Spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446/ST101) treatment rescues olfactory bulbectomy-induced memory impairment by activating Ca2+/calmodulin kinase II and protein kinase C in mouse hippocampus

Olfactory bulbectomy (OBX) in mice elicits impaired memory and cognitive functions. Here, we found that chronic oral administration of spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446/ST101) (0.1-1 mg/kg/day), a novel cognitive enhancer, significantly improved memory deficits as assessed by Y-maze and novel object recognition tasks in OBX mice. Immunostaining of cholinergic neurons in the medial septum by using an anti-choline acetyltransferase antibody indicated that chronic ZSET1446 treatment did not rescue cholinergic neurons. However, chronic treatment significantly restored OBX-induced decreases both in calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC) phosphorylation without improving decreased extracellular signal-regulated kinase phosphorylation in the hippocampal CA1 region. Consistent with enhanced CaMKII and PKC phosphorylation, ZSET1446 treatment improved glutamate receptor 1 (Ser-831) phosphorylation in the hippocampal CA1 region. ZSET1446 treatment also significantly rescued impaired long-term potentiation (LTP) in the hippocampal CA1 region of OBX mice. Taken together, the cognition-enhancing effect of ZSET1446 is probably mediated in part by stimulation of CaMKII and PKC activities, which in turn rescue impaired hippocampal LTP in OBX mice.     

Aortic arch replacement for degenerative aneurysms: advances during the last decade

During the last decade, treatment paradigm for degenerative aortic arch aneurysms has been changed by a better understanding of the pathophysiology of brain complication and introduction of endovascular technologies. To avoid neurocognitive dysfunction, safe duration of deep hypothermic circulatory arrest is now considered <25 min, and retrograde cerebral perfusion became less frequently used. Selective cerebral perfusion (SCP) is not associated with neurocognitive decline unless profound hypothermia (<20 °C) is used, which may suggest profound hypothermic SCP is not advantageous but may be detrimental. Attempts have been made to use mild to moderate hypothermia during SCP, and safe duration of distal circulatory arrest seems <60 min at 28 °C to avoid ischemic spinal cord injury. Three-vessel perfusion seems advantageous to provide adequate brain and spinal cord protection. To avoid aortogenic brain atheroembolism in the high risk patients, we previously proposed the “isolation” technique, where SCP is established before systemic perfusion. This technique has subsequently been modified to use both axillary and left carotid arteries for systemic arterial return, so that aortogenic emboli may not enter the brain circulation. In the TEVAR (thoracic endovascular aortic repair) era, hybrid operations such as the frozen elephant trunk or TEVAR completion after the elephant trunk are increasingly performed for extensive or distal arch aneurysms. It should be noted, however, that the frozen elephant trunk operation for extensive aneurysms carries an increased risk of paraplegia, and for distal arch aneurysms its outcome is not better than that after the standard open repair in Japan.     

Identification of the optimal structure required for a Shiga toxin neutralizer with oriented carbohydrates to function in the circulation

Shiga toxin (Stx) is a major virulence factor of Stx-producing Escherichia coli. Recently, we developed a therapeutic Stx neutralizer with 6 trisaccharides of globotriaosyl ceramide, a receptor for Stx, in its dendrimer structure (referred to as "SUPER TWIG [1]6") to function in the circulation. Here, we determined the optimal structure of SUPER TWIG for it to function in the circulation and identified a SUPER TWIG with 18 trisaccharides, SUPER TWIG (2)18, as another potent Stx neutralizer. SUPER TWIGs (1)6 and (2)18 shared a structural similarity, a dumbbell shape in which 2 clusters of trisaccharides were connected via a linkage with a hydrophobic chain. The dumbbell shape was found to be required for formation of a complex with Stx that enables efficient uptake and degradation of Stx by macrophages and, consequently, for potent Stx-neutralizing activity in the circulation. We also determined the binding site of the SUPER TWIGs on Stx.     

Bone mineral density in Japanese prostate cancer patients under androgen-deprivation therapy

Androgen-deprivation therapy (ADT) of patients with prostate cancer (PCa) is known to reduce bone mineral density (BMD). However, the most studies examined Caucasian or black patients and the effects of ADT on the bone metabolism of East Asians are unclear. Therefore, we performed a cross-sectional study to elucidate the influence of ADT on bone metabolism in Japanese patients. In total, 101 native Japanese patients with PCa were enrolled. They consisted of 58 ADT-treated and 43 hormone-naive patients. The BMD in the lumbar spine, total hip, and femoral neck was measured by dual energy X-ray absorptiometry and expressed in s.d. units relative to young adult men (T-score) or age-matched men (Z-score). Serum levels of bone metabolism markers were also measured. The BMDs at the three sites revealed that 2.3% (1/43) and 8.6% (5/58) of the hormone-naive and ADT-treated PCa patients had osteoporosis respectively, but this difference failed to achieve statistical significance (P=0.294). The two groups also did not differ significantly in their Z-scores of the three sites, and univariate and multivariate analyses indicated that ADT was not a significant risk factor for decreased BMD. In addition, a significant correlation between the duration of ADT and BMD was not observed for all three sites measured. However, the ADT-treated patients had significantly higher serum levels of N-terminal telopeptide of type I collagen (NTx) than the hormone-naive patients (P=0.017). To our knowledge, this is the first study to demonstrate the low prevalence of osteoporosis in both ADT-treated and hormone-naive Japanese PCa patients. Moreover, ADT did not significantly increase the prevalence of osteoporosis in this Japanese population.     

