Cerebral amyloid angiopathy-linked ß-amyloid mutations promote cerebral fibrin deposits via increased binding affinity for fibrinogen.

Cerebral amyloid angiopathy (CAA), where beta-amyloid (Aß) deposits around cerebral blood vessels, is a major contributor of vascular dysfunction in Alzheimer's disease (AD) patients. However, the molecular mechanism underlying CAA formation and CAA-induced cerebrovascular pathology is unclear. Hereditary cerebral amyloid angiopathy (HCAA) is a rare familial form of CAA in which mutations within the (Aß) peptide cause an increase in vascular deposits. Since the interaction between Aß and fibrinogen increases CAA and plays an important role in cerebrovascular damage in AD, we investigated the role of the Aß-fibrinogen interaction in HCAA pathology. Our work revealed the most common forms of HCAA-linked mutations, Dutch (E22Q) and Iowa (D23N), resulted in up to a 50-fold stronger binding affinity of Aß for fibrinogen. In addition, the stronger interaction between fibrinogen and mutant Aßs led to a dramatic perturbation of clot structure and delayed fibrinolysis. Immunofluorescence analysis of the occipital cortex showed an increase of fibrin(ogen)/Aß codeposition, as well as fibrin deposits in HCAA patients, compared to early-onset AD patients and nondemented individuals. Our results suggest the HCAA-type Dutch and Iowa mutations increase the interaction between fibrinogen and Aß, which might be central to cerebrovascular pathologies observed in HCAA.

High Risk of Fractures Within 7 Years of Diagnosis in Asian Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: In this nationwide population-based study, we investigated the risk of vertebral and hip fractures in patients with inflammatory bowel disease (IBD). METHODS: Using data from the Korean National Health Insurance claims database gathered between 2007 and 2016, we calculated the incidence rate ratios (IRRs) of vertebral and hip fractures in patients with newly diagnosed IBD (n = 18,228; 64.1% male, 65.9% ulcerative colitis) compared with an age- and sex-matched control population (matching ratio, 1:10; n = 186,871). RESULTS: During a median follow-up period of 4.5 years, the incidence rate and IRR of vertebral and hip fractures in patients with IBD were 2.88 per 1000 person-years and 1.24 (95% CI, 1.08-1.42), respectively. The cumulative risk of vertebral and hip fractures in IBD patients was 0.6%, 1.4%, and 1.9% at 2, 5, and 7 years after diagnosis, respectively, and this risk of fracture in IBD patients was higher than that in matched controls (P = .002). The use of corticosteroids further increased the risk of fractures in IBD patients (IRR, 1.37; 95% CI, 1.13-1.65) compared with matched controls. The risk of fractures was significantly higher in patients with Crohn's disease (CD) (IRR, 1.56; 95% CI, 1.19-2.04) than in matched controls, and this risk remained higher in patients with CD without corticosteroid exposure (IRR, 1.62; 95% CI, 1.12-2.34). The risk of fracture increased with age and was particularly high in females and in those with comorbidities. CONCLUSIONS: The risk of fractures was significantly high in newly diagnosed IBD patients, especially in those with CD regardless of corticosteroid exposure.

Aminopyrimidine Class Aggregation Inhibitor Effectively Blocks Aß-Fibrinogen Interaction and Aß-Induced Contact System Activation.

Accumulating evidence suggests that fibrinogen, a key protein in the coagulation cascade, plays an important role in circulatory dysfunction in Alzheimer's disease (AD). Previous work has shown that the interaction between fibrinogen and ß-amyloid (Aß), a hallmark pathological protein in AD, induces plasmin-resistant abnormal blood clots, delays fibrinolysis, increases inflammation, and aggravates cognitive function in mouse models of AD. Since Aß oligomers have a much stronger affinity for fibrinogen than Aß monomers, we tested whether amyloid aggregation inhibitors could block the Aß-fibrinogen interaction and found that some Aß aggregation inhibitors showed moderate inhibitory efficacy against this interaction. We then modified a hit compound so that it not only showed a strong inhibitory efficacy toward the Aß-fibrinogen interaction but also retained its potency toward the Aß42 aggregation inhibition process. Furthermore, our best hit compound, TDI-2760, modulated Aß42-induced contact system activation, a pathological condition observed in some AD patients, in addition to inhibiting the Aß-fibrinogen interaction and Aß aggregation. Thus, TDI-2760 has the potential to lessen vascular abnormalities as well as Aß aggregation-driven pathology in AD.

