A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder.

Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10-9), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (Pbest=5.8 × 10-10), and supported three regions previously implicated in BD susceptibility: MAD1L1 (Pbest=1.9 × 10-9), TRANK1 (Pbest=2.1 × 10-9) and ODZ4 (Pbest=3.3 × 10-9). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for 'within Japanese comparisons', Pbest~10-29, R2~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for 'trans-European-Japanese comparison,' Pbest~10-13, R2~0.27%). This 'trans population' effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD 'risk' effect are shared between Japanese and European populations.

Utility of a Multiparametric Quantitative MRI Model That Assesses Myelin and Edema for Evaluating Plaques, Periplaque White Matter, and Normal-Appearing White Matter in Patients with Multiple Sclerosis: A Feasibility Study.

BACKGROUND AND PURPOSE: T1 and T2 values and proton density can now be quantified on the basis of a single MR acquisition. The myelin and edema in a voxel can also be estimated from these values. The purpose of this study was to evaluate a multiparametric quantitative MR imaging model that assesses myelin and edema for characterizing plaques, periplaque white matter, and normal-appearing white matter in patients with MS. MATERIALS AND METHODS: We examined 3T quantitative MR imaging data from 21 patients with MS. The myelin partial volume, excess parenchymal water partial volume, the inverse of T1 and transverse T2 relaxation times (R1, R2), and proton density were compared among plaques, periplaque white matter, and normal-appearing white matter. RESULTS: All metrics differed significantly across the 3 groups (P < .001). Those in plaques differed most from those in normal-appearing white matter. The percentage changes of the metrics in plaques and periplaque white matter relative to normal-appearing white matter were significantly more different from zero for myelin partial volume (mean, -61.59 ± 20.28% [plaque relative to normal-appearing white matter], and mean, -10.51 ± 11.41% [periplaque white matter relative to normal-appearing white matter]), and excess parenchymal water partial volume (13.82 × 103 ± 49.47 × 103% and 51.33 × 102 ± 155.31 × 102%) than for R1 (-35.23 ± 13.93% and -6.08 ± 8.66%), R2 (-21.06 ± 11.39% and -4.79 ± 6.79%), and proton density (23.37 ± 10.30% and 3.37 ± 4.24%). CONCLUSIONS: Multiparametric quantitative MR imaging captures white matter damage in MS. Myelin partial volume and excess parenchymal water partial volume are more sensitive to the MS disease process than R1, R2, and proton density.

Synthetic MRI in the Detection of Multiple Sclerosis Plaques.

BACKGROUND AND PURPOSE: Synthetic MR imaging enables the creation of various contrast-weighted images including double inversion recovery and phase-sensitive inversion recovery from a single MR imaging quantification scan. Here, we assessed whether synthetic MR imaging is suitable for detecting MS plaques. MATERIALS AND METHODS: Quantitative and conventional MR imaging data on 12 patients with MS were retrospectively analyzed. Synthetic T2-weighted, FLAIR, double inversion recovery, and phase-sensitive inversion recovery images were produced after quantification of T1 and T2 values and proton density. Double inversion recovery images were optimized for each patient by adjusting the TI. The number of visible plaques was determined by a radiologist for a set of these 4 types of synthetic MR images and a set of conventional T1-weighted inversion recovery, T2-weighted, and FLAIR images. Conventional 3D double inversion recovery and other available images were used as the criterion standard. The total acquisition time of synthetic MR imaging was 7 minutes 12 seconds and that of conventional MR imaging was 6 minutes 29 seconds The lesion-to-WM contrast and lesion-to-WM contrast-to-noise ratio were calculated and compared between synthetic and conventional double inversion recovery images. RESULTS: The total plaques detected by synthetic and conventional MR images were 157 and 139, respectively (P = .014). The lesion-to-WM contrast and contrast-to-noise ratio on synthetic double inversion recovery images were superior to those on conventional double inversion recovery images (P = .001 and < 0.001, respectively). CONCLUSIONS: Synthetic MR imaging enabled detection of more MS plaques than conventional MR imaging in a comparable acquisition time. The contrast for MS plaques on synthetic double inversion recovery images was better than on conventional double inversion recovery images.

A miRNA signature suggestive of nodal metastases from laryngeal carcinoma.

