Search for the Majorana Nature of Neutrinos in the Inverted Mass Ordering Region with KamLAND-Zen.

The KamLAND-Zen experiment has provided stringent constraints on the neutrinoless double-beta (0νßß) decay half-life in ^{136}Xe using a xenon-loaded liquid scintillator. We report an improved search using an upgraded detector with almost double the amount of xenon and an ultralow radioactivity container, corresponding to an exposure of 970 kg yr of ^{136}Xe. These new data provide valuable insight into backgrounds, especially from cosmic muon spallation of xenon, and have required the use of novel background rejection techniques. We obtain a lower limit for the 0νßß decay half-life of T_{1/2}^{0ν}>2.3×10^{26} yr at 90% C.L., corresponding to upper limits on the effective Majorana neutrino mass of 36-156 meV using commonly adopted nuclear matrix element calculations.

Utility of synthetic MRI in predicting pathological complete response of various breast cancer subtypes prior to neoadjuvant chemotherapy.

AIM: To evaluate the usefulness of synthetic magnetic resonance imaging (MRI) performed before the initiation of neoadjuvant chemotherapy (NAC) in predicting whether breast cancers can achieve a pathological complete response (pCR) after the completion of NAC. MATERIALS AND METHODS: This retrospective study investigated 37 consecutive patients with 39 breast cancers (pCR: 14, and non-pCR: 25) who underwent dynamic contrast-enhanced (DCE)-MRI and synthetic MRI before the initiation of NAC. Using synthetic MRI images, quantitative values (T1 and T2 relaxation times, proton density [PD] and their standard deviations [SD]) were obtained in breast lesions, before (Pre-T1, Pre-T2, Pre-PD, SD of Pre-T1, SD of Pre-T2, SD of Pre-PD) and after (Gd-T1, Gd-T2, Gd-PD, SD of Gd-T1, SD of Gd-T2, SD of Gd-PD) contrast agent injection. The aforementioned quantitative values and several morphological features that were identified on DCE-MRI were compared between pCR and non-pCR. RESULTS: Multivariate analyses revealed that the SD of Pre-T2 (p=0.038) was significant and was an independent predictor of pCR, with an area under the receiver operating characteristics curve of 0.829. The sensitivity, specificity, and accuracy of the SD of Pre-T2 with an optimal cut-off value of 11.5 were 71.4%, 80%, and 76.3%, respectively. CONCLUSIONS: The SD of Pre-T2 obtained from synthetic MRI was used successfully to predict those breast cancers that would achieve a pCR after the completion of NAC; however, these results are preliminary and need to be verified by further studies.

Utility of synthetic MRI in predicting the Ki-67 status of oestrogen receptor-positive breast cancer: a feasibility study.

AIM: To evaluate the utility of synthetic magnetic resonance imaging (MRI) of the breast in predicting the Ki-67 status in patients with oestrogen receptor (ER)-positive breast cancer. MATERIALS AND METHODS: Forty-nine patients with 50 histopathologically proven breast cancers who underwent additional synthetic MRI were enrolled in the present study. Using synthetic MRI images, T1 and T2 relaxation times and their standard deviations (SD) in the breast lesions before (T1-Pre, T2-Pre, PD-Pre, SD of T1-Pre, SD of T2-Pre, SD of PD-Pre) and after (T1-Gd, T2-Gd, PD-Gd, SD of T1-Gd, SD of T2-Gd, SD of PD-Gd) contrast agent injection were obtained. These quantitative values were compared between the low Ki-67 expression (<14%) lesions (low-proliferation group: n=23) and high Ki-67 expression (≥14%) lesions (high-proliferation group: n=27). RESULTS: The univariate analysis showed that the SD of T1-Gd (p<0.001) and T2-Gd (p=0.042) were significantly higher in the high-proliferation group than in the low-proliferation group. Multivariate analysis further showed that the SD of T1-Gd was a significant and independent predictor of Ki-67 expression, with an area under the receiver operating characteristic (AUROC) curve of 0.885. The sensitivity, specificity, and accuracy of the SD of T1-Gd with an optimal cut-off value of 98.5 were 77.8%, 87%, and 82%, respectively. CONCLUSION: The SD of T1-Gd obtained from synthetic MRI was useful to predict Ki-67 status.