Biochemical and structural analysis of the interaction between ß-amyloid and fibrinogen.

The majority of patients with Alzheimer disease (AD) suffer from impaired cerebral circulation. Accumulating evidence suggests that fibrinogen, the main protein component of blood clots, plays an important role in this circulatory dysfunction in AD. Fibrinogen interacts with ß-amyloid (Aß), forming plasmin-resistant abnormal blood clots, and increased fibrin deposition is found in the brains of AD patients and mouse models. In this study, we investigated the biochemical and structural details of the Aß-fibrinogen interaction. We identified the central region of Aß42 as the most critical region for the interaction, which can be inhibited by specific antibodies against the central region of Aß and by naturally occurring p3 peptides, Aß17-40 and Aß17-42. X-ray crystallographic analysis revealed that Aß42 binding to fragment D of fibrinogen induced a structural change in the C-terminal region of the fibrinogen ß-chain (ß384-393). Furthermore, we identified an additional Aß-binding site within the αC region of fibrinogen. Aß binding to this αC region blocked plasmin-mediated fibrin cleavage at this site, resulting in the generation of increased levels of a plasmin-resistant fibrin degradation fragment. Overall, our study elucidates the Aß-fibrinogen interaction and clarifies the mechanism by which Aß-fibrinogen binding delays fibrinolysis by plasmin. These results may facilitate the development of effective therapeutics against the Aß-fibrinogen interaction to treat cerebrovascular abnormalities in AD.

Biocatalysis of Platycoside E and Platycodin D3 Using Fungal Extracellular ß-Glucosidase Responsible for Rapid Platycodin D Production.

Platycodi radix (i.e., Platycodon grandiflorum root) products (e.g., tea, cosmetics, and herbal supplements) are popular in East Asian nutraceutical markets due to their reported health benefits and positive consumer perceptions. Platycosides are the key drivers of Platycodi radixes' biofunctional effects; their nutraceutical and pharmaceutical activities are primarily related to the number and varieties of sugar side-chains. Among the various platycosides, platycodin D is a major saponin that demonstrates various nutraceutical activities. Therefore, the development of a novel technology to increase the total platycodin D content in Platycodi radix extract is important, not only for consumers' health benefits but also producers' commercial applications and manufacturing cost reduction. It has been reported that hydrolysis of platycoside sugar moieties significantly modifies the compound's biofunctionality. Platycodi radix extract naturally contains two major platycodin D precursors (platycoside E and platycodin D3) which can be enzymatically converted to platycodin D via ß-d-glucosidase hydrolysis. Despite evidence that platycodin D precursors can be changed to platycodin D in the Platycodi radix plant, there is little research on increasing platycodin D concentrations during processing. In this work, platycodin D levels in Platycodi radix extracts were significantly increased via extracellular Aspergillus usamii ß-d-glucosidase (n = 3, p < 0.001). To increase the extracellular ß-d-glucosidase activity, A. usamii was cultivated in a culture media containing cellobiose as its major carbon source. The optimal pH and temperature of the fungal ß-d-glucosidase were 6.0 and 40.0 °C, respectively. Extracellular A. usamii ß-d-glucosidase successfully converted more than 99.9% (w/v, n = 3, p < 0.001) of platycoside E and platycodin D3 into platycodin D within 2 h under optimal conditions. The maximum level of platycodin D was 0.4 mM. Following the biotransformation process, the platycodin D was recovered using preparatory High Performance Liquid Chromatography (HPLC) and applied to in vitro assays to evaluate its quality. Platycodin D separated from the Platycodi radix immediately following the bioconversion process showed significant anti-inflammatory effects from the Lipopolysaccharide (LPS)-induced macrophage inflammatory responses with decreased nitrite and IL-6 production (n = 3, p < 0.001). Taken together, these results provide evidence that biocatalysis of Platycodi radix extracts with A. usamii may be used as an efficient method of platycodin D-enriched extract production and novel Platycodi radix products may thereby be created.

