Attenuated relationship between salivary oxytocin levels and attention to social information in adolescents and adults with autism spectrum disorder: a comparative study.

BACKGROUND: Previous research studies have assessed the relationship between attention to social information and peripheral (e.g., plasma and salivary) oxytocin (OT) levels in typically developing (TD) children and children with autism spectrum disorder (ASD). A relationship between them was observed in TD children, but not in children with ASD. However, this relationship remains unexamined in other age groups. To clarify whether this lack of association is maintained throughout development in individuals with ASD, we aimed to assess the relationship between salivary OT levels and attention to social information in adolescents and adults with and without ASD. METHODS: We recruited male adolescents and adults with ASD (n = 17) and TD participants (n = 24). Using the all-in-one eye-tracking system Gazefinder, we measured the percentage fixation time allocated to social information. We also measured the salivary OT levels and Autism Spectrum Quotient (AQ) of participants. Subsequently, we confirmed group differences and conducted a correlation analysis to investigate the relationships between these three measures. RESULTS: Salivary OT levels did not show any significant difference between the ASD and TD groups and were negatively correlated with the AQ in the whole-group analysis, but not in within-group analysis. Individuals with ASD had significantly lower percentage fixation times than did TD individuals for eye regions in human faces with/without mouth motion, for upright biological motion, and for people regions in the people and geometry movies. The percentage of fixation for geometric shapes in the people and geometry movies was significantly higher in the ASD than in the TD group. In the TD group, salivary OT levels were positively correlated with percentage fixation times for upright biological motion and people and negatively correlated with inverted biological motion and geometry. However, no significant correlations were found in the ASD group. CONCLUSIONS: Our exploratory results suggest that salivary OT levels in adolescents and adults with ASD are less indicative of attention to social stimuli than they are in TD adolescents and adults. It is suggested that their association is slightly weaker in adolescents and adults with ASD and that this attenuated relationship appears to be maintained throughout development.

Local fungus-specific Immunoglobulin E production in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease, and its pathogenesis remains controversial. This study aimed to examine the involvement of fungi in CRSwNP pathogenesis. METHODS: We enrolled 29 controls and 111 CRSwNP patients. We analyzed fungi in the nasal secretions, serum fungus-specific immunoglobulin E (IgE) levels, and nasal polyp (NP) IgE levels. Moreover, we evaluated the correlation between patients' IgE levels and computed tomography (CT) scores. RESULTS: There was no difference in fungal detection rate between CRSwNP patients with and without asthma. Specific IgEs against various antigens were highly detectable in NPs of CRSwNP patients. In CRSwNP patients, fungus-specific IgE levels in NPs were correlated with CT scores. Serum fungus-specific IgEs became undetectable after operation in more than half of the CRSwNP patients without asthma but not in those with asthma. Other serum airborne antigen-specific IgEs did not become undetectable after operation. CONCLUSIONS: Fungus-specific IgEs were highly detectable in NPs of CRSwNP patients, and NPs comprised a major region of specific IgE production. Fungi may therefore play an important role in CRSwNP pathogenesis by inducing Th2 immune responses, including IgE synthesis.

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.

Reliability of ultrasonographic measurements of bovine sole structures in relation to sole horn thickness, measured by computed tomography, and sole horn hardness.