The discovery that miRNAs are frequently deregulated in tumours offers the opportunity to identify them as prognostic and diagnostic markers. The aim of this multicentric study is to identify a miRNA expression profile specific for laryngeal cancer. The secondary endpoint was to identify specific deregulated miRNAs with potential as prognostic biomarkers for tumour spread and nodal involvement, and specifically to search for a miRNA pattern pathognomonic for N+ laryngeal cancer and for N- tissues. We identified 20 miRNAs specific for laryngeal cancer and a tissue-specific miRNA signature that is predictive of lymph node metastases in laryngeal carcinoma characterised by 11 miRNAs, seven of which are overexpressed (upregulated) and four downregulated. These results allow the identification of a group of potential specific tumour biomarkers for laryngeal carcinoma that can be used to improve its diagnosis, particularly in early stages, as well as its prognosis.

High molecular weight organic compounds (HMW-OCs) in severe winter haze: Direct observation and insights on the formation mechanism.

High molecular weight organic compounds (HMW-OCs), formed as secondary organic aerosols (SOA), have been reported in many laboratory studies. However, little evidence of HMW-OCs formation, in particular during winter season in the real atmosphere, has been reported. In January 2013, Beijing faced historically severe haze pollution, in which the hourly PM2.5 concentration reached as high as 974 µg m-3. Four typical haze events (HE1 to HE4) were identified, and HE2 (Jan. 9-16) was the most serious of these. Based on the hourly observed chemical composition of PM2.5 and the daily organic composition analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), we found that abundant ion peaks in m/z 200-850 appeared on heavy haze days, whereas these were negligible on a clear day, indicating the existence of HMW-OCs in the wintertime haze. A negative nonlinear correlation between HMW-OCs and O3 suggested that gas oxidation was not likely to be the dominant mechanism for HMW-OCs formation. During the heavy haze events, the relative humidity and mass ratio of H2O/PM2.5 reached as high as 80% and 0.2, respectively. The high water content and its good positive correlation with HMW-OCs indicated that an aqueous-phase process may be a significant pathway in wintertime. The evidence that acidity was much higher during HE2 (0.37 µg m-3) than on other days, as well as its strong correlation with HMW-OCs, indicated that acid-catalyzed reactions likely resulted in HMW-OCs formation during the heavy winter haze in Beijing.

Cuticular protein and transcription factor genes expressed during prepupal-pupal transition and by ecdysone pulse treatment in wing discs of Bombyx mori.

We aimed to understand the underlying mechanism that regulates successively expressed cuticular protein (CP) genes around pupation in Bombyx mori. Quantitative PCR was conducted to clarify the expression profile of CP genes and ecdysone-responsive transcription factor (ERTF) genes around pupation. Ecdysone pulse treatment was also conducted to compare the developmental profiles and the ecdysone induction of the CP and ERTF genes. Fifty-two CP genes (RR-1 13, RR-2 18, CPG 8, CPT 3, CPFL 2, CPH 8) in wing discs of B. mori were examined. Different expression profiles were found, which suggests the existence of a mechanism that regulates CP genes. We divided the genes into five groups according to their peak stages of expression. RR-2 genes were expressed until the day of pupation and RR-1 genes were expressed before and after pupation and for longer than RR-2 genes; this suggests different construction of exo- and endocuticular layers. CPG, CPT, CPFL and CPH genes were expressed before and after pupation, which implies their involvement in both cuticular layers. Expression profiles of ERTFs corresponded with previous reports. Ecdysone pulse treatment showed that the induction of CP and ERTF genes in vitro reflected developmental expression, from which we speculated that ERTFs regulate CP gene expression around pupation.

Practices for Supporting and Confirming Decision-Making Involved in Kidney and Liver Donation by Related Living Donors in Japan: A Nationwide Survey.

This nationwide survey investigated the actual practices for supporting and confirming the decision-making involved in related living-organ donations in Japan, focusing on organ type and program size differences. Answers to a questionnaire survey were collected from 89 of the 126 (71%) kidney and 30 of the 35 (86%) liver transplantation programs in Japan that were involved in living-donor transplantations in 2013. In 70% of the kidney and 90% of the liver transplantation programs, all donors underwent "third-party" interviews to confirm their voluntariness. The most common third parties were psychiatrists (90% and 83%, respectively). Many programs engaged in practices to support decision-making by donor candidates, including guaranteeing the right to withdraw consent to donate (70% and 100%, respectively) and prescribing a set "cooling-off period" (88% and 100%, respectively). Most donors were offered care by mental health specialists (86% and 93%, respectively). Third parties were designated by more of the larger kidney transplant programs compared with the smaller programs. In conclusion, the actual practices supporting and confirming the decision to donate a living organ varied depending on the organ concerned and the number of patients in the program.

