Activation of Fyn tyrosine kinase in the mouse dorsal hippocampus is essential for contextual fear conditioning

Fyn-tyrosine-kinase-deficient mice exhibit defects in the Morris water maze test and long-term potentiation (LTP) induction in the hippocampus, and given that LTP has been postulated as the neural basis for memory formation, Fyn may be required for hippocampus-dependent memory formation. However, how Fyn is involved in the process of memory formation is unclear. To investigate the role of Fyn in hippocampal memory formation, we first tested the behavior of Fyn-deficient mice by contextual fear conditioning. A mouse was placed in a context and a foot shock was delivered, so that the mouse associated the context with the shock. We found that the freezing response of Fyn-deficient mice to the context was impaired at 24 h after conditioning. We then measured freezing at 1 h after conditioning, and found that their short-term contextual fear memory was also impaired. We used Western blotting to examine the mode of Fyn activation in dorsal hippocampal tissue following contextual fear conditioning. Fyn activation peaked as early as 5–10 min after contextual fear conditioning and persisted for at least 40 min. Concomitant increases in tyrosine phosphorylation of several proteins, including NR2B, were also observed, but no increases in tyrosine phosphorylation were observed in Fyn-deficient mice. Thus, both short-term and long-term (24-h) contextual fear memory were impaired in Fyn-deficient mice, and Fyn activation in the dorsal hippocampus transiently increased after contextual fear conditioning. These findings strongly suggest that activation of the Fyn signaling pathway is involved in hippocampus-dependent formation of contextual fear memory.     

Irinotecan+cisplatin and irradiation are effective for brain metastases of gastric cancer--two case reports

We treated two patients in whom irinotecan (CPT-11)+cisplatin (CDDP) and irradiation showed efficacy against brain metastases of gastric cancer. CPT-11 and CDDP were administered on days 1 and 15 of a 28-day cycle at 60 mg/m(2) and 30 mg/m(2), respectively. The first patient was a 63-year-old man,who complained of headache and weakness. In March 2003, he was diagnosed as having Stage IV gastric cancer with peritoneal dissemination (T3, Nx, P1) and underwent total gastrectomy with D1 dissection. Chemotherapy with S-1 was continued after surgery. Two years and two months later, a metastatic tumor was found in the upper lobe of the right lung. The protocol was changed to S-1+CDDP, but progression of his disease occurred. The weekly paclitaxel (PTX) therapy was tried instead. Seven months later, he developed headache and weakness, and multiple brain metastases were diagnosed by CT scanning. We performed total brain irradiation (30 Gy) and started CPT-11+CDDP therapy, which was continued on a fortnightly basis at 60 mg/m(2) and 30 mg/m(2), respectively. The brain metastases regressed (PR), and this therapy led to a marked improvement in his quality of life. The second patient was a 78-year-old man, who complained of weakness of the lower extremities and dizziness. In November 2003, he was diagnosed as having stage IB gastric cancer (T2 (ss), N0, P0), and underwent total gastrectomy and splenectomy with D2 dissection. One year and four months later, local recurrence at the anastomosis was detected, as well as a metastatic tumor in the right lung. S-1, S-1+CDDP, and weekly PTX therapy were all tried. One year later, the patient was admitted with weakness and dizziness,and brain metastases were detected by CT scanning. We then performed Cyber Knife treatment and administered CPT-11+CDDP. As a result, his brain metastases partially regressed (PR).     

Comparative studies on effect of risedronate and alfacalcidol against glucocorticoid-induced osteoporosis in rheumatoid arthritic patients

Osteoporosis is a common adverse reaction induced by glucocorticoid treatment. Bisphosphonate, vitamin D(3) (VD(3)) or vitamin K(2) (VK(2)) is recommended as first or second choice of drug for treatment of glucocorticoid-induced osteoporosis. In the present study, the treatment effect of risedronate against glucocorticoid-induced osteoporosis in rheumatoid arthritic patients was compared with that of alfacalcidol. Twelve patients were randomized to receive either risedronate (2.5 mg) or alfacalcidol (0.5 microg) daily for 48 weeks. Each patient also received 800 mg of calcium supplementation (800 mg/day) daily. Bone mineral density (BMD) and the biochemical markers of bone turnover were measured before (baseline) and 12, 24, and 48 weeks after treatment with risedronate or alfacalcidol, and the percentage changes in these parameters from baseline were compared.The BMD values 12, 24 and 48 weeks after treatment with risedronate increased by 3.9%, 4.1% and 5.2%, respectively, which were significantly higher than those after treatment with alfacalcidol (2.8%, 2.1% and 2.5%, respectively). Urinary excretion of N-telopeptides of type I collagen and deoxypyridinoline after risedronate treatment were more significantly decreased than that after alfacalcidol treatment. The present findings at least suggest that risedronate is more useful for the prevention and treatment of glucocorticoid-induced osteoporosis in patients with rheumatoid arthritis than alfacalcidol, although the number of patients studied was small.     

Brain metastases from urachal carcinoma

We present a case of brain metastases of the urachal carcinoma, which is extremely rare and malignant. Contrast-enhanced MRI was employed to detect them. A large mass was removed surgically and 4 other small metastases were treated by gamma knife radiosurgery. Six weeks after radiosurgery, the 4 lesions had disappeared on MRI. We emphasise the importance of early diagnosis using MRI and treatment by radiosurgery for this rare condition.     

