Thrombospondin-1 protects against Aβ-induced mitochondrial fragmentation and dysfunction in hippocampal cells.

Alzheimer's disease (AD) is often characterized by the impairment of mitochondrial function caused by excessive mitochondrial fragmentation. Thrombospondin-1 (TSP-1), which is primarily secreted from astrocytes in the central nervous system (CNS), has been suggested to play a role in synaptogenesis, spine morphology, and synaptic density of neurons. In this study, we investigate the protective role of TSP-1 in the recovery of mitochondrial morphology and function in amyloid β (Aβ)-treated mouse hippocampal neuroblastoma cells (HT22). We observe that TSP-1 inhibits Aβ-induced mitochondrial fission by maintaining phosphorylated-Drp1 (p-Drp1) levels, which results in reduced Drp1 translocation to the mitochondria. By using gabapentin, a drug that antagonizes the interaction between TSP-1 and its neuronal receptor α2δ1, we observe that α2δ1 acts as one of the target receptors for TSP-1, and blocks the reduction of the p-Drp1 to Drp1 ratio, in the presence of Aβ. Taken together, TSP-1 appears to contribute to maintaining the balance in mitochondrial dynamics and mitochondrial functions, which is crucial for neuronal cell viability. These data suggest that TSP-1 may be a potential therapeutic target for AD

Quantum Spin Excitations through the metal-to-insulator crossover in YBa2Cu3O6+yY Ba_2 Cu_3 O_{6+y}

We use inelastic neutron scattering to study the temperature dependence of the spin excitations of a detwinned superconducting YBa$_2$Cu$_3$O$_{6.45}$ ($T_c=48$ K). In contrast to earlier work on YBa$_2$Cu$_3$O$_{6.5}$ ($T_c=58$ K), where the prominent features in the magnetic spectra consist of a sharp collective magnetic excitation termed ``resonance'' and a large ($\hbar\omega\approx 15$ meV) superconducting spin gap, we find that the spin excitations in YBa$_2$Cu$_3$O$_{6.45}$ are gapless and have a much broader resonance. Our detailed mapping of magnetic scattering along the $a^\ast$/$b^\ast$-axis directions at different energies reveals that spin excitations are unisotropic and consistent with the ``hourglass''-like dispersion along the $a^\ast$-axis direction near the resonance, but they are isotropic at lower energies. Since a fundamental change in the low-temperature normal state of YBa$_2$Cu$_3$O$_{6+y}$ when superconductivity is suppressed takes place at $y\sim0.5$ with a metal-to-insulator crossover (MIC), where the ground state transforms from a metallic to an insulating-like phase, our results suggest a clear connection between the large change in spin excitations and the MIC. The resonance therefore is a fundamental feature of metallic ground state superconductors and a consequence of high-$T_c$ superconductivity.Comment: 9 pages, 7 figures, accepted by Phys. Rev.

Close Correlation of Monoamine Oxidase Activity with Progress of Alzheimer’s Disease in Mice, Observed by in Vivo Two-Photon Imaging

Monoamine oxidases (MAOs) play an important role in Alzheimer's disease (AD) pathology. We report in vivo comonitoring of MAO activity and amyloid-beta (A beta) plaques dependent on the aging of live mice with AD, using a two-photon fluorescence probe. The probe under the catalytic action of MAO produces a dipolar fluorophore that senses A beta plaques, a general AD biomarker, enabling us to comonitor the enzyme activity and the progress of AD indicated by A beta plaques. The results show that the progress of AD has a close correlation with MAO activity, which can be categorized into three stages: slow initiation stage up to three months, an aggressive stage, and a saturation stage from nine months. Histological analysis also reveals elevation of MAO activity around A beta plaques in aged mice. The close correlation between the MAO activity and AD progress observed by in vivo monitoring for the first time prompts us to investigate the enzyme as a potential biomarker of AD.1195Ysciescopu

Metastatic hepatocellular carcinoma presenting as facial nerve palsy and facial pain