High-gamma band fronto-temporal coherence as a measure of functional connectivity in speech motor control.

The neural basis of human speech is unclear. Intracranial electrophysiological recordings have revealed that high-gamma band oscillations (70-150Hz) are observed in the frontal lobe during speech production and in the temporal lobe during speech perception. Here, we tested the hypothesis that the frontal and temporal brain regions had high-gamma coherence during speech. We recorded electrocorticography (ECoG) from the frontal and temporal cortices of five humans who underwent surgery for medically intractable epilepsy, and studied coherence between the frontal and temporal cortex during vocalization and playback of vocalization. We report two novel results. First, we observed high-gamma band as well as theta (4-8Hz) coherence between frontal and temporal lobes. Second, both high-gamma and theta coherence were stronger when subjects were actively vocalizing as compared to playback of the same vocalizations. These findings provide evidence that coupling between sensory-motor networks measured by high-gamma coherence plays a key role in feedback-based monitoring and control of vocal output for human vocalization.

Weekly chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide followed by surgery for thymic carcinoma.

OBJECTIVE: We present our experience treating the patients with thymic carcinoma using induction chemotherapy according to weekly chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide (CODE) followed by surgery. PATIENTS AND METHODS: From January 2001 to December 2010, 17 patients were diagnosed as having thymic carcinoma at our hospital. We performed CODE chemotherapy for induction treatment followed by surgical resection in 7 of these patients. RESULTS: Seven patients consisted of 6 men and 1 woman, with an average age of 47.3 years (range 25-67 years). Five patients were clinically staged as Masaoka Stage III, and 2 were Stage IVa. A partial response was identified in 5 patients, and stable disease was observed in 2 patients. No cases of progressive disease were seen. Surgical resection was performed in all the patients: 6 underwent an R0 resection and 1 underwent an R1 resection. The estimated overall survival rates at 5 and 10 years were both 80%, and the relapse-free survival rates at 5 and 10 years were 68.6% and 53.6% respectively. CONCLUSIONS: Induction chemotherapy using the CODE regimen, followed by a complete surgical resection can be performed with a promising survival outcome for patients with thymic carcinoma with borderline resectable lesions.

A tryptophan metabolite, kynurenine, promotes mast cell activation through aryl hydrocarbon receptor.

BACKGROUND: Tryptophan metabolites have been suggested to play a role in immune modulation, wherein those have recently been shown to be endogenous ligands of aryl hydrocarbon receptor (AhR; a unique cellular chemical sensor). However, the involvement of tryptophan metabolites and AhR in modulating mast cell function remains to be fully defined. We therefore investigated that the functional impacts of tryptophan metabolites on human and mouse mast cell responses in vitro and their functional importance in vivo. METHODS: Three tryptophan metabolites, kynurenine (KYN), kynurenic acid (KA) and quinolinic acid (QA), were examined in terms of their effect on IgE-mediated responses in mouse bone marrow-derived mast cells (BMMCs) and in human peripheral blood-derived cultured mast cells (HCMCs) and on in vivo anaphylactic responses. For evaluation of AhR involvement, we examined the responses of mast cells from AhR-null or AhR-wild-type mice with the use of a known AhR antagonist, CH223191. RESULTS: Kynurenine, but not KA and QA, enhanced IgE-mediated responses, including degranulation, LTC4 release, and IL-13 production in BMMCs through the activation of PLCγ1, Akt, MAPK p38, and the increase of intracellular calcium. KYN also enhanced cutaneous anaphylaxis in vivo. These enhancing effects of KYN were not observed in AhR-deficient BMMCs and could be inhibited by CH223191 in BMMCs. Further, KYN had similar enhancing effects on HCMCs, which were inhibited by CH223191. CONCLUSION: The AhR-KYN axis is potentially important in modulating mast cell responses and represents an example of AhR's critical involvement in the regulation of allergic responses.

Concurrent chemotherapy inhibits herpes simplex virus-1 replication and oncolysis.

