Visualization of ferroaxial domains in an order-disorder type ferroaxial crystal.

Ferroaxial materials that exhibit spontaneous ordering of a rotational structural distortion with an axial vector symmetry have gained growing interest, motivated by recent extensive studies on ferroic materials. As in conventional ferroics (e.g., ferroelectrics and ferromagnetics), domain states will be present in the ferroaxial materials. However, the observation of ferroaxial domains is non-trivial due to the nature of the order parameter, which is invariant under both time-reversal and space-inversion operations. Here we propose that NiTiO3 is an order-disorder type ferroaxial material, and spatially resolve its ferroaxial domains by using linear electrogyration effect: optical rotation in proportion to an applied electric field. To detect small signals of electrogyration (order of 10-5 deg V-1), we adopt a recently developed difference image-sensing technique. Furthermore, the ferroaxial domains are confirmed on nano-scale spatial resolution with a combined use of scanning transmission electron microscopy and convergent-beam electron diffraction. Our success of the domain visualization will promote the study of ferroaxial materials as a new ferroic state of matter.

Bilateral cerebellar cysts and cerebral white matter lesions with cortical dysgenesis: Expanding the phenotype of LAMB1 gene mutations.

LAMB1 gene analysis should be considered for intellectually disabled patients with cerebellar cysts, white matter signal change, and cortical malformation. Muscular involvement is absent, in contrast to the α-dystroglycanopathy types of congenital muscular dystrophies.

Comparison of oncological safety between nipple sparing mastectomy and total mastectomy using propensity score matching.

INTRODCUTION: Although nipple sparing mastectomy (NSM) has attracted increased recognition as an alternative to traditional mastectomy approaches, its oncological safety is unclear. The purpose of this study was to compare the local recurrence rate between NSM and total mastectomy (TM). METHODS: Between 2003 and 2013, 121 and 557 patients with stage 0-III breast cancer underwent NSM and TM respectively. Multivariate Cox regression and propensity score models were used to compare the two groups. RESULTS: There was no significant difference in the five-year local recurrence rate between the NSM and TM groups (7.6% vs 4.9%, p=0.398). In multivariate analysis, NSM was not a risk factor for local recurrence (hazard ratio: 1.653, 95% confidence interval: 0.586-4.663, p=0.343). Propensity score matching found similar five-year local recurrence free survival rates between the two groups (92.3% vs 93.7%, p=0.655). CONCLUSIONS: Our results suggest that NSM may provide oncological safety comparable with mastectomy for carefully selected patients.

Fate of aorta and clinical outcomes in patients with chronic type B aortic dissection: over 20-year experience.

AIM: In type B double-barrel aortic dissection (AD), the fate of the affected aorta, causes of death, and very long-term clinical outcomes have not been completely elucidated. The purpose of this study was to clarify the fate of the affected aorta and long-term clinical outcomes in patients with type B AD during the chronic phase. MEHODS: One hundred and four patients were entered into this study, and regular follow-up CT studies (mean; 87.6 months) were performed. Also, clinical data including AD-related events (including aneurysm formation, rupture, ischemia, and re-dissection), AD-related deaths, and long-term survival were retrospectively reviewed. RESULTS: Forty-six of 104 patients (44.2%) had one more AD-related event during the follow-up period. The actuarial event-free rates for any AD-related events of all patients were 95±2%, 75±5%, 53±6%, and 13±7% at 1, 5, 10, and 20 years, respectively. Initial aortic diameter ≥40 mm and blood flow in the false lumen were significant risk factors for AD-related events in univariate and multivariate analysis. CONCLUSION: In type B chronic aortic dissection, the affected aortas have a high incidence of AD-related events during the follow-up period. Prophylactic surgery or endovascular treatment for patients at high risk may reduce the AD-related events.

Serine-204 in the linker region of Smad3 mediates the collagen-I response to TGF-ß in a cell phenotype-specific manner.