Precision Analysis of the

We present a precision analysis of the ^{136}Xe two-neutrino ßß electron spectrum above 0.8 MeV, based on high-statistics data obtained with the KamLAND-Zen experiment. An improved formalism for the two-neutrino ßß rate allows us to measure the ratio of the leading and subleading 2νßß nuclear matrix elements (NMEs), ξ_{31}^{2ν}=-0.26_{-0.25}^{+0.31}. Theoretical predictions from the nuclear shell model and the majority of the quasiparticle random-phase approximation (QRPA) calculations are consistent with the experimental limit. However, part of the ξ_{31}^{2ν} range allowed by the QRPA is excluded by the present measurement at the 90% confidence level. Our analysis reveals that predicted ξ_{31}^{2ν} values are sensitive to the quenching of NMEs and the competing contributions from low- and high-energy states in the intermediate nucleus. Because these aspects are also at play in neutrinoless ßß decay, ξ_{31}^{2ν} provides new insights toward reliable neutrinoless ßß NMEs.

Feasibility of virtual surgical simulation in the head and neck region for soft tissue reconstruction using free flap: a comparison of preoperative and postoperative volume measurement.

In the head and neck region, preoperative evaluation of the free flap volume is challenging. The current study validated preoperative three-dimensional (3D) virtual surgical simulation for soft tissue reconstruction by assessing flap volume and evaluated fat and muscle volume changes at follow-up in 13 head and neck cancer patients undergoing anterolateral craniofacial resection. Patients received 3D virtual surgical simulation, and the volume of the planned defects was estimated by surgical simulation. Following en bloc resection of the tumor, the defect in the skull base was covered using a rectus abdominis myocutaneous flap. Following surgery, computed tomography scans were acquired at day 1 and at 6 and 12 months. Virtual planned defect was on average 227 ml (range, 154-315) and was 10% smaller than the actual flap volume in patients without skin involvement of the tumor. Between day 1 and 12 months post-surgery, the volume of fat and muscle tissue in the free flap dropped by 9% and 58%, respectively. Our results indicate that 3D virtual surgical simulation provides essential information in determining the accurate volume of the required free flap for surgical defect repair and may thus help improve surgical planning and functional and esthetic outcome.

Cell therapy for facial anti-aging.

Two types of cell therapy for facial anti-aging in my clinical experience are introduced in this presentation. One therapy is cultured gingival fibroblasts injection. This procedure lasts for at least one year, making it a good option for patients. The other is platelet rich plasma injection. The results of the preliminary data are promising, but not yet well understood. More clinical data and long-term follow-up is needed.

Evaluation of circadian phenotypes utilizing fibroblasts from patients with circadian rhythm sleep disorders.

We evaluated the circadian phenotypes of patients with delayed sleep-wake phase disorder (DSWPD) and non-24-hour sleep-wake rhythm disorder (N24SWD), two different circadian rhythm sleep disorders (CRSDs) by measuring clock gene expression rhythms in fibroblast cells derived from individual patients. Bmal1-luciferase (Bmal1-luc) expression rhythms were measured in the primary fibroblast cells derived from skin biopsy samples of patients with DSWPD and N24SWD, as well as control subjects. The period length of the Bmal1-luc rhythm (in vitro period) was distributed normally and was 22.80±0.47 (mean±s.d.) h in control-derived fibroblasts. The in vitro periods in DSWPD-derived fibroblasts and N24SWD-derived fibroblasts were 22.67±0.67 h and 23.18±0.70 h, respectively. The N24SWD group showed a significantly longer in vitro period than did the control or DSWPD group. Furthermore, in vitro period was associated with response to chronotherapy in the N24SWD group. Longer in vitro periods were observed in the non-responders (mean±s.d.: 23.59±0.89 h) compared with the responders (mean±s.d.: 22.97±0.47 h) in the N24SWD group. Our results indicate that prolonged circadian periods contribute to the onset and poor treatment outcome of N24SWD. In vitro rhythm assays could be useful for predicting circadian phenotypes and clinical prognosis in patients with CRSDs.

