Activation of Lactate Receptor Positively Regulates Skeletal Muscle Mass in Mice.

G protein-coupled receptor 81 (GPR81), a selective receptor for lactate, expresses in skeletal muscle cells, but the physiological role of GPR81 in skeletal muscle has not been fully elucidated. As it has been reported that the lactate administration induces muscle hypertrophy, the stimulation of GPR81 has been suggested to mediate muscle hypertrophy. To clarify the contribution of GPR81 activation in skeletal muscle hypertrophy, in the present study, we investigated the effect of GPR81 agonist administration on skeletal muscle mass in mice. Male C57BL/6J mice were randomly divided into control group and GPR81 agonist-administered group that received oral administration of the specific GPR81 agonist 3-Chloro-5-hydroxybenzoic acid (CHBA). In both fast-twitch plantaris and slow-twitch soleus muscles of mice, the protein expression of GPR81 was observed. Oral administration of CHBA to mice significantly increased absolute muscle weight and muscle weight relative to body weight in the two muscles. Moreover, both absolute and relative muscle protein content in the two muscles were significantly increased by CHBA administration. CHBA administration also significantly upregulated the phosphorylation level of p42/44 extracellular signal-regulated kinase-1/2 (ERK1/2) and p90 ribosomal S6 kinase (p90RSK). These observations suggest that activation of GRP81 stimulates increased the mass of two types of skeletal muscle in mice in vivo. Lactate receptor GPR81 may positively affect skeletal muscle mass through activation of ERK pathway.

Alzheimer PHF-tau aggregates do not spread tau pathology to the brain via the Retino-tectal projection after intraocular injection in male mouse models.

Neurofibrillary tangles (NFT), a neuronal lesion found in Alzheimer's disease (AD), are composed of fibrillary aggregates of modified forms of tau proteins. The propagation of NFT follows neuroanatomical pathways suggesting that synaptically connected neurons could transmit tau pathology by the recruitment of normal tau in a prion-like manner. Moreover, the intracerebral injection of pathological tau from AD brains induces the seeding of normal tau in mouse brain. Creutzfeldt-Jacob disease has been transmitted after ocular transplants of cornea or sclera and the scrapie agent can spread across the retino-tectal pathway after intraocular injection of scrapie mouse brain homogenates. In AD, a tau pathology has been detected in the retina. To investigate the potential risk of tau pathology transmission during eye surgery using AD tissue material, we have analysed the development of tau pathology in the visual pathway of mice models expressing murine tau, wild-type or mutant human tau after intraocular injection of pathological tau proteins from AD brains. Although these pathological tau proteins were internalized in retinal ganglion cells, they did not induce aggregation of endogenous tau nor propagation of a tau pathology in the retino-tectal pathway after a 6-month incubation period. These results suggest that retinal ganglion cells exhibit a resistance to develop a tau pathology, and that eye surgery is not a major iatrogenic risk of transmission of tau pathology, contrary to what has been observed for transmission of infectious prions in prion diseases.

A systematic review of patient-reported outcome measures used to assess sleep in postpartum women using Consensus Based Standards for the Selection of Health Measurement Instruments (COSMIN) guidelines.

STUDY OBJECTIVES: We performed a systematic review to identify the best patient-reported outcome measure (PROM) of postpartum sleep in women. METHODS: We searched four databases for validated PROMs used to assess postpartum sleep. Studies were considered if they evaluated at least one psychometric measurement property of a PROM. An overall performance rating was assigned for each psychometric measurement property of each PROM based upon COSMIN criteria. A modified GRADE approach was used to assess the level of evidence and recommendations were then made for each PROM. RESULTS: We identified 15 validation studies of eight PROMs, in 9,070 postpartum women. An adequate number of sleep domains was assessed by five PROMs: Bergen Insomnia Scale (BIS), Pittsburgh Sleep Quality Index (PSQI), General Sleep Disturbance Scale (GSDS), Athens Insomnia Scale (AIS), and the Sleep Symptom Checklist (SSC). BIS and GSDS were the only PROMs to demonstrate adequate content validity and at least a low level of evidence of sufficient internal consistency, resulting in Class A recommendations. The BIS was the only PROM, which is easily accessible and free to use for noncommercial research, that achieved a Class A recommendation. CONCLUSION: The BIS is the best currently available PROM of postpartum sleep. However, this PROM fails to assess several important domains such as sleep duration (and efficiency), chronotype, sleep-disordered breathing and medication usage. Future studies should focus on evaluating the psychometric measurement properties of BIS in the North American setting and in different cultural groups, or to develop a more specific PROM of postpartum sleep.