Regulation of TGF-ß1/Smad3 signaling in fibrogenesis is complex. Previous work by our lab suggests that ERK MAP kinase phosphorylates the linker region (LR) of Smad3 to enhance TGF-ß-induced collagen-I accumulation. However the roles of the individual Smad3LR phosphorylation sites (T179, S204, S208 and S213) in the collagen-I response to TGF-ß are not clear. To address this issue, we tested the ability of Smad3 constructs expressing wild-type Smad3 or Smad3 with mutated LR phosphorylation sites to reconstitute TGF-ß-stimulated COL1A2 promoter activity in Smad3-null or -knockdown cells. Blocking ERK in fibroblasts and renal mesangial cells inhibited both S204 phosphorylation and Smad3-mediated COL1A2 promoter activity. Mutations replacing serine at S204 or S208 in the linker region decreased Smad3-mediated COL1A2 promoter activity, whereas mutating T179 enhanced basal COL1A2 promoter activity and did not prevent TGF-ß stimulation. Interestingly, mutation of all four Smad3LR sites (T179, S204, S208 and S213) was not inhibitory, suggesting primacy of the two inhibitory sites. These results suggest that in these mesenchymal cells, phosphorylation of the T179 and possibly S213 sites may act as a brake on the signal, whereas S204 phosphorylation by ERK in some manner releases that brake. Renal epithelial cells (HKC) respond differently from MEF or mesangial cells; blocking ERK neither changed TGF-ß-stimulated S204 phosphorylation nor prevented Smad3-mediated COL1A2 promoter activity in HKC. Furthermore, re-expression of wild type-Smad3 or the S204A-Smad3 mutant in Smad3-knockdown HKC reconstituted Smad3-mediated COL1A2 promoter activity. Collectively, these data suggest that Serine-204 phosphorylation in the Smad3LR is a critical event by which ERK enhances Smad3-mediated COL1A2 promoter activity in mesenchymal cells.

Hemoadsorption of high-mobility group box chromosomal protein 1 using a column for large animals.

BACKGROUND: High-mobility group box chromosomal protein 1 (HMGB1) has recently been identified as an important mediator of various kinds of acute and chronic inflammation. A method for efficiently removing HMGB1 from the systemic circulation could be a promising therapy for HMGB1-mediated inflammatory diseases. MATERIALS AND METHODS: In this study, we produced a new adsorbent material by chemically treating polystyrene fiber. We first determined whether the adsorbent material efficiently adsorbed HMGB1 in vitro using a bovine HMGB1 solution and a plasma sample from a swine model of acute liver failure. We then constructed a column by embedding fabric sheets of the newly developed fibers into a cartridge and tested the ability of the column to reduce plasma HMGB1 levels during a 4-hour extracorporeal hemoperfusion in a swine model of acute liver failure. RESULTS: The in vitro adsorption test of the new fiber showed high performance for HMGB1 adsorption (96% adsorption in the bovine HMGB1 solution and 94% in the acute liver failure swine plasma, 2 h incubation at 37°C; p < 0.05 vs. incubation with no adsorbent). In the in vivo study, the ratio of the HMGB1 concentration at the outlet versus the inlet of the column was significantly lower in swine hemoperfused with the newly developed column (53 and 61% at the beginning and end of perfusion, respectively) than in those animals hemoperfused with the control column (94 and 93% at the beginning and end of perfusion, respectively; p < 0.05). Moreover, the normalized plasma level of HMGB1 was significantly lower during perfusion with the new column than with the control column (p < 0.05 at 1, 2, and 3 h after initiation of perfusion). CONCLUSION: These data suggest that the newly developed column has the potential to effectively adsorb HMGB1 during hemoperfusion in swine.

Increased plasma levels of high mobility group box 1 in patients with acute liver failure.