The goal of the present study was to determine the effect of sole horn thickness (SHT) and sole horn hardness (SHD) on ultrasonographic visualization of sole structures in the inner and outer claws of 150 Holstein-Friesian cows, and to evaluate different ultrasound frequencies for this purpose. Ultrasonographic views of the sole structure were considered complete when 3 echogenic lines, representing the ventral surface of the sole horn, the borders of the sole horn and soft-tissue layer, and the ventral surface of the distal phalanx, were seen. The proportion of complete ultrasonographic views of the sole structures, designated as the ultrasonographic visualization proportion (UVP), and the measurement errors of SHT were evaluated by comparing images from computed tomography (CT) and ultrasonography. The latter images were generated using 3 different probes, frequencies of 6.5 and 5.0 MHz, and 2 different ultrasound machines (#1 and #2) to assess the apex, middle, and heel regions of the claws. The UVP were 60.8 to 77.9% for the 6.5-MHz probe in ultrasound machine #1 (probe A), which were lower than those (>90%) for both the 5.0-MHz probe in ultrasound machine #1 (probe B) and the 5.0-MHz probe in ultrasound machine #2 (probe C). The UVP was significantly lower in claws with an SHD ≥50 units than in claws with an SHD <40 or 40 to <50 units (UVP: 77.1% compared with 93.7 and 91.4%, respectively) when measured with probe B. In claws with an SHT <10 mm, the UVP was significantly lower when SHD was ≥50 units compared with <40 or 40 to >50 units; the values were 69.0% versus 91.3 and 85.9%, respectively, for probe A, and 89.7% versus 100 and 100%, respectively, for probe B. When SHT were measured by either probes A or B in ultrasound machine #1, the proportions of claws in which ultrasonographic values were within a ±1 mm range compared with the values obtained by CT were 84.9 to 91.3% for CT-determined SHT <5 mm, 66.7 to 71.9% for CT-determined SHT 5 to <7 mm, 28.9 to 51.2% for CT-determined SHT 7 to <10 mm, and 6.2 to 19.7% for CT-determined SHT ≥10 mm. The data indicated that increased SHT was associated with a decrease in ultrasonographic measurement accuracy. In claws with an SHT <5 mm, the high proportion of ultrasonographic values that were accurate within a ±1 mm range suggests that this imaging modality would be useful in cows with thin soles.

Chiral Domain Structure in Superfluid

The existence of a spatially varying texture in superfluid ^{3}He is a direct manifestation of the complex macroscopic wave function. The real space shape of the texture, namely, a macroscopic wave function, has been studied extensively with the help of theoretical modeling but has never been directly observed experimentally with spatial resolution. We have succeeded in visualizing the texture by a specialized magnetic resonance imaging. With this new technology, we have discovered that the macroscopic chiral domains, of which sizes are as large as 1 mm, and corresponding chiral domain walls exist rather stably in ^{3}He-A film at temperatures far below the transition temperature.

Pathogenicity of memory Th2 cells is linked to stage of allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) consists of three developmental stages that are based on the presence/absence of antigen-specific IgE and symptoms. The pathogenic Th2 (Tpath2) cells constitute a population of Th2 cells with additional potentially pathogenic characteristics. We examined the relationship between Tpath2 cells and the stages of allergic rhinitis by focusing on ST2, which is an IL-33 receptor. METHODS: Patients with Japanese cedar pollen-induced AR (JCP-AR) and healthy volunteers were divided into "nonsensitized," "asymptomatic sensitized (AS)," and "JCP-AR" groups. We analyzed the ST2 expression and the Th2 function of cultured CD4+ T cells. Next, we observed the progress of patients in the AS stage around the time of seasonal pollen dispersal, with the characteristics of Th2 cells. RESULTS: The ST2 expression of T cells was only upregulated in the AR group. The production of IL-4 and IL-13 was found in CD4+ T cells obtained from AS by stimulation with JCP, but reactivity to IL-33 was not observed. Although IL-33 did not induce the elevation of IL-4 production in the JCP-AR group, IL-33 substantially increased the production of IL-5 and IL-13 in comparison with antigen stimulation alone. In newly afflicted patients, the increased expression of ST2 and elevated reactivity to IL-33 was observed, even before the pollen dispersal season. CONCLUSIONS: Our study demonstrated that the pathogenicity of memory Th2 cells is linked to sensitization and the stage of allergic rhinitis. Therefore, Tpath2 cells may provide useful insights into the mechanism of the onset and progression of allergic rhinitis.

Identification of specifically reduced Th2 cell subsets in allergic rhinitis patients after sublingual immunotherapy.

