination. Statistical analyses included analysis of variance and correlation coefficient tests. The findings revealed that the results of bone photodensity and the mechanical three-point test are highly and positively correlated with the results of the vibration test. The use of the vibration test may provide a substitute for or augment the routine use of radiography for in vivo evaluation and monitoring of bone healing.

Ambulation-promoting effect of peppermint oil and identification of its active constituents.

Various plant-derived essential oils (EOs) have traditionally been used in the treatment of mental disorders, despite a lack of scientific evidence. In a previous study, we demonstrated that certain EOs possess behavioral effects, a finding that supports our original hypotheses that EOs possess psychoactive actions. The present study was conducted in order to obtain further evidence to support our hypothesis. Peppermint oil, a type of EO, is believed to be effective for treating mental fatigue. When the oil was administered intraperitoneally to ICR mice, the ambulatory activity of mice increased dramatically. We identified alpha-pinene, beta-pinene, (R)-(+)-limonene, 1,8-cineol, isomenthone, menthone, menthol, (R)-(+)-pulegone, menthyl acetate and caryophyllene as constituent elements of peppermint oil by GC-MS analysis. We then examined the effect of each constituent element of peppermint oil on ambulatory activity in mice. Intraperitoneal administration of 1,8-cineol, menthone, isomenthone, menthol, (R)-(+)-pulegone, menthyl acetate and caryophyllene significantly increased ambulatory activity in mice, suggesting that these chemicals are the behaviorally active elements of peppermint oil. Intravenous administration of these substances to mice induced a significant increase in ambulatory activity at much lower doses. The present study provides further evidence demonstrating that EOs possess pharmacological actions on behavior. In addition, our finding revealed that the action of peppermint oil comes from its constituent elements.

Design and synthesis of new orally active inhibitors of human neutrophil elastase.

To identify new orally active inhibitors, further modification of 1 (ONO-6818) was performed. Peptidic derivatives 4b, 4c and 4n showed more potent inhibitory activity than nonpeptidic derivatives 3a-c. As a result, a series of peptidic inhibitors, 4a-s and 5a-v, were discovered. Among these N-aryl derivatives 5a-g, 5i, 5m and 5o-v showed oral activity. Their oral activity showed good correlation with their metabolic stability. Compounds 5h and 5j-l, which were extremely metabolically unstable in hamster plasma, did not show oral activity. Oral activity was considered to be determined by a combination of at least two factors: oral absorption and metabolic stability.

TGF-beta1 null mutation leads to CD154 upregulated expression in affected tissues.

The TGF-beta1(-/-) mouse is a murine model for systemic autoimmune disease. The aim of this study is to elucidate the immunological mechanism that leads to multifocal tissue inflammation and autoantibody production in TGF-beta1(-/-) mice. Heart, lung, liver, and salivary gland from TGF-beta1(-/-) were assessed for CD154 expression by RT-PCR and immunohistochemistry. Compared to wild-type littermates, CD154 expression was elevated in all tissues studied. Furthermore, IL-12 mRNA was expressed in the salivary gland and heart of TGF-beta1(-/-) mice and not in wild-type littermates. This suggests that the CD154 pathway is activated in these tissues. This shows that TGF-beta1 regulates CD154 expression leading to spontaneous IL-12 production and autoimmunity.

A novel nuclear phosphoprotein, GANP, is up-regulated in centrocytes of the germinal center and associated with MCM3, a protein essential for DNA replication.

Antigen (Ag) immunization induces formation of the germinal center (GC), with large, rapidly proliferating centroblasts in the dark zone, and small, nondividing centrocytes in the light zone. We identified a novel nuclear protein, GANP, that is up-regulated in centrocytes. We found that GANP was up-regulated in GC B cells of Peyer's patches in normal mice and in spleens from Ag-immunized mice. GANP-positive cells appeared in the light zone of the GC, with coexpression of the peanut agglutinin (PNA) (PNA)-positive B220-positive phenotype. The expression of GANP was strikingly correlated with GC formation because Bcl6-deficient mice did not show the up-regulation of GANP. GANP-positive cells were mostly surrounded by follicular dendritic cells. Stimulation with anti-micro and anti-CD40 induced up-regulation of ganp messenger RNA as well as GANP protein in B220-positive B cells in vitro. GANP is a 210-kd protein localized in both the cytoplasm and nuclei, with a homologous region to Map80 that is associated with MCM3, a protein essential for DNA replication. Remarkably, GANP is associated with MCM3 in B cells and MCM3 is also up-regulated in the GC area. These results suggest that the up-regulation of GANP might participate in the development of Ag-driven B cells in GCs through its interaction with MCM3.

