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Background: Mild cognitive impairment (MCI) is a prodromal phase of dementia and is considered an important period for intervention to prevent conversion to dementia. It has been well established that multicomponent day-care programs including exercise training, cognitive intervention and music therapy have beneficial effects on cognition, but the effects on cerebral blood flow (CBF) in MCI remain unknown. This study examined whether a multicomponent day-care program would have beneficial effects on the longitudinal changes of CBF in MCI patients., Methods: Participants were 24 patients with MCI attending a day-care program; they underwent two 99 mTc-ethyl cysteinate dimer single photon emission computed tomography scans during the study period. We evaluated the association between the changes of regional cerebral blood flow and the attendance rate., Results: There was a significant negative correlation between the reduction of regional CBF in the right parietal region and the attendance rate. We found no significant relation between the baseline CBF images and the attendance rate., Conclusions: Our results suggest that continuous participation in a multicomponent day-care program might prevent reduction in brain activity in patients with MCI., (© 2022 Japanese Psychogeriatric Society.)

Introduction: Mild cognitive impairment (MCI) is considered an important period for interventions to prevent progression to dementia. Nonpharmacological interventions for MCI include exercise training, cognitive intervention, and music therapy. These play an important role in improving cognitive function, but their effects on brain plasticity in individuals with MCI are largely unknown. We investigated the effects of a multicomponent day-care program provided by the University of Tsukuba Hospital on the longitudinal brain volume changes in MCI patients., Methods: MCI patients who participated in the multicomponent day-care program and underwent whole-brain magnetic resonance imaging (MRI) twice during their participation (n = 14), were included. We divided them into two groups according to their attendance rate and conducted a between-group analysis of longitudinal volume changes in the whole cerebral cortex. Regional brain volumes derived from the patients' MRI were calculated with Freesurfer 6.0.0., Results: The neuroimaging analysis demonstrated that the left rostral anterior cingulate cortex volume was significantly preserved in the high-attendance group compared to that of the low-attendance group., Conclusion: Our results suggest that continuous participation in a multicomponent day-care program could help prevent a volume reduction in memory-related brain areas in patients with MCI., (© 2022 S. Karger AG, Basel.)

Hutchinson-Gilford progeria syndrome (HGPS) is a rare accelerated aging disorder characterized by premature death from myocardial infarction or stroke. It is caused by de novo single-nucleotide mutations in the LMNA gene that activate a cryptic splice donor site, resulting in the production of a toxic form of lamin A, which is termed progerin. Here we present a potential genetic therapeutic strategy that utilizes antisense peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) to block pathogenic splicing of mutant transcripts. Of several candidates, PPMO SRP-2001 provided the most significant decrease in progerin transcripts in patient fibroblasts. Intravenous delivery of SRP-2001 to a transgenic mouse model of HGPS produced significant reduction of progerin transcripts in the aorta, a particularly critical target tissue in HGPS. Long-term continuous treatment with SRP-2001 yielded a 61.6% increase in lifespan and rescue of vascular smooth muscle cell loss in large arteries. These results provide a rationale for proceeding to human trials.