BACKGROUND: Although Th2 cells are well known to play important roles in allergic diseases including allergic rhinitis (AR), the factors that induce and sustain the pathogenesis of AR remain unclear. The recent development of sublingual immunotherapy (SLIT) is expected to allow changes to the underlying pathogenesis of AR. However, which Th2 cell subsets are important in house dust mite-induced AR (HDM-AR), the influence of SLIT on the pathogenic Th2 cells, and the association of Th2 cell subsets with SLIT efficacy have not been clarified. METHODS: The cytokine production and frequency of HDM-reactive T-cell subsets in peripheral blood mononuclear cells (PBMCs) were evaluated using flow cytometry in 89 HDM-AR patients (placebo [n = 43] and HDM 300 IR [n = 46]) who participated in a placebo-controlled study of SLIT with HDM tablets. All patients provided samples both before treatment as a baseline and at the end of the 52-week study. The PBMCs were stained with CellTrace™ Violet (CTV) before culture with HDM extract, and HDM-reactive T cells were detected as the proliferated cells with diminished CTV. RESULTS: HDM-reactive IL-5+ IL-13+ CD27- CD161+ CD4+ cells and ST2+ CD45RO+ CD4+ cells were observed in the peripheral blood from each patient with HDM-AR; these cells significantly decreased after SLIT in the group treated with active tablets. HDM-reactive ST2+ CD45RO+ CD4+ cells were significantly lower in active-responders. CONCLUSION: Allergen-reactive ST2+ CD45RO+ CD4+ cells or those combined with IL-5+ IL-13+ CD27- CD161+ CD4+ cells may be useful as markers indicating the successful treatment of SLIT. These cells may play a crucial role in the pathogenesis of AR as pathogenic memory Th2 cells.

Changes in resting-state brain networks after cognitive-behavioral therapy for chronic pain.

BACKGROUND: Cognitive-behavioral therapy (CBT) is thought to be useful for chronic pain, with the pathology of the latter being closely associated with cognitive-emotional components. However, there are few resting-state functional magnetic resonance imaging (R-fMRI) studies. We used the independent component analysis method to examine neural changes after CBT and to assess whether brain regions predict treatment response. METHODS: We performed R-fMRI on a group of 29 chronic pain (somatoform pain disorder) patients and 30 age-matched healthy controls (T1). Patients were enrolled in a weekly 12-session group CBT (T2). We assessed selected regions of interest that exhibited differences in intrinsic connectivity network (ICN) connectivity strength between the patients and controls at T1, and compared T1 and T2. We also examined the correlations between treatment effects and rs-fMRI data. RESULTS: Abnormal ICN connectivity of the orbitofrontal cortex (OFC) and inferior parietal lobule within the dorsal attention network (DAN) and of the paracentral lobule within the sensorimotor network in patients with chronic pain normalized after CBT. Higher ICN connectivity strength in the OFC indicated greater improvements in pain intensity. Furthermore, ICN connectivity strength in the dorsal posterior cingulate cortex (PCC) within the DAN at T1 was negatively correlated with CBT-related clinical improvements. CONCLUSIONS: We conclude that the OFC is crucial for CBT-related improvement of pain intensity, and that the dorsal PCC activation at pretreatment also plays an important role in improvement of clinical symptoms via CBT.

Reliability of the SF-36 in Japanese patients with systemic lupus erythematosus and its associations with disease activity and damage: a two-consecutive year prospective study.

We aimed to validate the reliability of the Medical Outcomes Study Short Form-36 (SF-36) among Japanese patients with systemic lupus erythematosus (SLE). Japanese patients with SLE ( n = 233) completed the SF-36 and other related demographic questionnaires, and physicians simultaneously completed the SLE Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics Damage Index (SDI). Patients were prospectively followed for a repeat assessment the following year. The SF-36 subscales demonstrated acceptable internal consistency (Cronbach's α of 0.85-0.89), and an overall good test-retest reliability (intraclass correlation coefficient >0.70). The average baseline SF-36 subscale/summary scores except for "bodily pain" were significantly lower than those of the Japanese general population ( p < 0.05). The SDI showed an inverse correlation with the SF-36 subscale/summary scores except for "vitality" and "mental component summary" at baseline, whereas the SLEDAI-2K did not. In the second year, "social functioning" and "mental component summary" of the SF-36 deteriorated among patients whose SDI or SLEDAI-2K score increased (effect sizes < -0.20). In conclusion, the SF-36 demonstrated acceptable reliability among Japanese patients with SLE. Health-related quality of life measured by the SF-36 was reduced in Japanese patients with SLE and associated with disease damage, rather than disease activity.