Korean Ginseng Berry Fermented by Mycotoxin Non-producing Aspergillus niger and Aspergillus oryzae: Ginsenoside Analyses and Anti-proliferative Activities.

To transform ginsenosides, Korean ginseng berry (KGB) was fermented by mycotoxin non-producing Aspergillus niger and Aspergillus oryzae. Changes of ginsenoside profile and anti-proliferative activities were observed. Results showed that A. niger tended to efficiently transform protopanaxadiol (PPD) type ginsenosides such as Rb1, Rb2, Rd to compound K while A. oryzae tended to efficiently transform protopanaxatriol (PPT) type ginsenoside Re to Rh1 via Rg1. Butanol extracts of fermented KGB showed high cytotoxicity on human adenocarcinoma HT-29 cell line and hepatocellular carcinoma HepG2 cell line while that of unfermented KGB showed little. The minimum effective concentration of niger-fermented KGB was less than 2.5 µg/mL while that of oryzae-fermented KGB was about 5 µg/mL. As A. niger is more inclined to transform PPD type ginsenosides, niger-fermented KGB showed stronger anti-proliferative activity than oryzae-fermented KGB.

Effects of Dietary Supplementation of Barodon, an Anionic Alkali Mineral Complex, on Growth Performance, Feed Utilization, Innate Immunity, Goblet Cell and Digestibility in Olive Flounder (Paralichthys olivaceus).

A 15-wk feeding trial was conducted to examine the supplemental effects of Barodon on growth performance, gastrointestinal histology, feed digestibility and innate immunity in olive founder. A basal commercial diet was used as a control and two other diets were prepared by spraying 0.1% or 0.2% of Barodon. Triplicate groups of fish (BW, 145 g) were fed one of the test diets to apparent satiation twice daily. At the end of the feeding trial, fish growth performance was not significantly affected by dietary treatments; however, feed utilization was significantly improved (linear and quadratic, p<0.05) by Barodon supplementation. Significantly higher (p<0.05) survival rates were obtained in fish fed Barodon containing diets. Hepatosomatic index increased significantly in Barodon treated groups. Also, the use of Barodon resulted in significant increase (linear and quadratic, p<0.05) of intestine length and number of goblet cells. Significantly higher (Quadratic, p<0.05) apparent digestibility coefficient of DM was obtained by supplementation of Barodon. Lysozyme and myeloperoxidase activities increased quadratically and linearly, respectively, in Barodon treated fish. Also, significantly higher (linear and quadratic, p<0.05) superoxide dismutase activity was found in Barodon fed fish. The findings in this study show that inclusion of Barodon in diets for olive flounder improves feed utilization and digestibility, and positively affects digestive tract histology and innate immunity.

Alzheimer's disease peptide beta-amyloid interacts with fibrinogen and induces its oligomerization.

Increasing evidence supports a vascular contribution to Alzheimer's disease (AD), but a direct connection between AD and the circulatory system has not been established. Previous work has shown that blood clots formed in the presence of the ß-amyloid peptide (Aß), which has been implicated in AD, have an abnormal structure and are resistant to degradation in vitro and in vivo. In the present study, we show that Aß specifically interacts with fibrinogen with a K(d) of 26.3 ± 6.7 nM, that the binding site is located near the C terminus of the fibrinogen ß-chain, and that the binding causes fibrinogen to oligomerize. These results suggest that the interaction between Aß and fibrinogen modifies fibrinogen's structure, which may then lead to abnormal fibrin clot formation. Overall, our study indicates that the interaction between Aß and fibrinogen may be an important contributor to the vascular abnormalities found in AD.