Autologous fat injection therapy including a high concentration of adipose-derived regenerative cells in a vocal fold paralysis model: animal pilot study.

OBJECTIVES: To verify the effectiveness and safety of the addition of adipose-derived regenerative cells to autologous fat injection therapy. METHODS: Unilateral vocal fold paralysis models were made by cutting the right recurrent laryngeal nerve in two pigs. At day 30, 0.5 ml adipose-derived regenerative cells mixed with 1 ml autologous fat was injected into the right vocal fold of one pig, with the other receiving 0.5 ml Ringer's solution mixed with 1 ml autologous fat. At day 120, fibrescopy, laser Doppler flowmeter, computed tomography, vocal function evaluation and histological assessment were conducted. RESULTS: Although histological assessment revealed atrophy of the thyroarytenoid muscle fibre in both pigs, there was remarkable hypertrophy of the thyroarytenoid muscle fibre in the area surrounding the adipose-derived regenerative cells injection site. CONCLUSION: The addition of a high concentration of adipose-derived regenerative cells to autologous fat injection therapy has the potential to improve the treatment outcome for unilateral vocal fold paralysis.

VCP/p97 in abnormal protein aggregates, cytoplasmic vacuoles, and cell death, phenotypes relevant to neurodegeneration.

Neuronal cell death, abnormal protein aggregates, and cytoplasmic vacuolization are major pathologies observed in many neurodegenerative disorders such as the polyglutamine (polyQ) diseases, prion disease, Alzheimer disease, and the Lewy body diseases, suggesting common mechanisms underlying neurodegeneration. Here, we have identified VCP/p97, a member of the AAA+ family of ATPase proteins, as a polyQ-interacting protein in vitro and in vivo, and report on its characterization. Endogenous VCP co-localized with expanded polyQ (ex-polyQ) aggregates in cultured cells expressing ex-polyQ, with nuclear inclusions in Huntington disease patient brains, and with Lewy bodies in patient samples. Moreover, the expression of VCP mutants with mutations in the 2nd ATP binding domain created cytoplasmic vacuoles, followed by cell death. Very similar vacuoles were also induced by ex-polyQ expression or proteasome inhibitor treatment. These results suggest that VCP functions not only as a recognition factor for abnormally folded proteins but also as a pathological effector for several neurodegenerative phenotypes. VCP may thus be an ideal molecular target for the treatment of neurodegenerative disorders.

Sargachromenol, a novel nerve growth factor-potentiating substance isolated from Sargassum macrocarpum, promotes neurite outgrowth and survival via distinct signaling pathways in PC12D cells.

We previously found that the methanol extract of a marine brown alga, Sargassum macrocarpum showed marked nerve growth factor (NGF)-dependent neurite outgrowth promoting activity to PC12D cells. The active substance purified was elucidated to be sargachromenol. The median effective dose (ED50) was 9 microM against PC12D cells in the presence of 10 ng/ml NGF, although it showed no neurotrophic effect on its own. Pretreatment of cells with protein kinase A (PKA) inhibitor or U0126 substantially suppressed the sargachromenol-enhanced neurite outgrowth from PC12D cells, suggesting that the activation of cyclic AMP-mediated protein kinase and mitogen-activated protein (MAP) kinase 1/2 was apparently required for the action of sargachromenol. On the other hand, sargachromenol significantly promoted the survival of neuronal PC12D cells at 0-50 ng/ml NGF in serum-free medium. Neither PKA inhibitor nor U0126 could inhibit the survival supporting effect of sargachromenol, whereas wortmannin significantly blocked the sargachromenol-induced survival supporting effect on neuronal PC12D cells, suggesting that sargachromenol rescued neuronal PC12D cells by activating phosphatidylinositol-3 kinase. These results demonstrate that sargachromenol promotes neuronal differentiation of PC12D cells and supports the survival of neuronal PC12D cells via two distinct signaling pathways.

A steroidogenic cell line with differentiation potential from mouse granulosa cells, transfected with Ad4BP and SV40 large T antigen genes.