BACKGROUND: High-mobility group box 1 (HMGB1) is a monocyte-derived late-acting inflammatory mediator, which is released in conditions such as shock, tissue injury and endotoxin-induced lethality. In this study, we determined the plasma and hepatic tissue levels of HMGB1 in patients with acute liver failure (ALF). PATIENTS AND METHODS: We determined the plasma levels of HMGB1 and aspartate aminotransferase (AST) in 7 healthy volunteers (HVs), 40 patients with liver cirrhosis (LC), 37 patients with chronic hepatitis (CH), 18 patients with severe acute hepatitis (AH), and 14 patients with fulminant hepatitis (FH). The 14 patients with FH were divided into two subgroups depending upon the history of plasma exchange (PE) before their plasma sample collection. The hepatic levels of HMGB1 were measured in tissue samples from 3 patients with FH who underwent living-donor liver transplantation and from 3 healthy living donors. Hepatic tissue samples were also subjected to immunohistochemical examination for HMGB1. RESULTS: The plasma levels of HMGB1 (ng/ml) were higher in patients with liver diseases, especially in FH patients with no history of PE, than in HVs (0.3 ± 0.3 in HVs, 4.0 ± 2.0 in LC, 5.2 ± 2.6 in CH, 8.6 ± 4.8 in severe AH, 7.8 ± 2.7 in FH with a history of PE, and 12.5 ± 2.6 in FH with no history of PE, p < 0.05 in each comparison). There was a strong and statistically significant relationship between the mean plasma HMGB1 level and the logarithm of the mean AST level (R = 0.900, p < 0.05). The hepatic tissue levels of HMGB1 (ng/mg tissue protein) were lower in patients with FH than in healthy donors (539 ± 116 in FH vs. 874 ± 81 in healthy donors, p < 0.05). Immunohistochemical staining for HMGB1 was strong and clear in the nuclei of hepatocytes in liver sections from healthy donors, but little staining in either nuclei or cytoplasm was evident in specimens from patients with FH. CONCLUSION: We confirmed that plasma HMGB1 levels were increased in patients with ALF. Based on a comparison between HMGB1 contents in normal and ALF livers, it is very likely that HMGB1 is released from injured liver tissue.

Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib.

The B-cell translocation gene-2 (BTG2), a p53-inducible gene, is suppressed in mammary epithelial cells during gestation and lactation. In human breast cancer, decreased BTG2 expression correlates with high tumor grade and size, p53 status, blood and lymph vessel invasion, local and metastatic recurrence and decrease in overall survival, suggesting that suppression of BTG2 has a critical role in disease progression. To analyze the role of BTG2 in breast cancer progression, BTG2 expression was knocked down in mammary epithelial cells. Suppression of BTG2 enhances the motility of cells in vitro and tumor growth and metastasis in vivo. The effects of BTG2 knockdown are mediated through stabilization of the human epidermal growth factor receptor (HER) ligands neuregulin and epiregulin and activation of the HER2 and HER3 receptors, leading to elevated AKT phosphorylation. Suppression of HER activation using the tyrosine kinase inhibitor lapatinib abrogates the effects of BTG2 knockdown, including the increased cell migration observed in vitro and the enhancement of tumorigenesis and metastasis in vivo. These results link BTG2-dependent effects on tumor progression to ErbB receptor signaling, and raise the possibility that targeted inhibition of this pathway may be relevant in the treatment of breast cancers that have reduced BTG2 expression.

Non-sentinel lymph node status and prognosis of breast cancer patients with micrometastatic sentinel lymph nodes.

BACKGROUND: The prognostic significance of sentinel lymph node (SLN) micrometastases and the need for axillary lymph node dissection (ALND) on patients with micrometastases in SLNs remain controversial. METHODS: A prospective database of 657 breast cancer patients who underwent SLN biopsy (SLNB) was analyzed. SLNs were detected using a combined method of isosulfan blue dye and small-sized technetium-99m-labeled tin colloid. RESULTS: Micrometastases in SLNs were found in 50 (7.6%) of 657 patients. Twenty-nine (58.0%) of 50 patients with micrometastatic SLNs underwent ALND and no further metastases were found in non-sentinel lymph nodes. Among 21 patients (42.0%) with micrometastatic SLNs who decided to forego ALND, no axillary lymph node recurrence has been observed during a median follow-up time of 47 months. There is no significant difference in recurrence-free survival between the patients with micrometastatic and negative SLNs (p = 0.90). CONCLUSIONS: These data suggest that it may not be necessary to perform ALND on patients with micrometastases in SLNs and that the presence of micrometastases in SLNs may not be associated with prognosis.