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder caused by germline loss-of-function mutations in Folliculin gene (FLCN). BHD is characterized by lower lobe-predominant pulmonary cysts with risk of pneumothorax, benign skin tumors (fibrofolliculomas), and renal cell carcinoma, often of an unusual chromophobe/oncocytic hybrid histology. The FLCN protein functions in multiple signaling and metabolic pathways including positive regulation of mechanistic target of rapamycin complex 1 (mTORC1) activity via FLCN's GTPase (GAP) activity for Rag C, positive regulation of Wnt signaling (in mesenchymal cells), and negative regulation of TFE3 nuclear localization. Therefore, FLCN-deficient cells are predicted to have reduced mTORC1 and Wnt activity and enhanced TFE3 activity. Folliculin also has functions in autophagy, mitochondrial biogenesis, cell-cell adhesion, 5' AMP activated protein kinase activity, and other pathways. The specific contributions of these pathways to the lung manifestations of BHD are largely unknown. This review is focused on the pulmonary manifestations of BHD, highlighting selected recent advances in elucidating the cellular functions of FLCN and current hypotheses related to the pathogenesis of cystic lung disease in BHD, including the "stretch hypothesis." We also discuss important knowledge gaps in the field, including the genetic, cellular and physical mechanisms of cyst pathogenesis, and the timing of cyst initiation, which may occur during lung development., Competing Interests: Dr. Kennedy reports grants from National Institutes of Health-Loan Repayment Division, grants from National Institutes of Health-National Heart Lung and Blood Institute-T32, during the conduct of the study., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Herein, we present a case of gastric adenocarcinoma of fundic gland type (GA-FG) spreading to heterotopic gastric glands (HGG) in the submucosa. A 58-year-old man with epigastric pain was referred to our hospital and underwent an esophagogastroduodenoscopy. A Borrmann type II gastric cancer at the antrum and a 10 mm submucosal tumor-like lesion in the lesser curvature of the upper third of the stomach were detected. Histological examination of the biopsy specimens obtained from the submucosal tumor-like lesion suggested a GA-FG. Therefore, endoscopic submucosal dissection was performed as excisional biopsy, and histopathological examination of the resected specimen confirmed a GA-FG and HGG proximal to the GA-FG. Although the GA-FG invaded the submucosal layer slightly, the submucosal lesion of the GA-FG had a poor stromal reaction and was located just above the HGG in the submucosa. Therefore, we finally diagnosed the lesion as a GA-FG invading the submucosal layer by spreading to HGG., Competing Interests: Conflict-of-interest statement: We declare that there is no conflict of interest.

A 58-year-old man was brought to our hospital with left upper abdominal pain which suddenly appeared on the previous evening. An abdominal CT scan showed localized retention of ascites, a slightly high density mass under the left upper abdominal wall, with a high density area detected within the mass, which was suggestive of leakage of contrast medium from peripheral branches of the omental artery. From these findings intraperitoneal hemorrhage caused by bleeding from the greater omentum was suspected. Angiographic examination of the abdomen indicated extravasation of contrast medium from blood vessels of the right gastroepiploic artery. Transarterial embolization was carried out and permanent hemostasis was achieved. Injury, anticoagulant, neoplasms, varix, torsion of the omentum, and segmental arterial mediolysis (SAM) etc have been reported as causes of omental bleeding, but none of these were found in our case. We diagnosed the present case as idiopathic omental bleeding.

The clinical efficacy of gastroprotective drugs or low-dose H(2) receptor antagonists in the prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy is limited. The aim of the present study was to investigate efficacy of rebamipide and famotidine in Helicobacter pylori (H. pylori)-negative healthy volunteers taking NSAID. This study was a randomized, two way crossover study comparing the preventive effect rebamipide 100 mg, t.i.d. and famotidine 10 mg, b.i.d against indomethacin (25 mg, t.i.d.)-induced gastric mucosal injury in H. pylori-negative healthy volunteers. 12 subjects satisfied criteria and were randomized. Endoscopy was performed at baseline and again after the treatment for 7 days, and symptoms were recorded during the treatment. Tissue levels of lipid peroxides and myeloperoxidase and serum indomethacin concentrations were also measured. Subjective symptoms were developed in 58% (7/12) of the rebamipide group, and in 75% (9/12) of the famotidine group (no significant differences). The incidence of gastric lesions (modified Lanza score 2 or higher) was 17% (2/12) in the rebamipide group and 25% (3/12) in the famotidine group. Peptic ulcers did not occur in both groups. There were no significant differences in tissue levels of lipid peroxide and myeloperoxidase and serum level of indomethacin between two groups after the treatment. In conclusion, these data recommend rebamipide (100 mg, t.i.d.) or famotidine (10 mg, b.i.d.) for the prevention of acute gastric injury induced by NSAID in patients without a particular risk factor.

The present study was designed to determine the effect of eicosapentaenoic acid (EPA) on the susceptibility of tumor cells to treatments that kill the cells by lipid peroxidation. Using AH109A carcinoma, a rat liver cancer, we measured EPA content, levels of antioxidants, and degree of lipid peroxidation in tumor tissue and normal liver tissue after oral administration of EPA. In the control group treated with distilled water, EPA in tumor tissue was lower than in normal liver tissue, suggesting that its content of polyunsaturated fatty acids (the substrates for lipid peroxidation) was inherently low. Levels of antioxidants also tended to be lower in tumor tissue. EPA level increased in both tumor and normal tissues after oral administration of EPA. At the same time, glutathione peroxidase (GSH-Px) increased in normal tissue, whereas tumor tissue displayed no increase in antioxidants; instead GSH decreased. The EPA-induced change in balance between substrates for lipid peroxidation and antioxidants suggested that tumor tissue might become more susceptible to lipid peroxidation than normal liver tissue. In fact, hyperthermia treatment did enhance lipid peroxidation and antitumor action. Our results indicate that oral EPA specifically increases the susceptibility of liver tumor tissue to lipid peroxidation, and hence enhance the antitumor effect of hyperthermia and prolongs survival.