Genetic and phenotypic profile of 112 patients with X-linked Charcot-Marie-Tooth disease type 1.

BACKGROUND AND PURPOSE: X-linked Charcot-Marie-Tooth disease type 1 (CMTX1), caused by mutations in gap junction protein beta 1 (GJB1), is characterized by various central nervous system symptoms and gender differences of clinical severity. The aim of this study was to identify the frequency and mutation spectrum of CMTX1 patients in Japan and to demonstrate their phenotypic diversities. METHODS: Using three high-throughput sequencing systems, targeted gene panel sequencing on 1483 unrelated index patients with suspected Charcot-Marie-Tooth (CMT) disease was performed. The peripheral and central nervous system involvements of all patients with GJB1 variants were assessed retrospectively and a detailed gender comparison was conducted with the CMT examination score. RESULTS: Twenty-three novel and 36 described GJB1 variants were identified from 88 pedigrees, in which 34 female and 78 male patients were enrolled. Mean age at onset of the male patients was much younger than the females, 21.56 ± 17.63 years vs. 35.53 ± 23.72 years (P = 0.007). Male patients presented with more severe phenotypes in every examination item, but statistical differences were observed only in motor dysfunctions of the lower extremities and vibration sensation. No significant sensory difference was identified between genders, either clinically or electrophysiologically. Central nervous system dysfunctions were found in 15 patients from 12 pedigrees. Therein, six patients developed stroke-like phenotypes, with dysarthria as the leading symptom. CONCLUSIONS: A relatively lower frequency of CMTX1 (5.9%) was demonstrated and a broad mutation spectrum of GJB1 was described. Detailed clinical differences between genders and various central nervous system symptoms were also illustrated, even in the same pedigree.

The analgesic effect of rescue administration of intravenous acetaminophen in cancer patients may be associated with sex and opioid dose, and the effect would appear to patients administered under 45 mg/day opioid (oral morphine equivalents).

There have been no investigations examining the analgesic effect of rescue administration of intravenous acetaminophen (IV APAP) for pain in cancer patients. Fifty cancer patients who received IV APAP for pain at Ashiya Municipal Hospital (Hyogo, Japan) between January 2014 and July 2016 were retrospectively evaluated. The degree of pain was evaluated using a 4-point verbal rating scale. Pain intensity differences ≥ 1 defined the IV APAP effective group, and the patient' characteristics were compared by a medical chart review. Variables were extracted from medical records for logistic regression analyses of factors associated with analgesic effect. The cut-off value of opioid dose (oral morphine equivalent) was determined using receiver operator characteristic (ROC) curve analysis. Thirty eight (76%) patients experienced an analgesic effect of rescue administration of IV APAP. Sex (odds ratio [OR] 5.4014; p = 0.0397) and opioid dose used for pain control (OR 0.9901; p = 0.0147) were found to be associated with the efficacy of rescue administration of IV APAP. The cut-off value of opioid dose (oral morphine equivalent), which may be difficult to match the analgesic effect of IV APAP, was calculated to be more than 45 mg/day. This study demonstrated the efficacy of a rescue administration of IV APAP for pain in cancer patients, and revealed that sex and opioid dose may be associated with the analgesic effect. Furthermore, this study also proposes a criterion for the analgesic effect.

WNK1/HSN2 founder mutation in patients with hereditary sensory and autonomic neuropathy: A Japanese cohort study.

The clinical and genetic spectrum of hereditary sensory and autonomic neuropathy (HSAN) is still unknown in Japan. We collected a broad cohort of 33 unrelated patients with predominant sensory and/or autonomic dysfunctions, who were referred to our genetic laboratory. A gene panel sequencing targeting 18 HSAN-related genes was performed using a next-generation sequencing system. A recurrent frame shift mutation in the WNK1/HSN2 gene, c.3237_3238insT (p.Asp1080*), was detected in 5 patients. This mutation was homozygous in 4 cases and of a compound heterozygous genotype in 1 case. Geographic and haplotype analysis of all 5 patients suggested a founder event. In addition, a novel heterozygous nonsense variant, c.2615C>G (p.Ser872*), was identified. All the 5 patients presented with severe sensory and autonomic dysfunctions at birth or during adolescence. In 2 patients, an uncommon phenotype of acute pathological pain presented at ~50 years of age. Here, we present the first founder mutation of WNK1/HSN2, in addition to French Canadian, which accounts for ~15.2% of Japanese patients with HSAN in our cohort. We have also reviewed all previously described mutations in WNK1/HSN2 and reconciled their nomenclature strategy on the basis of the current longest transcript.