Determinants of women's dissatisfaction with anaesthesia care in labour and delivery.

Patient-centred care and factors associated with patient satisfaction with anaesthesia have been widely studied. However, the most important considerations in the setting of obstetric anaesthesia are uncertain. Identification of, and addressing, factors that contribute to patient dissatisfaction may improve quality of care. We sought to identify factors associated with < 100% satisfaction with obstetric anaesthesia care. At total of 4297 women treated by anaesthetists provided satisfaction data 24 h after vaginal and 48 h after caesarean delivery. As 78% of women were 100% satisfied, we studied factors associated with the dichotomous variable, 100% satisfied vs. < 100% satisfied. We evaluated patient characteristics and peripartum factors using multivariable sequential logistic regression. The following factors were strongly associated with maternal dissatisfaction after vaginal delivery: pain intensity during the first stage of labour; pain intensity during the second stage of labour; postpartum pain intensity; delay > 15 min in providing epidural analgesia and postpartum headache (all p < 0.0001). Pruritus (p = 0.005) also contributed to dissatisfaction after vaginal delivery, whereas non-Hispanic ethnicity was negatively associated with dissatisfaction (p = 0.01). After caesarean delivery, the intensity of postpartum pain (p < 0.0001), headache (p = 0.001) and pruritus (p = 0.001) were linked to dissatisfaction. Hispanic ethnicity also had a negative relationship with dissatisfaction after caesarean delivery (p = 0.005). Thus, inadequate or delayed analgesia and treatment-related side-effects are associated with maternal dissatisfaction with obstetric anaesthesia care. Development of protocols to facilitate identification of ineffective analgesia and provide an appropriate balance between efficacy and side-effects, are important goals to optimise maternal satisfaction.

Bendamustine-120 plus rituximab therapy for relapsed or refractory follicular lymphoma: a multicenter phase II study.

The optimal dose, schedule, and other aspects of bendamustine plus rituximab treatment remain unclear for patients with relapsed or refractory follicular lymphoma (FL). Herein, we analyzed the efficacy of bendamustine combined with rituximab (RB-120) treatment for Japanese patients with relapsed or refractory FL. This phase II clinical trial included patients with relapsed or refractory FL who received 375 mg/m2 rituximab on day 1 and 120 mg/m2 bendamustine on days 2 and 3 every 28 days for up to 6 cycles. The primary endpoint was the overall response rate (ORR), and the secondary endpoints included the complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and safety. Thirty-seven patients were enrolled in the trial (median age 62 years, range 42-75 years). All patients were previously treated with rituximab-containing chemotherapy, and 83.8% were previously treated with the R-CHOP regimen. A median of 5 cycles (range 1-6) and 48.6% of patients completed 6 cycles. The ORR was 91.9% (95% confidence interval [CI] 78.1-98.3%), with a CR rate of 86.5% (95% CI 71.2-95.5%). The 3-year PFS and OS were 70.9% (95% CI 52.3-83.3%) and 88.9% (95% CI 73.1-95.7%), respectively, with the median 39.5 months follow-up duration. The most-frequently observed grade 3/4 adverse events were hematologic: lymphopenia (95%) and neutropenia (70%). No treatment-related deaths were observed. RB-120 showed a good efficacy with equivalent toxicities, compared with the bendamustine 120 mg/m2 monotherapy. However, the problem of high drop-out incidences cannot be ignored.

Systemic Immunologic Consequences of Chronic Periodontitis.

Chronic periodontitis (ChP) is a prevalent inflammatory disease affecting 46% of the US population. ChP produces a profound local inflammatory response to dysbiotic oral microbiota that leads to destruction of alveolar bone and tooth loss. ChP is also associated with systemic illnesses, including cardiovascular diseases, malignancies, and adverse pregnancy outcomes. However, the mechanisms underlying these adverse health outcomes are poorly understood. In this prospective cohort study, we used a highly multiplex mass cytometry immunoassay to perform an in-depth analysis of the systemic consequences of ChP in patients before (n = 28) and after (n = 16) periodontal treatment. A high-dimensional analysis of intracellular signaling networks revealed immune system-wide dysfunctions differentiating patients with ChP from healthy controls. Notably, we observed exaggerated proinflammatory responses to Porphyromonas gingivalis-derived lipopolysaccharide in circulating neutrophils and monocytes from patients with ChP. Simultaneously, natural killer cell responses to inflammatory cytokines were attenuated. Importantly, the immune alterations associated with ChP were no longer detectable 3 wk after periodontal treatment. Our findings demarcate systemic and cell-specific immune dysfunctions in patients with ChP, which can be temporarily reversed by the local treatment of ChP. Future studies in larger cohorts are needed to test the boundaries of generalizability of our results.