Herpes simplex virus-1 (HSV-1) replication in cancer cells leads to their destruction (viral oncolysis) and has been under investigation as an experimental cancer therapy in clinical trials as single agents, and as combinations with chemotherapy. Cellular responses to chemotherapy modulate viral replication, but these interactions are poorly understood. To investigate the effect of chemotherapy on HSV-1 oncolysis, viral replication in cells exposed to 5-fluorouracil (5-FU), irinotecan (CPT-11), methotrexate (MTX) or a cytokine (tumor necrosis factor-α (TNF-α)) was examined. Exposure of colon and pancreatic cancer cells to 5-FU, CPT-11 or MTX in vitro significantly antagonizes both HSV-1 replication and lytic oncolysis. Nuclear factor-κB (NF-κB) activation is required for efficient viral replication, and experimental inhibition of this response with an IκBα dominant-negative repressor significantly antagonizes HSV-1 replication. Nonetheless, cells exposed to 5-FU, CPT-11, TNF-α or HSV-1 activate NF-κB. Cells exposed to MTX do not activate NF-κB, suggesting a possible role for NF-κB inhibition in the decreased viral replication observed following exposure to MTX. The role of eukaryotic initiation factor 2α (eIF-2α) dephosphorylation was examined; HSV-1-mediated eIF-2α dephosphorylation proceeds normally in HT29 cells exposed to 5-FU, CPT-11 or MTX. This report demonstrates that cellular responses to chemotherapeutic agents provide an unfavorable environment for HSV-1-mediated oncolysis, and these observations are relevant to the design of both preclinical and clinical studies of HSV-1 oncolysis.

Functional connection between posterior superior temporal gyrus and ventrolateral prefrontal cortex in human.

The connection between auditory fields of the temporal lobe and prefrontal cortex has been well characterized in nonhuman primates. Little is known of temporofrontal connectivity in humans, however, due largely to the fact that invasive experimental approaches used so successfully to trace anatomical pathways in laboratory animals cannot be used in humans. Instead, we used a functional tract-tracing method in 12 neurosurgical patients with multicontact electrode arrays chronically implanted over the left (n = 7) or right (n = 5) perisylvian temporal auditory cortex (area PLST) and the ventrolateral prefrontal cortex (VLPFC) of the inferior frontal gyrus (IFG) for diagnosis and treatment of medically intractable epilepsy. Area PLST was identified by the distribution of average auditory-evoked potentials obtained in response to simple and complex sounds. The same sounds evoked little if there is any activity in VLPFC. A single bipolar electrical pulse (0.2 ms, charge-balanced) applied between contacts within physiologically identified PLST resulted in polyphasic evoked potentials clustered in VLPFC, with greatest activation being in pars triangularis of the IFG. The average peak latency of the earliest negative deflection of the evoked potential on VLPFC was 13.48 ms (range: 9.0-18.5 ms), providing evidence for a rapidly conducting pathway between area PLST and VLPFC.

Distinct developmental principles underlie the formation of ipsilateral and contralateral whisker-related axonal patterns of layer 2/3 neurons in the barrel cortex.

Axonal organizations with specific patterns underlie the functioning of local intracortical circuitry, but their precise anatomy and development still remain elusive. Here, we selectively visualized layer 2/3 neurons using in utero electroporation and examined their axonal organization in the barrel cortex contralateral to the electroporated side. We found that callosal axons run preferentially in septal regions of layer 4 and showed a whisker-related pattern in the contralateral barrel cortex in rats and mice. In addition, presynaptic marker proteins were found in this whisker-related axonal organization. Although the whisker-related patterns were observed in both the ipsilateral and contralateral barrel cortex, we found a difference in their developmental processes. While the formation of the whisker-related pattern in the ipsilateral cortex consisted of two distinct steps, that in the contralateral cortex did not have the 1st step, in which the axons were diffusely distributed without preference to septal or barrel regions. We also found that these more diffuse axons ran close to radial glial fibers. Together, our results uncovered a whisker-related axonal pattern of callosal axons and two independent developmental processes involved in the formation of the axonal trajectories of layer 2/3 neurons.

N,N-Dimethylformamide-stabilized gold nanoclusters as a catalyst for the reduction of 4-nitrophenol.