Facial nerve palsy due to temporal bone metastasis of hepatocellular carcinoma (HCC) has rarely been reported. We experienced a rare case of temporal bone metastasis of HCC that initially presented as facial nerve palsy and was diagnosed by surgical biopsy. This patient also discovered for the first time that he had chronic hepatitis B and C infections due to this facial nerve palsy. Radiation therapy greatly relieved the facial pain and facial nerve palsy. This report suggests that hepatologists should consider metastatic HCC as a rare but possible cause of new-onset cranial neuropathy in patients with chronic viral hepatitis

Emphysematous Gastritis Associated with Invasive Gastric Mucormycosis: A Case Report

Emphysematous gastritis is a rare form of phlegmonous gastritis, characterized by air in the wall of the stomach due to invasion by gas-forming microorganisms. The most commonly involved microorganisms are streptococci, Escherichia coli, Pseudomonas aeruginosa, Clostrodium perfrigens and Staphylococcus aureus. Gastrointestinal mucormycosis is another rare condition, which is most frequently occurs in the stomach. Because emphysematous gastritis associated with invasive gastric mucormycosis is an extremely rare clinical condition and both are life-threatening diseases, early precise diagnosis and early treatment should be done to avoid mortality. Herein we present an extremely rare case of emphysematous gastritis associated with invasive gastric mucormycosis. A 43-yr-old man, suffering from alcoholism and diabetes, has experienced diffuse abdominal pain for 4 days. Abdominal computed tomography scan demonstrated gas within the stomach wall. A histologic examination of the total gastrectomy specimen showed several gas-filled bubbles in the wall, along with numerous fungal hyphae throughout the necrotic stomach wall. He died of multiorgan failure secondary to disseminated mucormycosis, despite the intensive medical therapy

The Possible Role of Nitric Oxide on Enteric Nerves-Mediated Relaxation of the Gastric Smooth Muscle of the Guinea Pig

The influence of the enteric nerves stimulation on the contractility of gastric circular muscle was studied in guinea pig stomachs. The enteric nerves were activated by electric field stimulation(EFS; 90 V, 1 rns, 32 Hz square pulses for 1 s), EFS produced initial transient contraction followed by relaxation and slow recovery. The initial contraction was sensitively blocked by treatment with atropine. The following relaxation still occurred in nonadrenergic noncholinergidNANC) state. EFSinduced relaxation was reduced by LG-nitro-L-arginine(L-NNA), a nitric oxide(NO) synthase inhibitor. The relaxation was restored from the suppressed state after the application of L-arginine(L-arg), a substrate of nitric oxide synthase. With conventional intracellular recording, slow wave and inhibitory junction potential(IJP) were recorded. L-NNA had no effect on IJP, while apamin blocked it. In conclusion, it is suggested that NO may playa major role in EFS-induced relaxation. The exact mechanism of this relaxation is unknown, but the relaxation does not result from the IJP induced by the activation of apamin-sensitive potassium channels

Enhancement of Gastric Ulcer Healing and Angiogenesis by Cochinchina Momordica Seed Extract in Rats

Cochinchina momordica seed is the dried ripe seed of Momordica cochinchinensis, a perennial vine. The antiulcer effect of an extract from cochinchina momordica seeds (SK-MS10) was evaluated in a rat model of acetic acid-induced gastric ulcers. Gastric ulcers were produced by subserosal injection of acetic acid. SK-MS10 (200 mg/kg) or vehicle was administered orally once per day for 14 days after the acetic acid injection. The stomach was removed and the ulcer size measured at day 7 and 14 of the treatment. Expression of vascular endothelial growth factor (VEGF) was assessed by real-time RT-PCR and Western blot analysis. In addition, the microvasculature density (MVD) adjacent to the ulcer margin was examined by immunohistochemistry. The treatment with SK-MS10 for 7 and 14 days significantly accelerated ulcer healing and increased the expression of mRNA (at day 7) as well as VEGF protein (at day 14) compared to the vehicle-treated rats. The MVD for factor VIII was also higher in the SK-MS10 treatment group compared to the vehicle-treated rats; however, these differences were not statistically significant. These results suggest that SK-MS10 treatment accelerates the healing of gastric ulcers via upregulation of VEGF and angiogenesis in an acetic acid rat model

Subclassification of advanced-stage hepatocellular carcinoma with macrovascular invasion: combined transarterial chemoembolization and radiotherapy as an alternative first-line treatment