Loss of p300 accelerates MDS-associated leukemogenesis.

The role that changes in DNA methylation and histone modifications have in human malignancies is poorly understood. p300 and CREB-binding protein (CBP), two distinct but highly homologous lysine acetyltransferases, are mutated in several cancers, suggesting their role as tumor suppressors. In the current study, we found that deletion of p300, but not CBP, markedly accelerated the leukemogenesis ofNup98-HoxD13 (NHD13) transgenic mice, an animal model that phenotypically copies human myelodysplastic syndrome (MDS). p300 deletion restored the ability of NHD13 expressing hematopoietic stem and progenitor cells (HSPCs) to self-renew in vitro, and to expand in vivo, with an increase in stem cell symmetric self-renewal divisions and a decrease in apoptosis. Furthermore, loss of p300, but not CBP, promoted cytokine signaling, including enhanced activation of the MAPK and JAK/STAT pathways in the HSPC compartment. Altogether, our data indicate that p300 has a pivotal role in blocking the transformation of MDS to acute myeloid leukemia, a role distinct from that of CBP.

Modifications of the endosomal compartment in peripheral blood mononuclear cells and fibroblasts from Alzheimer's disease patients.

Identification of blood-based biomarkers of Alzheimer's disease (AD) remains a challenge. Neuropathological studies have identified enlarged endosomes in post-mortem brains as the earliest cellular change associated to AD. Here the presence of enlarged endosomes was investigated in peripheral blood mononuclear cells from 48 biologically defined AD patients (25 with mild cognitive impairment and 23 with dementia (AD-D)), and 23 age-matched healthy controls using immunocytochemistry and confocal microscopy. The volume and number of endosomes were not significantly different between AD and controls. However, the percentage of cells containing enlarged endosomes was significantly higher in the AD-D group as compared with controls. Furthermore, endosomal volumes significantly correlated to [C(11)]PiB cortical index measured by positron emission tomography in the AD group, independently of the APOE genotype, but not to the levels of amyloid-beta, tau and phosphorylated tau measured in the cerebrospinal fluid. Importantly, we confirmed the presence of enlarged endosomes in fibroblasts from six unrelated AD-D patients as compared with five cognitively normal controls. This study is the first, to our knowledge, to report morphological alterations of the endosomal compartment in peripheral cells from AD patients correlated to amyloid load that will now be evaluated as a possible biomarker.

Long-distance propagation of a surface plasmon on the surface of a ferromagnetic metal.

A method for the reduction of the propagation loss of surface plasmons was proposed and experimentally demonstrated. A plasmonic structure, which contains a metal and two dielectric layers of different refractive indexes, is proposed in order to optimize the optical confinement and to reduce the propagation loss of the surface plasmons. Long-distance propagation of a surface plasmon on the surface of a ferromagnetic metal was demonstrated. A low propagation loss of 0.17 dB/µm for a surface plasmon in a Fe/MgO/AlGaAs plasmonic structure was achieved.

Voxel-based morphometry of the marmoset brain: In vivo detection of volume loss in the substantia nigra of the MPTP-treated Parkinson's disease model.

Movement dysfunction in Parkinson's disease (PD) is caused by the degeneration of dopaminergic (DA) neurons in the substantia nigra (SN). Here, we established a method for voxel-based morphometry (VBM) and automatic tissue segmentation of the marmoset monkey brain using a 7-T animal scanner and applied the method to assess DA degeneration in a PD model, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated animals, with tyrosine-hydroxylase staining. The most significant decreases of local tissue volume were detected in the bilateral SN of MPTP-treated marmoset brains (-53.0% in right and -46.5% in left) and corresponded with the location of DA neurodegeneration found in histology (-65.4% in right). In addition to the SN, the decreases were also confirmed in the locus coeruleus, and lateral hypothalamus. VBM using 7-T MRI was effective in detecting volume loss in the SN of the PD-model marmoset. This study provides a potential basis for the application of VBM with ultra-high field MRI in the clinical diagnosis of PD. The developed method may also offer value in automatic whole-brain evaluation of structural changes for the marmoset monkey.