Several steroidogenic cell lines of granulosa cells (GC) have been used to elucidate differentiation mechanisms of GC during folliculogenesis. These cell lines, however, are of limited usefulness since they have lost some of their differentiation potential. The transcription factor adrenal-4 binding protein (Ad4BP), also known as steroidogenic factor-1 or NR5A1, is essential for the expression of all P-450 steroidogenic enzymes. By transfection with the Ad4BP gene together with SV40 DNA, we have generated several steroidogenic cell lines. One selective clone, named 4B2, retained its steroidogenic potential and was therefore analyzed in depth. This cell line responded to 8-Br-cAMP by displaying differentiation characteristics similar to those occurring in the differentiation process of primary cultured GC, including enhanced progesterone secretion, a cell shape change from a fibroblastic to epithelioid conformation, elongated mitochondria, increased gap junction formation and inhibition of cell proliferation. Prostaglandin E2 (PGE2), an intraovarian regulator of GC, stimulated cAMP production, and this eicosanoid, like 8-Br-cAMP, induced differentiation properties with the exception of cell conformation in 4B2 cells. These results suggest that expression of Ad4BP may provide the basis for a repertoire of cAMP-sensitive differentiation properties, including morphological alterations and growth inhibition. Thus, the 4B2 cell line may serve as a tool for elucidation of differentiation mechanisms that are under the control of Ad4BP.

Maternal epidermal growth factor deficiency causes fetal hypoglycemia and intrauterine growth retardation in mice: possible involvement of placental glucose transporter GLUT3 expression.

We investigated the physiological role of epidermal growth factor (EGF) in fetal growth in mice in which midgestational sialoadenectomy induced maternal EGF deficiency. Sialoadenectomy decreased the fetal weight significantly, indicating that maternal EGF deficiency caused intrauterine growth retardation. The weight of the fetal liver in the sialoadenectomized mice was reduced in proportion to the decrease in body weight (82.7+/-10.2 vs. 70.9+/-10.9 mg), whereas the brain weight was not reduced. Sialoadenectomy significantly decreased the glucose concentration in fetal plasma (86.0+/-13.0 vs. 63.0+/-11.8 mg/dl) without affecting the maternal plasma level of glucose. Transplacental transfer of 3H-2-deoxyglucose was significantly decreased by sialoadenectomy (5.17+/-1.25 vs. 2.94+/-1.02%), but transfer of 14C-aminoisobutyric acid was not affected. Northern blot analysis and in situ hybridization of glucose transporter isoform GLUT1 and GLUT3 messenger RNAs (mRNAs) in placenta revealed that sialoadenectomy significantly reduced the expression of GLUT3 mRNA without affecting GLUT1 mRNA levels. Administration of anti-EGF antiserum enhanced the effects of EGF deficiency, which were almost completely corrected by EGF supplementation. These results indicate that EGF plays an important role in fetal growth by regulating the transplacental supply of glucose via GLUT3 expression in the placenta.

Diurnal fluctuation of sleep propensity and hormonal secretion across the menstrual cycle.

BACKGROUND: The fact that most women experience sleep changes across the menstrual cycle is thought to be associated with changes in circadian rhythms; however, few studies have investigated this relationship. METHODS: We applied an ultrashort sleep-wake schedule to eight healthy women and studied diurnal fluctuations in sleep propensity, sleepiness, rectal temperature, and serum concentrations of melatonin, thyroid-stimulating hormone, and cortisol in the follicular and luteal phases. RESULTS: In the luteal phase, amplitude of core body temperature, total melatonin secretions, and amplitudes of TSH and cortisol rhythms were significantly decreased, whereas sleepiness and occurrence of slow-wave sleep during the daytime were significantly increased. Differences in the amount of daytime slow-wave sleep across the menstrual cycle were positively correlated with differences in the daily mean rectal temperature. CONCLUSIONS: The findings suggest that the amplitude of circadian oscillation may be dampened in the luteal phase. Increased daytime sleepiness in the luteal phase may be associated with increased daytime slow-wave sleep, due possibly to changes in thermoregulation in the luteal phase.

Cloning and sequencing of the gene encoding the mouse vitamin D receptor.

The mouse vitamin D receptor (VDR)-encoding cDNA was cloned and the coding regions were sequenced. Comparison of the amino-acid sequence to that of humans and rats revealed high homology in the DNA- and ligand-binding domains. Divergence appeared in the internal region between the two domains.