Physiologically based pharmacokinetics of digoxin in mdr1a knockout mice.

To determine the contribution of the mdr1a gene product to digoxin pharmacokinetics, we constructed a physiologically based pharmacokinetic model for digoxin in mdr1a (-/-) and mdr1a (+/+) mice. After intravenous administration, total body clearance and tissue-to-plasma concentration ratios for muscle and heart were decreased in mdr1a (-/-) mice as compared with mdr1a (+/+) mice, and in particular, the digoxin concentration in the brain was 68-fold higher than that in mdr1a (+/+) mice at 12 h. On the other hand, mdr1a gene disruption did not change the contributions of renal and bile clearances to total clearance, the plasma protein binding, or the blood-to-plasma partition coefficient. Brain concentration-time profiles in mdr1a (+/+) and mdr1a (-/-) mice showed a different pattern from those in plasma and other tissues, indicating digoxin accumulation in the brain tissue. Because there was no difference in the uptake or release of digoxin by brain tissue slices from the two types of mice, we assumed the brain tissue compartment to consist of two parts (a well-stirred part with influx and efflux clearance and an accumulative part). Simulation with this model gave excellent agreement with observation when active efflux clearance across the blood-brain barrier was assumed to be zero in mdr1a (-/-) mice. The observations in other tissues in both types of mice were also well simulated.

Three-dimensional image analysis of hepatic restructuring in liver cirrhosis.

OBJECTIVE: To investigate the three-dimensional structure, including the angioarchitecture, of the cirrhotic liver and clarify morphogenesis of the cirrhotic nodule. STUDY DESIGN: The three-dimensional liver structure of nontumor areas in two partially hepatectomized cases of hepatitis C virus-positive liver cirrhosis with hepatocellular carcinoma was examined by computerized reconstruction from serial tissue sections. RESULTS: Our image analysis revealed the following: (1) The parenchyma consisted of two kinds of cirrhotic nodules. The first was the nodule centrifugally formed around the portal veins, and their flows drained into the hepatic veins inside and around the nodule. The second was the nodule derived from the first. The latter was divided into the former by bridging fibrosis-induced intranodular septation. (2) The stroma consisted of the newly formed fibrovascular tissue--i.e., the septum and intranodular inflow and outflow vascular systems and the preexisting one. CONCLUSION: Our computerized reconstruction suggested, from an angioarchitectural point of view, that the first and second kind of cirrhotic nodule might be named the stable and the unstable nodule, respectively, and that the first kind of cirrhotic nodule could be derived from the regenerative nodule appearing in the course of chronic hepatitis.

Three-dimensional image analysis of the hepatic restructuring process in chronic active hepatitis.

OBJECTIVE: To elucidate the process of hepatic restructuring in the course of chronic hepatitis from a morphologic viewpoint. STUDY DESIGN: The three-dimensional (3-D) liver structure was investigated by computer-aided reconstruction in five cases (one autopsy and four surgical cases) of chronic active hepatitis (type C), including early to late stages of restructuring. RESULTS: Our 3-D reconstruction revealed the following. At an early stage, portal and periportal inflammation and fibrosis widened the portal tracts, giving rise to the formation of portal-to-portal and portal-to-hepatic venous connections, although most central veins were still located at an almost normal site in the hepatic lobules. In a middle stage, bridging fibrosis developed to create a network of interstitium where the central veins were rather decreased in number, with regenerative nodules multiplying in the parenchyma. At the late stage, the lobular structure was destroyed, and the parenchyma consisted uniformly of regenerative nodules, with remaining but rearranged lobules among them. CONCLUSION: The above changes of liver structure suggest that in cirrhogenesis from chronic hepatitis, a combination of nodular regeneration and formation of an interstitial network come to replace the normal lobular structure, hastening the development of liver cirrhosis.