Water's tensile strength measured using an optofluidic chip.

In this paper, for the first time, the tensile strength of water is directly measured using an optofluidic chip based on the displacement of air-water interface deformation with homogeneous nucleation. When water in a microchannel is stretched dynamically via laser-induced shock reflection at the air-water interface, the shock pressures are determined by measuring the displacements of the deformed interface. Observation of the vapor bubbles is used as a probe to identify the cavitation threshold with a critical distance, and the tensile strength of water at 20 °C is measured to be -33.3 ± 2.8 MPa. This method can be extended to investigate the tensile strength of other soft materials such as glycerol, which is measured to be -59.8 ± 10.7 MPa at 20 °C.

Droplet generation via a single bubble transformation in a nanofluidic channel.

Here we report the first demonstration on droplet generation from the transformation of a single bubble in a nanofluidic channel by a laser-induced jet. A viscous two-dimensional Rayleigh-Plesset-type model is derived to describe the bubble dynamics in the nanofluidic channel, which accounts for the effect of shear stresses from the channel wall. The droplet generation (number and volume) is investigated experimentally by controlling the jet velocity via laser energy and distance. This study expands the understanding of jetting in the nanofluidic channel and demonstrates a novel method for femtoliter-volume single or multiple droplet formation. It is envisioned that this work will open new doors in on-demand generation of nanodroplets.

Characteristic patterns of relapse after allogeneic hematopoietic SCT for adult T-cell leukemia-lymphoma: a comparative study of recurrent lesions after transplantation and chemotherapy by the Nagasaki Transplant Group.

Allogeneic hematopoietic SCT (allo-SCT) is a promising therapy that may provide long-term durable remission for adult T-cell leukemia-lymphoma (ATL) patients; however, the incidence of relapse associated with ATL remains high. To determine the clinical features of these patients at relapse, we retrospectively analyzed tumor lesions in 30 or 49 patients who relapsed following allo-SCT or chemotherapy (CHT), respectively, at three institutions in Nagasaki prefecture between 1997 and 2011. A multivariate analysis revealed that the development of abnormal lymphocytes in the peripheral blood of patients at relapse was less frequent after allo-SCT than after CHT (P<0.001). Furthermore, relapse with a new lesion only in the absence of the primary lesion was more frequent in allo-SCT (P=0.014). Lesions were more frequently observed in the central nervous systems of patients who relapsed with new lesions only (P=0.005). Thus, the clinical manifestation of relapsed ATL was slightly complex, especially in post-transplant patients. Our results emphasized the need to develop adoptive modalities for early and accurate diagnoses of relapsed ATL.

Acute leukemia during pregnancy: an investigative survey of the past 11 years.

INTRODUCTION: The management of pregnant women with acute leukemia is usually challenging. We collected data concerning pregnant women with acute leukemia in the Kanagawa area in Japan. METHODS: A questionnaire was sent to 24 institutions in the Kanagawa area. RESULTS: Data were obtained for 11 patients, median age of 31 years (range, 20-36). Eight patients had acute myeloid leukemia and three had acute lymphoblastic leukemia. Six patients were diagnosed in the first trimester of pregnancy, one in the second trimester, and four in the third trimester. Five of six patients diagnosed in the first trimester had abortions before chemotherapy, and one had an elective abortion after receiving chemotherapy. All patients diagnosed in the second or third trimester delivered live infants. Of the six patients diagnosed in the first trimester, two died of recurrent leukemia, and four remained in remission. Of the five patients diagnosed in the second or third trimester, four achieved complete remission and remained in remission. One patient died of sepsis 4 days after cesarean section. CONCLUSIONS: Careful surveillance and monitoring of the fetus and close co-operation among hematologists, gynecologists, and pediatricians are essential to successfully treat pregnant women with acute leukemia.

Increased Salt Sensitivity in Obese Hypertension:Role of the Sympathetic Nervous System.

