Mice lacking BCAS1, a novel myelin‐associated protein,display hypomyelination,schizophrenia‐like abnormal behaviors,and upregulation of inflammatory genes in the brain

The abnormal expression and function of myelin‐related proteins contribute to nervous system dysfunction associated with neuropsychiatric disorders; however, the underlying mechanism of this remains unclear. We found here that breast carcinoma amplified sequence 1 (BCAS1), a basic protein abundant in the brain, was expressed specifically in oligodendrocytes and Schwann cells, and that its expression level was decreased by demyelination. This suggests that BCAS1 is a novel myelin‐associated protein. BCAS1 knockout mice displayed schizophrenia‐like behavioral abnormalities and a tendency toward reduced anxiety‐like behaviors. Moreover, we found that the loss of BCAS1 specifically induced hypomyelination and the expression of inflammation‐related genes in the brain. These observations provide a novel insight into the functional link between oligodendrocytes and inflammation and/or abnormal behaviors.     

Current state of practice for colonic diverticular bleeding in 37 hospitals in Japan: A multicenter questionnaire study

AIM To clarify the current state of practice for colonic diverticular bleeding(CDB) in Japan.METHODS We conducted multicenter questionnaire surveys of the practice for CDB including clinical settings(8 questions),diagnoses(8 questions),treatments(7 questions),and outcomes(4 questions) in 37 hospitals across Japan.The answers were compared between hospitals with high and low number of inpatient beds to investigate which factor influenced the answers.RESULTS Endoscopists at all 37 hospitals answered the questions,and the mean number of endoscopists at these hospitals was 12.7.Of all the hospitals,computed tomography was performed before colonoscopy in 67% of the hospitals.The rate of bowel preparation was 46.0%.Early colonoscopy was performed within 24 h in 43.2% of the hospitals.Of the hospitals,83.8% performed clipping as first-line endoscopic therapy.More than half of the hospitals experienced less than 20% rebleeding events after endoscopic hemostasis.No significant difference was observed in the annual number of patients hospitalized for CDB between high-(≥700 beds) and low-volume hospitals.More emergency visits(P=0.012) and endoscopists(P=0.015),and less frequent participation of nursing staff in early colonoscopy(P=0.045) were observed in the high-volume hospitals.CONCLUSION Some practices unique to Japan were found,such as performing computed tomography before colonoscopy,no bowel preparation,and clipping as first-line therapy.Although,the number of staff differed,the practices for CDB were common irrespective of hospital size.     

Indications,applications, and outcomes of inferior vena cava filters for venous thromboembolism in Japanese patients

A recent multicenter registry study of venous thromboembolism (VTE) patients in Japan demonstrated a high prevalence of inferior vena cava (IVC) filter placement. However, data regarding indications, applications, and outcomes of IVC filters in Japanese patients are quite limited. This study was an observational, single-center, retrospective cohort study of all consecutive patients with acute VTE treated between March 2006 and February 2014. Data extracted included patient demographics, indications, applications, and complications of IVC filters, as well as VTE recurrence and death. A total of 257 consecutive patients were analyzed. Seventy-eight patients (30 %) received IVC filters. The proportions of IVC filter placement were 26 % for deep-vein thrombosis (DVT) alone, 10 % for pulmonary embolism (PE) alone, and 46 % for both DVT and PE. There was no significant difference in patient demographics between the IVC filter group and no-IVC filter group. Stated indications for filter placement were 24 cases (30 %) of DVT in intrapelvic veins, 16 cases (20 %) of DVT in proximal veins, and 11 cases (14 %) of contraindication to anticoagulant therapy. In the IVC filter group, cases of class I indication (guidelines: JCS 75:1258–1281, 2009) numbered only 6 (8 %). Many of the retrievable IVC filters were not removed and placed permanently and the retrieval rate was 42 %. We found complications of IVC filters in 8 cases (10 %). IVC filter placement was significantly associated with a better survival rate and a higher incidence of DVT recurrence during a mean observation period of 541 days. Our research suggests the frequent use of IVC filters for VTE treatment, combined with a low retrieval rate. Most of the stated indications of IVC filter placement for VTE in Japanese patients were cases of DVT in intrapelvic veins or proximal veins, not cases of contraindication to anticoagulant therapy.     