Striatal fibrinogen extravasation and vascular degeneration correlate with motor dysfunction in an aging mouse model of Alzheimer's disease.

Introduction: Alzheimer's Disease (AD) patients exhibit signs of motor dysfunction, including gait, locomotion, and balance deficits. Changes in motor function often precede other symptoms of AD as well as correlate with increased severity and mortality. Despite the frequent occurrence of motor dysfunction in AD patients, little is known about the mechanisms by which this behavior is altered. Methods and Results: In the present study, we investigated the relationship between cerebrovascular impairment and motor dysfunction in a mouse model of AD (Tg6799). We found an age-dependent increase of extravasated fibrinogen deposits in the cortex and striatum of AD mice. Interestingly, there was significantly decreased cerebrovascular density in the striatum of the 15-month-old as compared to 7-month-old AD mice. We also found significant demyelination and axonal damage in the striatum of aged AD mice. We analyzed striatum-related motor function and anxiety levels of AD mice at both ages and found that aged AD mice exhibited significant impairment of motor function but not in the younger AD mice. Discussion: Our finding suggests an enticing correlation between extravasated fibrinogen, cerebrovascular damage of the striatum, and motor dysfunction in an AD mouse model, suggesting a possible mechanism underlying motor dysfunction in AD.

Fiberoptic hemodynamic spectroscopy reveals abnormal cerebrovascular reactivity in a freely moving mouse model of Alzheimer's disease.

Many Alzheimer's disease (AD) patients suffer from altered cerebral blood flow and damaged cerebral vasculature. Cerebrovascular dysfunction could play an important role in this disease. However, the mechanism underlying a vascular contribution in AD is still unclear. Cerebrovascular reactivity (CVR) is a critical mechanism that maintains cerebral blood flow and brain homeostasis. Most current methods to analyze CVR require anesthesia which is known to hamper the investigation of molecular mechanisms underlying CVR. We therefore combined spectroscopy, spectral analysis software, and an implantable device to measure cerebral blood volume fraction (CBVF) and oxygen saturation (SO2) in unanesthetized, freely-moving mice. Then, we analyzed basal CBVF and SO2, and CVR of 5-month-old C57BL/6 mice during hypercapnia as well as during basic behavior such as grooming, walking and running. Moreover, we analyzed the CVR of freely-moving AD mice and their wildtype (WT) littermates during hypercapnia and could find impaired CVR in AD mice compared to WT littermates. Our results suggest that this optomechanical approach to reproducibly getting light into the brain enabled us to successfully measure CVR in unanesthetized freely-moving mice and to find impaired CVR in a mouse model of AD.

Vascular endothelial growth factor associated dissimilar cerebrovascular phenotypes in two different mouse models of Alzheimer's Disease.

Vascular perturbations and cerebral hypometabolism are emerging as important components of Alzheimer's disease (AD). While various in vivo imaging modalities have been designed to detect changes of cerebral perfusion and metabolism in AD patients and animal models, study results were often heterogenous with respect to imaging techniques and animal models. We therefore evaluated cerebral perfusion and glucose metabolism of two popular transgenic AD mouse strains, TgCRND8 and 5xFAD, at 7 and 12 months-of-age under identical conditions and analyzed possible molecular mechanisms underlying heterogeneous cerebrovascular phenotypes. Results revealed disparate findings in these two strains, displaying important aspects of AD progression. TgCRND8 mice showed significantly decreased cerebral blood flow and glucose metabolism with unchanged cerebral blood volume (CBV) at 12 months-of-age whereas 5xFAD mice showed unaltered glucose metabolism with significant increase in CBV at 12 months-of-age and a biphasic pattern of early hypoperfusion followed by a rebound to normal cerebral blood flow in late disease. Finally, immunoblotting assays suggested that VEGF dependent vascular tone change may restore normoperfusion and increase CBV in 5xFAD.