The anti-pruritic efficacy of TS-022, a prostanoid DP1 receptor agonist, is dependent on the endogenous prostaglandin D2 level in the skin of NC/Nga mice

TS-022 is a prostanoid DP(1) receptor agonist, originally developed as a novel anti-pruritic drug for atopic dermatitis. The drug has been shown to suppress scratching and improve the skin inflammation in the NC/Nga (NC) mouse, a model of atopic dermatitis. Corticosteroids are commonly used as effective agents for the treatment of atopic dermatitis. We examined the anti-pruritic efficacy of TS-022 in NC mice cohabited with skin-lesioned NC mice, which showed spontaneous scratching without skin lesions in the early phase and chronic itching with severe dermatitis in the late phase, in comparison with that of dexamethasone. We have previously reported that prostaglandin D(2) might have a physiological role in the inhibition of pruritus. While after 2 weeks of cohabitation with skin-lesioned NC mice (early phase of dermatitis, characterized by the appearance of spontaneous scratching), topically applied TS-022 exhibited a weak anti-pruritic effect in the NC mice, after 6 weeks of cohabitation (late phase, characterized by both chronic scratching and dermatitis), the drug exerted potent anti-pruritic activity. In contrast, dexamethasone exerted potent anti-pruritic effect in both the early and late phases. Indomethacin aggravated the scratching in the early phase, but had no effect in the late phase. The skin prostaglandin D(2) level was significantly increased in the early phase, to subsequently declined and return to the basal level in the late phase. The cutaneous ability for prostaglandin D(2) production following topical application of arachidonic acid or mechanical scratching was decreased in the late phase. Moreover, the expression level of the prostanoid DP(1) receptor in the skin was increased in the late phase. These findings suggest that the potent anti-pruritic activity of TS-022 in the late phase might be attributable to the decrease of endogenous prostaglandin D(2) production and increase of prostanoid DP(1) receptor expression.     

QOL assessment after palliative surgery for malignant bowel obstruction caused by peritoneal dissemination of gastric cancer: a prospective multicenter observational study

Background

Patients with peritoneal dissemination of gastric cancer have poor oral intake caused by malignant bowel obstruction (MBO). Palliative surgery has often been undertaken to improve quality of life (QOL), but few prospective studies on palliative surgery in this patient population have been published.

Patients and methods

We prospectively investigated the significance of palliative surgery using patient-reported QOL measures. Patients underwent palliative surgery by small intestine/colon resection or small intestine/colon bypass or ileostomy/colostomy for MBO. The primary endpoint was change in QOL assessed at baseline, 14 days, 1 month, and 3 months following palliative surgery using the Euro QoL Five Dimensions (EQ-5D?) questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire gastric cancer module (QLQ-STO22). Secondary endpoints were postoperative improvement in oral intake and surgical complications.

Results

Between April 2013 and March 2018, 63 patients were enrolled from 14 institutions. The mean EQ-5D? utility index baseline score of 0.6 remained consistent. Gastric-specific symptoms mostly showed statistically significant improvement from baseline. Forty-two patients (67%) were able to eat solid food 2 weeks after palliative surgery and 36 patients (57%) tolerated it for 3 months. The rate of overall morbidity of?≥?grade III according to the Clavien–Dindo classification was 16% (10 patients) and the 30-day postoperative mortality rate was 3.2% (2 patients).

Conclusions

In patients with MBO caused by peritoneal dissemination of gastric cancer, palliative surgery did not improve QOL while improving solid food intake, with an acceptable postoperative morbidity and mortality rate.

     

Classifying genotype F of hepatitis B virus into F1 and F2 subtypes

AIM: To explore the propriety of providing hepatitis B virus (HBV) genotypes F and H with two distinct genotypes. METHODS: Eleven HBV isolates of genotype F (HBV/F) were recovered from patients living in San Francisco, Japan, Panama, and Venezuela, and their full-length sequences were determined. Phylogenetic analysis was carried out among them along with HBV isolates previously reported. RESULTS: Seven of them clustered with reported HBV/F isolates in the phylogenetic tree constructed on the entire genomic sequence. The remaining four flocked on another branch along with three HBV isolates formerly reported as genotype H. These seven HBV isolates, including the four in this study and the three reported, had a sequence divergence of 7.3-9.5% from the other HBV/F isolates, and differed by > 13.7% from HBV isolates of the other six genotypes (A-E and G). Based on a marked genomic divergence, falling just short of > 8% separating the seven genotypes, these seven HBV/F isolates were classified into F2 subtype and the former seven into F1 subtype provisionally. In a pairwise comparison of the S-gene sequences among the 7 HBV/F2 isolates and against 47 HBV/F1 isolates as well as 136 representing the other six genotypes (A-E and G), two clusters separated by distinct genetic distances emerged. CONCLUSION: Based on these analyses, classifying HBV/F isolates into two subtypes (F1 and F2) would be more appropriate than providing them with two distinct genotypes (F and H).     

Atrial blood cyst with ischemic heart disease.

A 52-year-old male with coronary artery disease had the extremely rare occurrence of a blood cyst in the right atrium. Surgical removal with coronary artery bypass grafting was performed successfully.