Liquid biopsy in patients with pancreatic cancer: Circulating tumor cells and cell-free nucleic acids

Despite recent advances in surgical techniques and perioperative management, the prognosis of pancreatic cancer(PCa) remains extremely poor. To provide optimal treatment for each patient with Pca, superior biomarkers are urgently needed in all phases of management from early detection to staging, treatment monitoring, and prognosis. In the blood of patients with cancer, circulating tumor cells(CTCs) and cell-free nucleic acids(cf NAs), such as DNA, m RNA, and noncoding RNA have been recognized. In the recent years, their presence in the blood has encouraged researchers to investigate their potential use as novel blood biomarkers, and numerous studies have demonstrated their potential clinical utility as a biomarker for certain types of cancer. This concept, called "liquid biopsy" has been focused on as a less invasive, alternative approach to cancer tissue biopsy for obtaining genetic and epigenetic aberrations that contribute to oncogenesis and cancer progression. In this article, we review the available literature on CTCs and cfN As in patients with cancer, particularly focusing on PCa, and discuss future perspectives in this field.     

Recent traction methods for endoscopic submucosal dissection

Endoscopic mucosal resection(EMR) is problematic with regard to en bloc and curable resection rates.Advancements in endoscopic techniques have enabled novel endoscopic approaches such as endoscopic submucosal dissection(ESD), which has overcome some EMR problems, and has become the standard treatment for gastrointestinal tumors. However, ESD is technically difficult. Procedure time is longer and complications such as intraoperative perforation and bleeding occur more frequently than in EMR. Recently various traction methods have been introduced to facilitate ESD procedures, such as clip with line, external forceps, clip and snare, internal traction, double scope, and magnetic anchor. Each method must be used appropriately according to the anatomical characteristics. In this review we discuss recently proposed traction methods for ESD based on the characteristics of various anatomical sites.     

Physiologic Effect of Stent Therapy for Inferior Vena Cava Obstruction Due to Malignant Liver Tumor

Purpose To understand systemic the influence of stent therapy for inferior vena cava (IVC) obstruction due to advanced liver tumor. Methods Seven patients with symptomatic IVC obstruction due to advanced primary (n = 4) or secondary (n = 3) liver tumor were subjected to stent therapy. Enrollment criteria included high IVC pressure over 15 mmHg and the presence of edema and ascites. Z-stents were deployed using coaxial sheath technique via femoral venous puncture. Physiologic and hematobiochemical parameters were analyzed. Results All procedures were successful, and the stents remained patent until patient death. Promptly after stent placement, the IVC flow recovered, and the venous blood pressure in the IVC below the obstruction level showed a significant decrease from 20.8 ± 1.2 mmHg (mean ± SE) to 10.7 ± 0.7 mmHg (p < 0.01). Transient mild increase of right atrial pressure was observed in 1 patient. During the following week prominent diuresis was observed in all patients. Mean urine output volume in the 3 days before the stent therapy was 0.81 ± 0.09 l/day compared with 2.1 ± 0.2 l/day (p < 0.01) in the 3 days after. The edema and ascites decreased in all patients. The caval pressure change correlated well (r > 0.6) with the urine volume increase, and with the decreased volume of edema and ascites. The urine volume increase correlated well with the decrement of edema, but not with that of ascites. Improvements for various durations in the levels of blood urea nitrogen, serum creatinine, lactate dehydrogenase, fibrinogen, and platelet count were found (p < 0.05). These hematobiochemical changes were well correlated with each other and with the decrement of ascites. Two patients showed a low blood sodium level of 128.5 mEq/l after intensive natriuresis, and one of them died on day 21 with hepatic failure, which was interpreted as maladaptation aggravation. The mean survival time was 94.1 ± 34.1 days (mean ± SD), ranging from 21 to 140 days after stent treatment. Conclusion The stent therapy for IVC obstruction due to malignant liver tumors was followed by a series of physiologic and hematobiochemical consequences, most of them favorable but some possibly unfavorable. Rational interpretations and predictions of sequelae based on physiologic science including cardiology, hepatology, and nephrology would facilitate the best management of stent therapy for malignant IVC obstruction.     

Hemodynamic characterization of focal hepatic lesions: role of ferucarbotran-enhanced dynamic MR imaging using T2-weighted multishot spin-echo echo-planar sequence