Microbial biocatalysis of quercetin-3-glucoside and isorhamnetin-3-glucoside in Salicornia herbacea and their contribution to improved anti-inflammatory activity.

Salicornia herbacea (glasswort) is a traditional Asian medicinal plant which exhibits multiple nutraceutical and pharmaceutical properties. Quercetin-3-glucoside and isorhamnetin-3-glucoside are the major flavonoid glycosides found in S. herbacea. Multiple researchers have shown that flavonoid glycosides can be structurally transformed into minor aglycone molecules, which play a significant role in exerting physiological responses in vivo. However, minor aglycone molecule levels in S. herbacea are very low. In this study, Bifidobacterium animalis subsp. lactis AD011, isolated from infant feces, catalyzed >85% of quercetin-3-glucoside and isorhamnetin-3-glucoside into quercetin and isorhamnetin, respectively, in 2 h, without breaking down flavonoid backbones. Functionality analysis demonstrated that the quercetin and isorhamnetin produced showed improved anti-inflammatory activity vs. the original source molecules against lipopolysaccharide induced RAW 264.7 macrophages. Our report highlights a novel protocol for rapid quercetin and isorhamnetin production from S. herbacea flavonoids and the applicability of quercetin and isorhamnetin as nutraceutical molecules with enhanced anti-inflammatory properties.

Production and Characterization of Anti-Inflammatory Monascus Pigment Derivatives.

The prevention and treatment of chronic inflammation using food-derived compounds are desirable from the perspectives of marketing and safety. Monascus pigments, widely used as food additives, can be used as a chronic inflammation treatment. Orange Monascus pigments were produced by submerged fermentation in a 5 L bioreactor, and multiple orange Monascus pigment derivatives with anti-inflammatory activities were synthesized using aminophilic reaction. A total of 41 types of pigment derivatives were produced by incorporating amines and amino acids into the orange pigments. One derivative candidate that inhibited nitric oxide (NO) production in Raw 264.7 cells and exhibited low cell cytotoxicity was identified via in vitro assay. The 2-amino-4 picoline derivative inhibited NO production of 48.4%, and exhibited cell viability of 90.6%. Expression of inducible NO synthase, an important enzyme in the NO synthesis pathway, was suppressed by such a derivative in a dose-dependent manner. Therefore, this derivative has potential as a functional food colorant with anti-inflammatory effects.

c-Rel, an NF-kappaB family transcription factor, is required for hippocampal long-term synaptic plasticity and memory formation.

Transcription is a critical component for consolidation of long-term memory. However, relatively few transcriptional mechanisms have been identified for the regulation of gene expression in memory formation. In the current study, we investigated the activity of one specific member of the NF-kappaB transcription factor family, c-Rel, during memory consolidation. We found that contextual fear conditioning elicited a time-dependent increase in nuclear c-Rel levels in area CA1 and DG of hippocampus. These results suggest that c-rel is active in regulating transcription during memory consolidation. To identify the functional role of c-Rel in memory formation, we characterized c-rel(-/-) mice in several behavioral tasks. c-rel(-/-) mice displayed significant deficits in freezing behavior 24 h after training for contextual fear conditioning but showed normal freezing behavior in cued fear conditioning and in short-term contextual fear conditioning. In a novel object recognition test, wild-type littermate mice exhibited a significant preference for a novel object, but c-rel(-/-) mice did not. These results indicate that c-rel(-/-) mice have impaired hippocampus-dependent memory formation. To investigate the role of c-Rel in long-term synaptic plasticity, baseline synaptic transmission and long-term potentiation (LTP) at Schaffer collateral synapses in c-rel(-/-) mice was assessed. c-rel(-/-) slices had normal baseline synaptic transmission but exhibited significantly less LTP than did wild-type littermate slices. Together, our results demonstrate that c-Rel is necessary for long-term synaptic potentiation in vitro and hippocampus-dependent memory formation in vivo.