Superiority of radioisotope over blue dye for sentinel lymph node detection in breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is commonly performed using radioisotopes and/or blue dye. However, it is still undefined which reagent is more suitable for identifying sentinel lymph nodes (SLN). PATIENTS AND METHODS: A consecutive series of 640 breast cancer patients who had undergone SLNB at the Keio University Hospital from 2001 to 2006 was analyzed. The SLN was identified by a combination of technetium-99m tin colloid and isosulfan blue dye. The correlation between clinicopathological factors and the distribution of radioisotopes and blue dye was analyzed. The single metastatic lymph node revealed by axillary lymph node dissection (ALND) is the 'true SLN', and the distribution of radioisotopes and blue dye to the 'true SLN' was also analyzed. RESULTS: Blue-dye- and radioisotope-positive SLN were identified in 79.6 and 94.7% of the patients, respectively. Taken together, SLN were identified in 625 patients (97.7%) by radioisotope and/or blue dye. No significant correlation was observed between clinicopathological features and the distribution of the reagents. ALND found 73 patients with single lymph node metastasis, and 73 'true SLN' were identified by blue dye in 65.7% (48/73), and by radioisotope in 95.9% (70/73) of the cases. CONCLUSION: These data suggest that radioisotopes are superior to blue dye in detecting SLN in breast cancer.

A phase II trial of capecitabine and docetaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide (FEC) as preoperative treatment in women with stage II/III breast cancer.

BACKGROUND: Capecitabine (X) and docetaxel (T) have demonstrated a synergistic effect in preclinical models and a survival benefit in metastatic breast cancer. This study's purpose was to determine the efficacy of X and T followed by 5-fluorouracil/epirubicin/cyclophosphamide (FEC) in the preoperative setting. PATIENTS AND METHODS: Patients with stage II/III breast cancer received four cycles of XT (capecitabine 1650 mg/m(2) on days 1-14 and docetaxel 60 mg/m(2) on day 8 every 3 weeks), followed by four cycles of FEC (5-fluorouracil 500 mg/m(2), epirubicin 90 mg/m(2), and cyclophosphamide 500 mg/m(2) on day 1 every 3 weeks). Primary end points were the pathological complete response (pCR) rate and adverse drug reactions. RESULTS: Seventy-four patients were enrolled and 71 patients were assessable for clinical and pathological responses. The overall response rate was 91.5%. The pCR rate was 14.1% (10 of 71). Grade 3/4 neutropenia was observed in 32.4% of patients. The most common grade 3/4 non-hematologic adverse event was hand-foot syndrome, observed in 11.3% of patients. With 29 months median follow-up, 2-year disease-free survival was estimated 85% for all patients. CONCLUSION: These data indicate that the sequential combination of XT followed by FEC is a well-tolerated, effective neoadjuvant treatment of stage II/III breast cancer.

Galectin-1 suppresses alpha2(I) collagen through Smad3 in renal epithelial cells.

Transforming growth factor (TGF-beta1) promotes renal fibrogenesis through activation of Smads. Galectin-1 is reported to prevent experimental glomerulonephritis. Here we investigated the fact that transfected galectin-1 significantly suppressed the transcription of alpha2(I) collagen (COL1A2) in TGF-beta1- activated human renal epithelial cells. Conversely, galectin-1 silencing RNA reduced secretion of type I collagen by HKC cells. Galectin-1 significantly decreased activation of a TGF-beta1-responsive reporter construct and of a minimal reporter construct that contains four repeats of the Smad binding element (SBE). Galectin-1 had no effect on phosphorylation of Smad3 at the linker region and C-terminus, whereas it decreased affinity of Smad3 to the SBE. Additionally, the inhibitory effect of galectin-1 disappeared using a mutated reporter construct, 376 m-LUC, in which a potential Smad recognition site within the promoter is mutated. Taken together, the results suggest that galectin-1 decreases Smad3-complex from binding to the SBE, down-regulating transcription of COL1A2 in TGF-beta1-stimulated renal epithelial cells.