The importance of pancreatic enzymes, particularly phospholipase A2 (PLA2), for bacterial translocation, which is considered to be one of the aggravating causes of acute pancreatitis, was investigated. Male rats were administered an intraperitoneal or intravenous injection of normal saline, PLA2, or amylase. Four days later, the mesenteric lymph nodes (MLNs) and portal blood of the animals were cultured. None of the animals had a positive portal blood culture. The MLNs contained enteric bacteria in 78% of the animals given 50 mg/kg of PLA2 intraperitoneally. 5 mg/kg of PLA2 intraperitoneally, 50 mg/kg of amylase intraperitoneally, or 50 mg/kg of PLA2 intravenously showed positive cultures in 25%, 20%, and 11%, respectively. None of the animals given intraperitoneal or intravenous normal saline had positive cultures of their MLNs. Intraperitoneal injection of 25 mg/kg of nafamostat mesilate just before intraperitoneal PLA2 (50 mg/kg) resulted in a reduction of positive MLNs from 70% to 30%. The cecal myeroperoxidase (MPO) activity of animals administered 50 mg/kg of PLA2 intraperitoneally was significantly higher compared with animals administered saline intraperitoneally. These results indicate that intraperitoneal leakage of PLA2 plays an important role in bacterial translocation during acute pancreatitis and that administration of a protease inhibitor may be effective against the bacterial translocation.

The aim of the present study was to evaluate rebamipide in the prevention of indomethacin-induced gastric mucosal injury in healthy volunteers. Twenty healthy males (mean age 21.8 years, range 20-26) participated. This is a randomized, double-blind, placebo-controlled study. The 20 subjects were randomized to either indomethacin 25 mg three times a day and placebo three times a day or indomethacin and rebamipide 100 mg three times a day for seven days. Endoscopy was performed at baseline and again after the treatment. In the placebo group, eight of 10 subjects (80%) developed symptoms compared to three of seven (43%) in the rebamipide group. The incidence of gastric lesions was 70% in the placebo group, which was significantly higher than that in the rebamipide group (14%). The lipid peroxide levels in the mucosa of the gastric body significantly increased in the placebo group. This increase was not inhibited by rebamipide. Myeloperoxidase activity in the gastric mucosa tended to increase in the placebo group, but tended to decrease in the rebamipide group. These results indicate that rebamipide may be an effective prophylaxis against indomethacin-induced gastropathy in humans.

The interactions of polymorphonuclear leukocytes (PMN) and endothelial cells are modulated by adhesion molecules, inflammatory cytokines, and shear stress. We investigated the changes in PMN-endothelial cell interactions induced by interleukin (IL)-1 beta under low flow conditions. PMN were isolated from the venous blood of healthy adults, and endothelial cells were obtained from human umbilical veins. The number of PMN that adhered to the endothelial cells monolayer that was treated with IL-1 increased significantly at shear stresses from .5 to 4.0 dyn/cm2 as compared with untreated endothelial cells. Anti-intercellular adhesion molecule (ICAM)-1 monoclonal antibody (mAb), anti-E-selectin mAb, and anti-CD18 mAb each significantly inhibited the increase in PMN adherence induced by IL-1 at a low shear stress (1.0 dyn/cm2). Anti-CD18 mAb significantly reduced the number of PMN that migrated through the endothelial monolayer by blocking the adherence of PMN to the luminal surface of the endothelial cells, as well as their transendothelial migration. In contrast, anti-ICAM-1 and anti-E-selectin mAb each reduced the number of PMN that migrated by reducing the number of PMN that adhered to the luminal surface without significantly influencing the percent of the adherent PMN that had migrated. Although anti-L-selectin mAb reduced the adherence and migration of PMN, these effects were not statistically significant. These results indicated that under low flow conditions, as well as in the nonflow state, PMN-endothelial cell interactions were elicited via CD11/CD18 and ICAM-1 without the involvement of selectins.