Clinical and mutational spectrum of Japanese patients with Charcot-Marie-Tooth disease caused by GDAP1 variants.

BACKGROUND: Mutations in GDAP1 are responsible for heterogeneous clinical and electrophysiological phenotypes of Charcot-Marie-Tooth disease (CMT), with autosomal dominant or recessive inheritance pattern. The aim of this study is to identify the clinical and mutational spectrum of CMT patients with GDAP1 variants in Japan. MATERIALS AND METHODS: From April 2007 to October 2014, using three state-of-art technologies, we conducted gene panel sequencing in a cohort of 1,030 patients with inherited peripheral neuropathies (IPNs), and 398 mutation-negative cases were further analyzed with whole-exome sequencing. RESULTS: We identified GDAP1 variants from 10 patients clinically diagnosed with CMT. The most frequent recessive variant in our cohort (5/10), c.740C>T (p.A247V), was verified to be associated with a founder event. We also detected three novel likely pathogenic variants: c.928C>T (p.R310W) and c.546delA (p.E183Kfs*23) in Case 2 and c.376G>A (p.E126K) in Case 8. Nerve conduction study or sural nerve biopsy of all 10 patients indicated axonal type peripheral neuropathy. CONCLUSION: We identified GDAP1 variants in approximately 1% of our cohort with IPNs, and established a founder mutation in half of these patients. Our study originally described the mutational spectrum and clinical features of GDAP1-related CMT patients in Japan.

Systematic characterization of human testis-specific actin capping protein ß3 as a possible biomarker for male infertility.

STUDY QUESTION: Is actin capping protein (CP) ß3 involved in human spermatogenesis and male infertility? SUMMARY ANSWER: Human CPß3 (hCPß3) is expressed in testis, changes its localization dynamically during spermatogenesis, and has some association with male infertility. WHAT IS KNOWN ALREADY: The testis-specific α subunit of CP (CPα3) was previously identified in human, and mutations in the cpα3 gene in mouse were shown to induce malformation of the sperm head and male infertility. However, CPß3, which is considered to be a heterodimeric counterpart of CPα3, has been neither characterized in human nor reported in association with male infertility. STUDY DESIGN, SIZE, DURATION: To confirm the existence of CPß3 in human testis, fresh semen samples from proven fertile men were analyzed. To investigate protein expression during spermatogenesis, cryopreserved testis obtained from men with obstructive azoospermia were examined by immunofluorescent analysis. To assess the association of CP with male infertility, we compared protein expression of human CPα3 (hCPα3) and hCPß3 using immunofluorescent analysis of cryopreserved sperm between men with normozoospermia (volunteers: Normo group, n = 20) and infertile men with oligozoospermia and/or asthenozoospermia (O + A group, n = 21). PARTICIPANTS/MATERIALS, SETTING, METHODS: The tissue-specific expression of hCPß3 was investigated by RT-PCR and Western blot analysis. To investigate whether hCPα3 and hCPß3 form a heterodimer, a tandem expression vector containing hcpα3 tagged with monomeric red fluorescent protein 1 and hcpß3 tagged with enhanced green fluorescent protein in a single plasmid was constructed and analyzed by co-immunoprecipitation (Co-IP) assay. The protein expression profiles of hCPα3 and hCPß3 during spermatogenesis were examined by immunohistochemical analysis using human spermatogenic cells. The protein expressions of hCPα3 and hCPß3 in sperm were compared between the Normo and O + A groups by immunohistochemical analysis. MAIN RESULTS AND THE ROLE OF CHANCE: RT-PCR showed that mRNA of hcpß3 was expressed exclusively in testis. Western blot analysis detected hCPß3 with anti-bovine CPß3 antibody. Co-IP assay with recombinant protein showed that hCPα3 and hCPß3 form a protein complex. At each step during spermatogenesis, the cellular localization of hCPß3 changed dynamically. In spermatogonia, hCPß3 showed a slight signal in cytoplasm. hCPß3 expression was conspicuous mainly from spermatocytes, and hCPß3 localization dynamically migrated from cytoplasm to the acrosomal cap and acrosome. In mature spermatozoa, hCPß3 accumulated in the postacrosomal region and less so at the midpiece of the tail. Double-staining analysis revealed that hCPα3 localization was identical to hCPß3 at every step in the spermatogenic cells. Most spermatozoa from the Normo group were stained homogenously by both hCPα3 and hCPß3. In contrast, significantly more spermatozoa in the O + A versus Normo group showed heterogeneous or lack of staining for either hCPα3 or hCPß3 (abnormal staining) (P < 0.001). The percentage of abnormal staining was higher in the O + A group (52.4 ± 3.0%) than in the Normo group (31.2 ± 2.5%). Even by confining the observations to morphologically normal spermatozoa selected in accordance with David's criteria, the percentage of abnormal staining was still higher in the O + A group (39.9 ± 2.9%) versus the Normo group (22.5 ± 2.1%) (P < 0.001). hCPß3 in conjunction with hCPα3 seemed to play an important role in spermatogenesis and may be associated with male infertility. LARGE SCALE DATA: Not applicable. LIMITATIONS REASONS FOR CAUTION: Owing to the difficulty of collecting fresh samples of human testis, we used cryopreserved samples from testicular sperm extraction. To examine the interaction of spermatogenic cells or localization in seminiferous tubules, fresh testis sample of healthy males are ideal. WIDER IMPLICATIONS OF THE FINDINGS: The altered expression of hCPα3 and hCPß3 may not only be a cause of male infertility but also a prognostic factor for the results of ART. They may be useful biomarkers to determine the fertilization ability of human sperm in ART. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science (JP16K20133). The authors declare no competing interests.