Detection of endotoxin in sera from children hospitalized for treatment of diarrhea in Bangladesh

The level of circulating endotoxin was determined in the sera from children hospitalized for treatment of diarrhea at the International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh. A significant level of endotoxin was detected in the sera from 23 (54%) of 42 children. On the other hand, in 32 normal controls, endotoxin was below the limits of detection of the assay. Antibiotic and fluid therapy markedly reduced the level of serum endotoxin and improved the general condition of most patients. Non-survivors (n = 5) had higher levels of circulating endotoxin before treatment than survivors (n = 37), suggesting a significant correlation between the serum endotoxin level before treatment and mortality. Malnutrition did not affect the serum endotoxin level in the patients with diarrhea. It was suggested that infection of Gram-negative bacteria might be involved in a significant number of patients with diarrhea in Bangladesh and that endotoxin might play a pathogenic role in those patients.     

Plasma atrial natriuretic peptide concentration inversely correlates with left atrial collagen volume fraction in patients with atrial fibrillation: plasma ANP as a possible biochemical marker to predict the outcome of the maze procedure.

OBJECTIVES: We hypothesized that the plasma atrial natriuretic peptide (ANP) level reflects atrial degenerative change and may predict the outcome of the maze procedure. BACKGROUND: Although a larger preoperative left atrial dimension and longer duration of atrial fibrillation (AF) have been reported in patients with persistent AF than in those with sinus rhythm (SR), these individual factors were not enough to predict the outcome of the maze procedure. METHODS: Preoperative plasma ANP levels were measured in consecutive 62 patients who underwent the Kosakai's modified maze procedure. Moreover, we performed histological and molecular biological examinations in the resected left atrial tissues. RESULTS: The preoperative plasma ANP was lower in the AF group (n = 13) than it was in the SR group (n = 49) (p < 0.001). Multiple logistic regression analysis revealed that duration of AF and plasma ANP were independently associated with postoperative cardiac rhythm. Among 41 patients with a higher plasma ANP or shorter duration of AF than the median value, SR was restored in 95% of patients. In contrast, in 21 patients with a lower plasma ANP and a longer duration of AF than the median value, SR was restored only in 48% of patients. Histological examination revealed that the collagen volume in the left atrial tissue was higher in AF than it was in SR and inversely correlated with plasma ANP. In addition, the messenger RNA expressions of ANP, collagen type I and type III were lower in AF than they were in SR. CONCLUSIONS: These results suggest that a combination of plasma ANP and/or duration of AF may predict the success rate for the maze operation. Advanced atrial degenerative change may result in a decrease of atrial ANP secretion.     

Clinicopathologic features and prognostic factors of resected solitary small-sized hepatocellular carcinoma

BACKGROUND/AIMS: Solitary small-sized HCCs tend to be considered as less aggressive cancer, and non-surgical treatments have recently been preferred. The aim of this study was to clarify the clinicopathological features and the prognostic factors of small-sized HCCs and to evaluate the significance of hepatic resection for them. METHODOLOGY: Eighty patients with HCC up to 2cm in diameter who had undergone hepatic resection were enrolled in this study. We investigated the clinicopathological features and evaluated the prognostic factors by univariate and multivariate analyses. RESULTS: The overall survival rates at 3, 5 and 10 years were 83%, 69% and 36%, respectively, and the corresponding disease-free survival rates were 63%, 41% and 10%. Well-differentiated, moderately differentiated and poorly differentiated HCC were detected in 29%, 65% and 6% of the patients, respectively. Furthermore, microscopic portal vein invasion (vp), hepatic vein invasion (vv) and intrahepatic metastasis (im) were positive in 15%, 4% and 10% of the patients, respectively. Multivariate analysis revealed that Child-Pugh classification (p=0.005) and vp (p=0.0008) were independent prognostic factors for survival rate and that platelet count (p=0.002) and tumor differentiation (p=0.0016) were independent prognostic factors for disease-free survival rate. CONCLUSIONS: Even solitary small-sized (up to 2cm in diameter) HCC already have the characteristics of advanced HCC. When hepatic function is well preserved, hepatic resection should be the first choice for local control, especially in cases of moderately to poorly differentiated HCC, because the frequency of microscopic vascular invasion is high.     

Surgical experiences with inflammatory arterial aneurysms due to Takayasu's arteritis

This report shows clinical manifestations and provides aspects of surgical strategy for inflammatory aneurysms due to Takayasu's arteritis. Fourteen cases of inflammatory aneurysms among 81 patients with Takayasu's arteritis who underwent surgery in our institute were reviewed. The patient group consisted of six males and eight females, ages from 20 to 61 (mean 39.6±3.5) years. Aneurysmal lesions were located in the ascending aorta or aortic arch (type I) in six (42.9%) patients and the thoracic and/or abdominal aorta (type II) in six patients (42.9%). Type III distribution was determined for two patients (14.3%). Operative procedures for aneurysms included aortic replacement using prosthetic graft (n=6), aneurysmorraphy (n=1), patch angioplasty (n=1), Hardy operation (n=1), aortic valve replacement (AVR) (n=2), and AVR associated with mesh wrapping or aneurysmorraphy (n=3). Operative mortality was 21.4% (three cases) at initial operation and late deaths were found in five cases. Causes of late deaths included rupture of suture aneurysms, rupture of the aortic aneurysm at other aortic lesions, and sudden death due to acute perivalvular leakage. Aggressive surgical approach prior to rupture is required for cases with progressive aortic dilatation even if inflammation signs appear to be controlled. Careful long-term follow-up using periodical angiogram or computed tomography are essential to the best prognosis in pre- and postoperative periods.