In this study, we investigated the catalytic properties of N,N-dimethylformamide (DMF)-stabilized gold nanoclusters (AuNCs) in the reduction of 4-nitrophenol (PNP) to 4-aminophenol by NaBH(4), a well known model reaction to be catalyzed by metal surfaces. The DMF-stabilized AuNCs were prepared in DMF by a surfactant-free method. The DMF-stabilized AuNCs showed high catalytic activity even when used in small quantities (∼10(-7) g). The pseudo-first-order rate constant (k(app)) and activation energy were estimated to be 3 × 10(-3) s(-1) and 31 kJ mol(-1), respectively, with 1.0 µM of the gold catalyst at 298 K. The catalytic activity of the DMF-stabilized AuNCs was strongly influenced by the layer of adsorbed DMF on the Au NCs. This layer of adsorbed DMF prohibited the reactants from penetrating to the surface of the AuNCs via the diffusion at the beginning of the reaction, resulting in an induction time (t(0)) before PNP reduction began. Restructuring of the DMF layer (essentially a form of activation) was the key to achieving high catalytic activity. In addition, atomically monodisperse Au(25)(SG)(18)NCs (SG: glutathione) showed higher catalytic activity in the PNP reduction (k(app) = 8 × 10(-3) s(-1)) even with a low catalyst concentration (1.0 µM), and there was no induction time (t(0)) in spite of the strongly binding ligand glutathione. This suggested that the catalytically active surface sites of the Au(25)(SG)(18)NCs were not sterically hindered, possibly because of the unique core-shell-like structure of the NCs. Retaining these open sites on AuNCs may be the key to making the NCs effective catalysts.

[Application of the lower partial sternotomy approach to patients who may need tracheostomy in the early period after cardiac surgery].

Recent good results of cardiovascular surgery have led to expansion of its indication to elderly patients and patients with serious complications. Such patients may have serious respiratory complications after cardiac surgery and need to undergo tracheostomy relatively early in the postoperative period. Although the full sternotomy approach is the standard in almost all cardiac surgeries, superficial and deep sternal infections are rather common after early tracheostomy in full sternotomy patients. The lower partial sternotomy approach is a safer and more useful procedure in patients who will need tracheostomy in the early period after cardiac surgery. We report on 2 patients who were successfully tracheostomized within a week after cardiac surgery, with a review of the literature.

Preliminary results of a study comparing conventional radiography with phase-contrast radiography for assessing root morphology of mandibular third molars.

OBJECTIVES: The aim of this study was to evaluate the usefulness of phase-contrast radiography for assessing root morphology of mandibular third molars in comparison with conventional radiography. METHODS: We studied 37 extracted mandibular third molars. One oral surgeon compared the number of roots and root curvature of the extracted teeth on conventional radiographs with those on phase-contrast images. RESULTS: The number of roots and root curvature on conventional images differed significantly from those on phase-contrast images. CONCLUSIONS: Our results suggest the possibility that phase-contrast radiography is more useful than conventional radiography for assessing the root morphology of mandibular third molars.

Paracrine control of mesenteric perivascular axo-axonal interaction.

Immunohistochemical study of rat mesenteric arteries showed dense innervation of adrenergic nerves, calcitonin gene-related peptide (CGRP)-containing nerves (CGRPergic nerves), nitric oxide-containing nerves (nitrergic nerves). Double-immunostaining revealed that most CGRPergic or nitrergic nerves were in close contact with adrenergic nerves. CGRPergic and transient receptor potential vanilloid-1 (TRPV1)-immunopositive nerves appeared in the same neurone. In rat perfused mesenteric vascular beds without endothelium and with active tone, perfusion of nicotine, or bolus injection of capsaicin and acetylcholine and periarterial nerve stimulation (PNS) lowered pH levels of out flowed perfusate concomitant with vasodilation. Cold-storage denervation of preparations abolished pH lowering induced by nicotine and PNS. Guanethidine inhibited PNS- and nicotine-, but not acetylcholine- and capsaicin-, induced pH lowering. Pharmacological analysis showed that protons were released not only from adrenergic nerves but also from CGRPergic nerves. A study using a fluorescent pH indicator demonstrated that nicotine, acetylcholine and capsaicin applied outside small mesenteric artery lowered perivascular pH levels, which were not observed in Ca(2+) free medium. Exogenously injected hydrochloric acid in denuded preparations induced pH lowering and vasodilation, which was inhibited by denervation, TRPV1 antagonists and capsaicin without affecting pH lowering. These results suggest that excitement of adrenergic nerves releases protons to activate TRPV1 in CGRPergic nerves and thereby induce vasodilation. It is also suggested that CGRPergic nerves release protons with exocytosis to facilitate neurotransmission via a positive feedback mechanism.