PURPOSE: To investigate the role of ferucarbotran-enhanced dynamic MR imaging using multishot spin-echo echo-planar sequence in the evaluation of hemodynamics of focal hepatic lesions. MATERIALS AND METHODS: Sixty-three focal hepatic lesions (24 benign and 39 malignant) from 53 consecutive patients who underwent both ferucarbotran-enhanced MR imaging and dynamic computed tomography (CT) were included in this study. MR imaging was performed with a 1.5-T scanner with a phased-array coil. T2-weighted multishot spin-echo echo-planar sequences (TR/TE = 1714-2813/80 msec) were obtained during a single breathhold before and 15, 60, 120, 180, and 600 seconds after intravenous injection of ferucarbotran. The enhancement patterns of lesions were classified into three categories by a study coordinator on the basis of dynamic CT images as hypervascular, hypovascular, and hemangioma type. The study coordinator created mean contrast-to-noise ratio of lesions vs. time curves for each enhancement pattern for quantitative analyses. Moreover, three radiologists separately and blindly reviewed MR images, and then assigned three confidence scores for the three enhancement patterns to each lesion. Sensitivity, specificity, and receiver operating characteristic analyses were performed. RESULTS: Quantitative analyses showed characteristic enhancement curves for each enhancement pattern. Mean sensitivities/specificities were 0.816/0.882, 0.897/0.863, and 0.800/0.989 for hypervascular, hypovascular, and hemangioma types, respectively. Mean areas under the receiver operating characteristic curve were 0.886 for hypervascular type and 0.913 for hypovascular type. CONCLUSION: Ferucarbotran-enhanced dynamic MR imaging can be used to successfully characterize the hemodynamics of focal hepatic lesions.     

Distribution and functional activity of P-glycoprotein and multidrug resistance-associated proteins in human brain microvascular endothelial cells in hippocampal sclerosis

Multidrug resistance protein, also referred as P-glycoprotein (P-gp, MDR1; ABCB1) and multidrug resistance-associated protein (MRP) 1 (ABCC1) and 2 (ABCC2) are, thus far, candidates to cause antiepileptic drug (AED) resistance epilepsy. In this study, we investigated P-gp, MRP1 and MRP2 expression, localization and functional activity on cryosections and isolated human brain-derived microvascular endothelial cells (HBMEC) from epileptic patients (HBMEC-EPI) with hippocampal sclerosis (HS), as compared with HBMEC isolated from normal brain cortex (HBMEC-CTR). We examined the expression and distribution of three transporters, P-gp, MRP1 and MRP2 on two major parts of the resected tissue, the hippocampus and the parahippocampal gyrus (Gph). P-gp showed diffuse expression not only in endothelium but also by parenchymal cells in both the hippocampus and the Gph. MRP1 labeling was observed in parenchymal cells in the Gph. By contrast, MRP2 was mainly found in endothelium of the hippocampus. P-gp and MRP1 expression in the Gph was relatively high in the patient with long-term seizure history. Quantitative RT-PCR analysis of HBMEC revealed that MDR1, MRP1 as well as MRP5 (ABCC5) and MRP6 (ABCC6) were overexpressed in HBMEC-EPI at the mRNA level. HBMEC from both normal and epilepsy groups displayed protein expression of P-gp, whereas MRP1 and MRP2 were seen only in HBMEC-EPI. Accordingly, it is of particular interest that MRP functional activities were observed in HBMEC-EPI, but not in HBMEC-CTR. Our results suggest that complex MDR expression changes not only in the hippocampus but in the Gph may play a role in AED pharmacoresistance in intractable epilepsy patients with mesial temporal lobe epilepsy (MTLE) by altering the permeability of AEDs across the blood-brain barrier (BBB).     

Intrathecal injection of epidermal growth factor and fibroblast growth factor 2 promotes proliferation of neural precursor cells in the spinal cords of mice with mutant human SOD1 gene

We investigated three steps of neural precursor cell activation--proliferation, migration, and differentiation--in amyotrophic lateral sclerosis spinal cord treated with intrathecal infusion of epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2) into the lumbar spinal cord region of normal and symptomatic transgenic (Tg) mice with a mutant human Cu/Zn superoxide dismutase (SOD1) gene. We observed that 5-bromodeoxyuridine (BrdU) + nestin double-labeled neural precursor cells increased in the spinal cords of Tg mice compared with non-Tg mice, with a much greater increase produced by EGF and FGF2 treatment. The number of BrdU + nestin double-labeled cells was larger than that of BrdU + ionized calcium-binding adapter molecule-1 (Iba1), BrdU + glial fibrillary acidic protein (GFAP), or BrdU + highly polysialylated neural cell adhesion molecule (PSA-NCAM) double-labeled cells, but none expressed neuronal nuclear antigen (NeuN). On further analysis of the gray matter of Tg mice, the number of BrdU + nestin and BrdU + PSA-NCAM double-labeled cells increased more in the ventral horns than the dorsal horns, which was again greatly enhanced by EGF and FGF2 treatment. Because neural precursor cells reside close to the ependyma of central canal, the present study suggests that proliferation and migration of neural precursor cells to the ventral horns is greatly activated in symptomatic Tg mice and is further enhanced by EGF and FGF2 treatment and, furthermore, that the neural precursor cells preferentially differentiate into neuronal precursor cells instead of astrocytes in Tg mice with EGF and FGF2 treatment.