Diagnostic utility of waveform analysis of compound muscle action potentials for carpal tunnel syndrome.

PURPOSE: To determine the diagnostic utility of waveform analysis of compound muscle action potentials (CMAP) for carpal tunnel syndrome (CTS). METHODS: A total of 131 hands in 71 patients diagnosed with CTS (grouped according to severity) and 80 hands in 44 normal subjects were evaluated using nerve conduction test through the carpal tunnel combined with waveform analysis of CMAP. RESULTS: Compared to normal subjects, the sensory nerve conduction velocity and mean frequency of the CMAP waveform were significantly reduced in patients with CTS. Compared with distal motor latency and sensory nerve conduction velocity, the mean frequency of the CMAP decreased significantly with increasing clinical severity. CONCLUSION: This study suggests that waveform analysis of CMAP is of diagnostic value in CTS, and is also of value in objective evaluation of postoperative recovery of carpal median nerve dysfunction.

Spinal reconstruction for symptomatic thoracic haemangioma using a titanium cage.

Most vertebral haemangiomas are asymptomatic. A case of spinal reconstruction for symptomatic extraosseous thoracic haemangioma using a titanium cage is reported. Radiographs of the T11 vertebra demonstrated characteristic vertical striations. Magnetic resonance imaging and computed tomography showed spinal cord compression by extraosseous tumour extension. Several tumour feeding vessels were shown by angiography. Through a transpedicular biopsy, a histological diagnosis of cavernous haemangioma was made. Embolisation of feeding vessels was performed using coils before surgery. Laminectomy and subtotal vertebrectomy were performed by a single posterior approach. Rigid stabilisation of the spine was achieved with pedicle screw systems and a cage filled with an autogenous bone graft. Five months postoperatively, stabilisation of the spine was established without loosening of the cage or pedicle screws. Clinical symptoms were improved.

Role for central ghrelin in food intake and secretion profile of stomach ghrelin in rats.

Ghrelin, a 28-amino-acid peptide, has recently been isolated from the rat stomach as an endogenous ligand for the GH secretagogue receptor. We have reported previously that central or peripheral administration of ghrelin stimulates food intake, and the secretion of GH and gastric acid in rats. In the present study, we investigated how much endogenous centrally released ghrelin is involved in the control of food intake and body weight gain. We also examined the profile of ghrelin secretion from the stomach by RIA using two kinds of anti-ghrelin antiserum, one raised against the N-terminal ([Cys(12)]-ghrelin[1-11]) region and one raised against the C-terminal ([Cys(0)]-ghrelin [13-28]) region of the peptide. The former antibody recognizes specifically ghrelin with n- octanoylated Ser 3 (acyl ghrelin), and does not recognize des-acyl ghrelin. The latter also recognizes des-acyl ghrelin (i.e. total ghrelin). Intracerebroventricular treatment with the anti-ghrelin antiserum against the N-terminal region twice a day for 5 days decreased significantly both daily food intake and body weight. Des-acyl ghrelin levels were significantly higher in the gastric vein than in the trunk. Either fasting for 12 h, administration of gastrin or cholecystokinin resulted in increase of both acyl and des-acyl ghrelin levels. The ghrelin levels exhibited a diurnal pattern, with the bimodal peaks occurring before dark and light periods. These two peaks were consistent with maximum and minimum volumes of gastric content respectively. These results suggest that (1) endogenous centrally released ghrelin participates in the regulation of food intake and body weight, (2) acyl ghrelin is secreted from the stomach, (3) intestinal hormones stimulate ghrelin release from the stomach, and (4) regulation of the diurnal rhythm of ghrelin is complex, since ghrelin secretion is augmented under conditions of both gastric emptying and filling.

Ghrelin in neonatal rats: distribution in stomach and its possible role.