Salt sensitivity of blood pressure (BP) is increased in hypertension associated with obesity and/or metabolic disorders. Reversely, patients with salt-sensitive hypertension often reveal metabolic disorders. Thus, salt excess and overeating, which are major bad dietary habits in civilized men and women, strengthen the effect to increase BP each other. Actually, there are similar pathophysiological characteristics between hypertension induced by high salt intake and obesity: the sympathetic excitation has been suggested to contribute to increase in BP of the two types of hypertension. Also, several investigators indicated that reactive oxygen species (ROS) production is increased in important organs of salt-sensitive and/or obese hypertension. Recently, we demonstrated that, in salt- and obesity-induced hypertension, hypothalamic ROS levels was elevated and intracerebroventricular antioxidants suppress BP and renal sympathetic nerve activity more profoundly, compared to their control. Thus, it is suggested that brain ROS overproduction increases BP through central symapthoexcitation in salt- and obesity-induced hypertension, which are often associated.

Expression of myeloperoxidase in acute myeloid leukemia blasts mirrors the distinct DNA methylation pattern involving the downregulation of DNA methyltransferase DNMT3B.

Myeloperoxidase (MPO) has been associated with both a myeloid lineage commitment and favorable prognosis in patients with acute myeloid leukemia (AML). DNA methyltransferase inhibitors (decitabine and zeburaline) induced MPO gene promoter demethylation and MPO gene transcription in AML cells with low MPO activity. Therefore, MPO gene transcription was directly and indirectly regulated by DNA methylation. A DNA methylation microarray subsequently revealed a distinct methylation pattern in 33 genes, including DNA methyltransferase 3 beta (DNMT3B), in CD34-positive cells obtained from AML patients with a high percentage of MPO-positive blasts. Based on the inverse relationship between the methylation status of DNMT3B and MPO, we found an inverse relationship between DNMT3B and MPO transcription levels in CD34-positive AML cells (P=0.0283). In addition, a distinct methylation pattern was observed in five genes related to myeloid differentiation or therapeutic sensitivity in CD34-positive cells from AML patients with a high percentage of MPO-positive blasts. Taken together, the results of the present study indicate that MPO may serve as an informative marker for identifying a distinct and crucial DNA methylation profile in CD34-positive AML cells.

RUNX3 interacts with MYCN and facilitates protein degradation in neuroblastoma.

RUNX3, a runt-related transcription factor, has a crucial role in dorsal root ganglion neurogenesis. Recent studies have suggested that RUNX3 acts as a tumor suppressor in stomach, colon and breast cancer. However, the biological role of RUNX3 in neuroblastoma remains elusive. Here we report that high levels of RUNX3 expression contribute to the favorable outcome in patients with neuroblastoma, whereas low levels of RUNX3 expression result in poor outcome. Array-based analysis suggested that the allelic loss at chromosome 1p36 is one of the reasons why expression of RUNX3 is downregulated in advanced neuroblastomas. Interestingly, the several patients survived from neuroblastoma with both high mRNA expressions of MYCN and RUNX3, suggesting that RUNX3 high expression might overcome the aggressive behavior of MYCN. Exogenous expression of RUNX3 strongly inhibits cell proliferation and migration in neuroblastoma cell lines. Furthermore, RUNX3 reduces the stability of MYCN protein in MYCN-amplified neuroblastoma cell lines, and this RUNX3-mediated MYCN degradation may depend on the physical interaction between RUNX3 and MYCN. Thus, our findings provide a tumor-suppressing mechanism by which RUNX3 inhibits the MYCN activity in neuroblastoma.

Highly sensitive nanoscale spin-torque diode.

Highly sensitive microwave devices that are operational at room temperature are important for high-speed multiplex telecommunications. Quantum devices such as superconducting bolometers possess high performance but work only at low temperature. On the other hand, semiconductor devices, although enabling high-speed operation at room temperature, have poor signal-to-noise ratios. In this regard, the demonstration of a diode based on spin-torque-induced ferromagnetic resonance between nanomagnets represented a promising development, even though the rectification output was too small for applications (1.4 mV mW(-1)). Here we show that by applying d.c. bias currents to nanomagnets while precisely controlling their magnetization-potential profiles, a much greater radiofrequency detection sensitivity of 12,000 mV mW(-1) is achievable at room temperature, exceeding that of semiconductor diode detectors (3,800 mV mW(-1)). Theoretical analysis reveals essential roles for nonlinear ferromagnetic resonance, which enhances the signal-to-noise ratio even at room temperature as the size of the magnets decreases.