Background/Aim The Barcelona Clinic Liver Cancer (BCLC) guidelines recommend systemic therapy as the only first-line treatment for patients with BCLC stage C hepatocellular carcinoma (HCC) despite its heterogeneity of disease extent. We aimed to identify patients who might benefit from combined transarterial chemoembolization (TACE) and radiation therapy (RT) by subclassifying BCLC stage C. Methods A total of 1,419 treatment-naïve BCLC stage C patients with macrovascular invasion (MVI) who were treated with combined TACE and RT (n=1,115) or systemic treatment (n=304) were analyzed. The primary outcome was overall survival (OS). Factors associated with OS were identified and assigned points by the Cox model. The patients were subclassified into three groups based on these points. Results The mean age was 55.4 years, and 87.8% were male. The median OS was 8.3 months. Multivariate analysis revealed a significant association of Child-Pugh B, infiltrative-type tumor or tumor size ≥10 cm, main or bilateral portal vein invasion, and extrahepatic metastasis with poor OS. The sub-classification was categorized into low (point ≤1), intermediate (point=2), and high (point ≥3) risks based on the sum of points (range, 0–4). The OS in the low, intermediate, and high-risk groups was 22.6, 8.2, and 3.8 months, respectively. In the low and intermediate-risk groups, patients treated with combined TACE and RT exhibited significantly longer OS (24.2 and 9.5 months, respectively) than those who received systemic treatment (6.4 and 5.1 months, respectively; P<0.0001). Conclusions Combined TACE and RT may be considered as a first-line treatment option for HCC patients with MVI when classified into low- and intermediate-risk groups

Loss of Autophagy Diminishes Pancreatic β Cell Mass and Function with Resultant Hyperglycemia

SummaryAutophagy is a cellular degradation-recycling system for aggregated proteins and damaged organelles. Although dysregulated autophagy is implicated in various diseases including neurodegeneration, its role in pancreatic β cells and glucose homeostasis has not been described. We produced mice with β cell-specific deletion of Atg7 (autophagy-related 7). Atg7 mutant mice showed impaired glucose tolerance and decreased serum insulin level. β cell mass and pancreatic insulin content were reduced because of increased apoptosis and decreased proliferation of β cells. Physiological studies showed reduced basal and glucose-stimulated insulin secretion and impaired glucose-induced cytosolic Ca2+ transients in autophagy-deficient β cells. Morphologic analysis revealed accumulation of ubiquitinated protein aggregates colocalized with p62, which was accompanied by mitochondrial swelling, endoplasmic reticulum distension, and vacuolar changes in β cells. These results suggest that autophagy is necessary to maintain structure, mass and function of pancreatic β cells, and its impairment causes insulin deficiency and hyperglycemia because of abnormal turnover and function of cellular organelles

Hypereosinophilia Presenting as Eosinophilic Vasculitis and Multiple Peripheral Artery Occlusions without Organ Involvement

We report here a case with hypereosinophilia and peripheral artery occlusion. A 32-yr-old Korean woman presented to us with lower extremity swelling and pain. Angiography revealed that multiple lower extremity arteries were occlusive. The biopsy specimen showed perivascular and periadnexal dense eosinophilic infiltration in dermis and subcutaneous adipose tissue. Laboratory investigations revealed a persistent hypereosinophilia. She was prescribed prednisolone 60 mg daily. Her skin lesion and pain were improved and the eosinophil count was dramatically decreased. After discharge, eosinophil count gradually increased again. Cyanosis and pain of her fingers recurred. She had been treated with cyclophosphamide pulse therapy. Her eosinophilia was decreased, but the cyanosis and tingling sense were progressive. The extremity arterial stenoses were slightly progressed. Skin biopsy showed perivascular eosinophilic infiltration in the dermis and CD40 ligand (CD40L) positive eosinophilic infiltration. The serum TNF-α was markedly increased. These results suggest that CD40L (a member of TNF-α superfamily) could play a role in the inflammatory processes when eosinophil infiltration and activation are observed. We prescribed prednisolone, cyclophosphamide, clopidogrel, cilostazol, beraprost and nifedipine, and she was discharged