Ghrelin, a 28 amino acid peptide, has recently been isolated from the rat stomach as an endogenous ligand for the GH secretagogue receptor. The fact that administration of ghrelin, centrally or peripherally, stimulates both food intake and GH secretion suggests that stomach ghrelin has an important role in the growth of rats. We used immunohistochemistry and radioimmunoassay to determine the age at which ghrelin-immunostained cells begin to appear in the rat stomach. Ghrelin-immunoreactive cells were found to be expressed in the fetal stomach from pregnancy day 18. The number of ghrelin-immunoreactive cells in the fetal stomach increased as the stomach grew. The amount of ghrelin in the glandular part of the rat stomach also increased, in an age-dependent manner, from the neonatal stage to adult. Eight hours of milk restriction significantly decreased the ghrelin concentration in the stomachs of 1-week-old rats, and increased the ghrelin concentration in their plasma. Administration of ghrelin to 1- and 3-week-old rats increased plasma GH concentrations. The daily subcutaneous administration of ghrelin to pregnant rats from day 15 to day 21 of pregnancy caused an increase in body weight of newborn rats. In addition, daily subcutaneous administration of ghrelin to neonatal rats from birth advanced the day of vaginal opening from day 30.7+/-0.94 to day 27.9+/-0.05. These results suggest that ghrelin may be involved in neonatal development.

Salt-loading elevates blood pressure and aggravates insulin resistance in Wistar fatty rats: a possible role for enhanced Na+ -H+ exchanger activity.

OBJECTIVE: Increased Na+-H+ exchanger activity (NHE) has been reported as an intermediate phenotype in hypertensive subjects, particularly those with insulin resistance. To investigate whether NHE abnormality plays a role in hypertension, Wistar fatty rat (WFR) with overt obesity, hyperglycemia and marked hyperinsulinemia was examined. METHODS: WFR and Wistar lean rats (WLR) as a control (n = 12, each) were fed either with normal (0.38%) or high sodium (4% NaCl) diet for 12 weeks and then sacrificed to examine platelets NHE activity. RESULTS: Mean arterial pressure (MAP) was higher in WFR than in WLR (113 +/- 4 versus 96 +/- 7 mmHg, P < 0.05) under a normal chow. Vmax values of NHE activity were significantly higher in WFR than in WLR. WFR fed with a high sodium diet showed higher MAP than those with a normal chow (128 +/- 3 versus 113 +/- 4 mmHg, P < 0.05). Though Km values were not different between WFR and WLR under a normal chow, both maximal transport rate (Vmax) and half maximal transport (Km) values were significantly higher in WFR with a high salt diet than those with a control diet. Vmax showed significant correlation with MAP, whereas Km values correlated with immunoreactive insulin (IRI) levels. Significant interaction between dietary sodium intake and the strain differences was observed both on blood pressure and on IRI levels by two-way analysis of variance (ANOVA). CONCLUSION: WFR presented salt-sensitive blood pressure elevation. NHE activity was enhanced in WFR in correlation with the blood pressure. These results suggest that augmented NHE activity contributes to the development of salt-sensitive blood pressure elevation in WFR.

Ghrelin in domestic animals: distribution in stomach and its possible role.

Ghrelin, a novel growth-hormone-releasing acylated peptide, was recently isolated from rat and human stomachs. In rat, peripheral or central administration of ghrelin stimulates the secretion of growth hormone (GH) from the pituitary gland. Recent work suggests that ghrelin plays an important role in energy homeostasis, body weight, and food intake. We examined the distribution of cells immunoreactive to ghrelin in the stomachs of domestic animals and rats, using a polyclonal antibody for the N-terminal fragment of rat ghrelin [1-11]. We measured the plasma levels of ghrelin before and after feeding in cows, and GH levels after central administration of ghrelin in Shiba goats, to elucidate the possible role of ghrelin. Immunostained cells were widely distributed from the neck to the base of the oxyntic gland in all animals. The plasma ghrelin concentration in cows decreased significantly 1 h after feeding, and then recovered to pre-feeding levels. Administration of ghrelin into the third ventricle in Shiba goats dramatically increased the plasma GH concentration dose-dependently. These results suggest that ghrelin plays an important role in GH secretion and feeding regulation in domestic animals.