Neurosteroids ameliorate conditioned fear stress: an association with sigma receptors.

Mice exhibited a marked suppression of motility (conditioned fear stress) when placed in an environment in which they had previously received an electric footshock. This conditioned fear stress response was dose-dependently attenuated by neurosteroids such as dehydroepiandrosterone sulfate (DHEAS; 25 and 50 mg/kg, s.c.) and pregnenolone sulfate (PREGS; 10-50 mg/kg, s.c.), and by a putative sigma(1) receptor agonist, (+)-N-allylnormetazocine ((+)-SKF-10,047; 3 and 6 mg/kg, s.c.). However, progesterone (PROG; 10-50 mg/kg, s.c. ) and allopregnanolone (5 and 20 mg/kg, s.c.) had no effect on this stress response. The attenuating effects of DHEAS (50 mg/kg, s.c.), PREGS (50 mg/kg, s.c.), and (+)-SKF-10,047 (6 mg/kg, s.c.) were reversed by NE-100 (5 mg/kg, i.p.), a sigma(1) receptor antagonist and PROG (5 or 10 mg/kg, i.p.). When DHEAS (25 mg/kg) was co-administered with (+)-SKF-10,047 (3 mg/kg) at doses that do not affect the conditioned fear stress response by themselves, motor suppression was significantly attenuated. In mice showing the conditioned fear stress response, the serum concentration of DHEAS was lower than that in non-shocked mice. These results suggest that the attenuating effects of DHEAS and PREGS on the conditioned fear stress response are mediated via sigma(1) receptors and that PROG has a sigma(1) receptor antagonistic property. Further, the endogenous DHEAS may be involved in the expression of conditioned fear stress response in mice.

Three distinct classes of the alpha-subunit of the nuclear pore-targeting complex (importin-alpha) are differentially expressed in adult mouse tissues.

The process of active nuclear protein transport is mediated by the nuclear localization signal (NLS). An NLS-containing karyophile forms a stable complex, termed the nuclear pore-targeting complex, to target nuclear pores. The alpha-subunit of the complex (importin-alpha) binds to the NLS and the beta-subunit (importin-beta) carries the alpha-subunit, bound to the NLS substrate, into the nucleus. To date, five mouse alpha-subunits have been identified and classified into three subfamilies (alpha-P, alpha-Q, and alpha-S). The expression of these alpha-subunits and the beta-subunit in various adult mouse tissues was examined by immunoblotting and immunohistochemistry using antibodies specific for each subfamily of the alpha-subunit or the beta-subunit. The beta-subunit was found to be ubiquitously expressed, whereas each subfamily of the alpha-subunit showed a unique expression pattern in various tissues, especially in brain and testis. In brain, the expression of alpha-P was not observed, whereas alpha-S was significantly expressed in Purkinje cells, and pyramidal cells of the hippocampus and cerebral cortex. In testis, alpha-P was expressed predominantly in primary spermatocytes, whereas alpha-Q was found mainly in Leydig cells. Expression of alpha-S was detected in almost all cells in convoluted seminiferous tubules and Leydig cells to a similar extent. These results suggest that nuclear protein import may be controlled in a tissue-specific manner by alpha-subunit family proteins.

The phenol red thread tear test: a cross-cultural study.

PURPOSE: To examine the results of the phenol red thread tear test in a cross-cultural comparison. METHODS: Two groups of 500 controlled normal subjects who do not wear contact lenses from the United States and Japan were investigated. RESULTS: The mean wet length of the thread for the United States was 23.9 mm (SD 9.5 mm). The mean for Japan was 18.8 mm (SD 8.6 mm). There was a significant difference between the two countries (P < 0.05). Males subjects had significantly longer wet lengths than females for both countries (P < 0.05). There was a moderate correlation between right and left eye results for both countries. CONCLUSIONS: The phenol red thread tear test was found to be easy to administer. Results were in line with current knowledge and theories of the lacrimal system. Results also indicated that this test may disclose subtle differences not previously found with other tear tests.

Poor compensatory function for sleep loss as a pathogenic factor in patients with delayed sleep phase syndrome.