Inflaming the Brain.

Exactly how cerebrovascular alterations contribute to Alzheimer's disease (AD) is still unknown. Merlini et al. (2019) show that blood-derived fibrinogen leads to dendritic spine elimination and cognitive deficit via microglial CD11b/CD18. Fibrinogen may be a significant contributor to AD pathogenesis.

Analysis of ß-Amyloid-induced Abnormalities on Fibrin Clot Structure by Spectroscopy and Scanning Electron Microscopy.

This article presents methods for generating in vitro fibrin clots and analyzing the effect of beta-amyloid (Aß) protein on clot formation and structure by spectrometry and scanning electron microscopy (SEM). Aß, which forms neurotoxic amyloid aggregates in Alzheimer's disease (AD), has been shown to interact with fibrinogen. This Aß-fibrinogen interaction makes the fibrin clot structurally abnormal and resistant to fibrinolysis. Aß-induced abnormalities in fibrin clotting may also contribute to cerebrovascular aspects of the AD pathology such as microinfarcts, inflammation, as well as, cerebral amyloid angiopathy (CAA). Given the potentially critical role of neurovascular deficits in AD pathology, developing compounds which can inhibit or lessen the Aß-fibrinogen interaction has promising therapeutic value. In vitro methods by which fibrin clot formation can be easily and systematically assessed are potentially useful tools for developing therapeutic compounds. Presented here is an optimized protocol for in vitro generation of the fibrin clot, as well as analysis of the effect of Aß and Aß-fibrinogen interaction inhibitors. The clot turbidity assay is rapid, highly reproducible and can be used to test multiple conditions simultaneously, allowing for the screening of large numbers of Aß-fibrinogen inhibitors. Hit compounds from this screening can be further evaluated for their ability to ameliorate Aß-induced structural abnormalities of the fibrin clot architecture using SEM. The effectiveness of these optimized protocols is demonstrated here using TDI-2760, a recently identified Aß-fibrinogen interaction inhibitor.

Regulation of nuclear factor kappaB in the hippocampus by group I metabotropic glutamate receptors.

An increasing amount of evidence suggests that the family of nuclear factor kappaB (NF-kappaB) transcription factors plays an important role in synaptic plasticity and long-term memory formation. The present study investigated the regulation of NF-kappaB family members p50, p65/RelA, and c-Rel in the hippocampus in response to metabotropic glutamate receptor (mGluR) signaling. Activation of group I metabotropic glutamate receptors (GpI-mGluRs) with the agonist (S)-3,5-dihydroxyphenylglycine (DHPG) resulted in a time-dependent increase in DNA binding activity of p50, p65, and c-Rel in area CA1 of the hippocampus. An antagonist of mGluR5, 2-Methyl-6-(phenylethynyl)pyridine, inhibited the DHPG-induced activation of NF-kappaB, whereas an antagonist of mGluR1, (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid, did not. Using a series of inhibitors, we investigated the signaling pathways necessary for DHPG-induced activation of NF-kappaB and found that they included the phosphatidyl inositol 3-kinase, protein kinase C, mitogen-activated protein kinase kinase, and p38-mitogen-activated protein kinase pathways. To determine the functional significance of mGluR-induced regulation of NF-kappaB, we measured long-term depression (LTD) of Schaffer-collateral synapses in the hippocampus of c-Rel knock-out mice. Early phase LTD was normal in c-rel(-/-) mice. However, late-phase LTD (>90 min) was impaired in c-rel(-/-) mice. The observations of this deficit in hippocampal synaptic plasticity prompted us to further investigate long-term memory formation in c-rel(-/-) mice. c-rel(-/-) mice exhibited impaired performance in a long-term passive avoidance task, providing additional evidence for c-Rel in long-term memory formation. These results demonstrate that the NF-kappaB transcription factor family is regulated by GpI-mGluRs in the hippocampus and that the c-Rel transcription factor is necessary for long-term maintenance of LTD and formation of long-term memory.