OBJECTIVE: Delayed sleep phase syndrome (DSPS) is a condition in which the patient is unable to reset or phase-advance his/her sleep timing properly after transient sleep delay and consequently shows persistent sleep phase delay. Prior studies suggested that DSPS is associated with a phase delay in the circadian pacemaker, but there was no evidence to explain the patient's inability to reset sleep phase. SUBJECTS AND METHODS: We used an ultra-short sleep-wake schedule together with simultaneous measurement of dim light melatonin rhythm after 24-hour sleep deprivation to allow the differential observation of diurnal sleep propensity fluctuation both from circadian and homeostatic aspects in 11 patients with DSPS (17-37 years; 8 men, 3 women) and 15 healthy controls (19-32 years; 8 men, 7 women). SETTING: NA. PATIENTS OR PARTICIPANTS: NA. INTERVENTIONS: NA. RESULTS: DSPS patients showed less ability to compensate for previous sleep loss during their circadian day and first hours of their circadian nighttime determined by dim light melatonin onset compared with controls, while controls compensated for previous sleep loss at most circadian times. Though shapes of dim light melatonin rhythm did not differ between the groups, phase angle between melatonin and sleep propensity rhythms was wider in DSPS patients than in controls. CONCLUSIONS: These findings suggest that poor compensatory function for sleep loss predisposes DSPS patients to failure to reset their sleep phase. Our results provide implications for understanding not only the pathophysiology of DSPS but also the biological basis for why some people can change their sleep schedule easily according to personal or social demands while others cannot.

Immunosuppression by anti-ICAM-1 and anti-LFA-1 monoclonal antibodies of free and vascularized skin allograft rejection.

Immunosuppression by anti-adhesion molecule antibody of free or vascularized skin allograft rejection was investigated in rats. Lewis (LEW, RT11) rats were used as donors and Fisher (F344, RT11v1) rats as the recipients. When F344 rats were treated intraperitoneally (i.p.) with anti-intercellular adhesion molecule-1 (ICAM-1) mAb (1A29) (3 mg/kg/day) and anti-leukocyte function-associated antigen-1 (LFA-1) mAb (WT.1) (3 mg/kg/day) one day prior to grafting and daily after grafting for nine days, free skin graft survival was prolonged only slightly compared with that in control rats which were injected i.p. with a daily dose of 6 mg/kg of anti-TNP mAbs (H1-6-2) one day prior to grafting and daily after grafting for nine days. (Mean survival time [MST] of the free skin graft was 11.2 +/- 0.6 days in the control group and 13.4 +/- 0.3 days in the 1A29 + WT-1 treated group [p < 0.01], respectively.) On the other hand, the vascularized graft survival was prolonged significantly in anti-ICAM-1/LFA-1 mAbs-treated F344 rats as compared with that in control rats. (The mean vascularized graft survival time was 14.2 +/- 0.7 days in the control group and 21.5 +/- 1.9 days in 1A29 + WT-1 treated group [p < 0.002]). Our results suggest that interaction with ICAM-1 and LFA-1 is more important in the rejection of vascularized skin allografts than that of free skin allografts.

Infrared angiography of the anterior ocular segment.

We performed angiography with indocyanine green (ICG) and fluorescein using a scanning laser ophthalmoscope (SLO) in the anterior segments of seven normal and 35 diseased eyes. ICG angiography revealed the radical stromal vessels and minor arterial circle in brown irides, which were not detected by fluorescein angiography. High penetration of infrared fluorescence through the pigmented tissue and absence of extravasation of ICG facilitated demonstration of the fine structure of iris rubeosis and its origins from stromal vessels. In 11 diabetic eyes, the iris rubeosis showed three basic patterns of location: along the pupillary margin; originating from the iris root; and arising from stromal radial vessels near the collarette. ICG gonioangiography with SLO showed fine structure of angle rubeosis because of its high resolution and greater depth in focus. Rubeotic vessels in the chamber angle were perfused by neovascular trunks which arose from the iris root in all 12 rubeotic eyes. Rubeosis in the iris and the angle consistently showed no extravasation of the ICG dye, while fluorescein quickly leaked out. ICG angiography with SLO in the anterior ocular segment proved to be a useful means to study the structure and the hemodynamics of normal and newly formed vessels.