Baumann Skin Type in the Korean Female Population.

BACKGROUND: To meet the need for a subspecialized skin type system, the Baumann skin type (BST) system was proposed. OBJECTIVE: To evaluate the distribution of BST types and influencing factors among Korean women. METHODS: BST questionnaires were administered to 1,000 Korean women. The possible responses were as follows: oily (O) or dry (D), sensitive (S) or resistant (R), pigmented (P) or non-pigmented (N), and wrinkled (W) or tight (T). The correlations of the BST with the subjects' age, location, ultraviolet (UV) ray exposure, drinking and smoking habits, and blood type were assessed. RESULTS: The OSNT, DSNT, DRNT, and OSNW skin types were the most common skin types (55.3%). The O, S, P, and W types accounted for 46.6%, 68.8%, 23.2%, and 31.9%, respectively. The proportion of the O and S type was the highest in Gyeongsangbuk-do (55.0%) and Seoul (77.2%). The proportion of the P and W type was the highest in Gyeongsangbuk-do (33.0%) and Chungcheong-do (39.0%). The O type decreased in the higher age group, whereas the P and W type showed a reversed tendency. In smokers, the proportion of W type was significantly higher than in the non-smokers (66.3% vs. 24.1%, p<0.05). CONCLUSION: The 4 most common BST types were OSNT, DSNT, DRNT, and OSNW. In the comparison across the 4 BST parameters according to the age, region, smoking and drinking habits, occupation, blood type, and UV exposure, significant differences were observed. Individualized and customized skin care is required according to the personal skin type.

An unusual case with membranous lipodystrophy in a hypertensive patient with transepidermal elimination.

Membranous lipodystrophy represents a peculiar type of fat necrosis that is present in patients with various types of skin disease. It is characterized by the presence of microcysts and macrocysts and is lined by amorphous eosinophilic material with a crenelated arabesque appearance. These findings have been associated with lupus erythematosus, diabetes mellitus, erythema nodosum, trauma, etc. We report a case of a 43-year-old woman who had a red to purple asymptomatic indurated plaque, approximately seven cm in diameter and on the left arm. She was a chronic hepatitis B antigen carrier and had hypertension for four years. Histopathology of the biopsied lesion showed transepidermal elimination of altered collagen and elastic fibers, as well as membranous lipodystrophy changes. There were hypertensive vascular changes including lymphohistiocytic infiltration around the vascular wall, swelling of endothelial cells, increased thickness of the vascular walls, and narrowing of the lumen. We report a case showing transepidermal elimination with membranous lipodystrophy. We carefully suggest that the secondary phenomenon of transepidermal elimination was associated with membranous lipodystrophy and degenerate connective tissues.

A bioinformatics analysis of memory consolidation reveals involvement of the transcription factor c-rel.

Consolidation of long-term memory (LTM) is a complex process requiring synthesis of new mRNAs and proteins. Many studies have characterized the requirement for de novo mRNA and protein synthesis; however, few studies have comprehensively identified genes regulated during LTM consolidation. We show that consolidation of long-term contextual memory in the hippocampus triggers altered expression of numerous genes encompassing many aspects of neuronal function. Like contextual memory formation, this altered gene expression required NMDA receptor activation and was specific for situations in which the animal formed an association between a physical context and a sensory stimulus. Using a bioinformatics approach, we found that regulatory elements for several transcription factors are over-represented in the upstream region of genes regulated during consolidation of LTM. Using a knock-out mouse, we found that c-rel, one of the transcription factors identified in our bioinformatics study, is necessary for hippocampus-dependent long-term memory formation.