Classical Spin Nematic Transition in LiGa_{0.95}In_{0.05}Cr_{4}O_{8}.

We present the results of a combined ^{7}Li-NMR and diffraction study on LiGa_{0.95}In_{0.05}Cr_{4}O_{8}, a member of the LiGa_{1-x}In_{x}Cr_{4}O_{8} "breathing" pyrochlore family. Via specific heat and NMR measurements, we find that the complex sequence of first-order transitions observed for LiGaCr_{4}O_{8} is replaced by a single second-order transition at T_{f}=11 K. Neutron and x-ray diffraction rule out both structural symmetry lowering and magnetic long-range order as the origin of this transition. Instead, reverse Monte Carlo fitting of the magnetic diffuse scattering indicates that the low-temperature phase may be described as a collinear spin nematic state, characterized by a quadrupolar order parameter. This state also shows signs of short-range order between collinear spin arrangements on tetrahedra, revealed by mapping the reverse Monte Carlo spin configurations onto a three-state color model.

House dust mite sublingual tablet is effective and safe in patients with allergic rhinitis.

BACKGROUND: House dust mite (HDM) is the major indoor allergen for allergic diseases such as allergic rhinitis (AR) and asthma. Although sublingual immunotherapy is a curative treatment for HDM-induced AR, data from large-scale studies are limited. We evaluated the efficacy and safety of HDM tablets in adolescent and adult patients (aged 12-64 years) with HDM-induced AR with or without intermittent asthma. METHODS: In a double-blind trial in Japan, 968 subjects were randomized 1 : 1 : 1 to 300 index of reactivity (IR), 500 IR, or placebo groups. The primary endpoint was the Average Adjusted Symptom Score (AASS) in the last eight weeks of the 52-week treatment. Secondary endpoints included individual nasal and ocular symptom scores, rescue medication use, and the Japanese Rhinoconjunctivitis Quality of Life Questionnaire (JRQLQ) scores. RESULTS: The AASS in the last eight weeks of treatment significantly improved in both the 300 IR and the 500 IR groups compared to that in the placebo group (P < 0.001). In the 300 IR group, the onset of action occurred at week 8-10. All four nasal symptoms significantly improved in both active treatment groups; rescue medication use and JRQLQ outcome improved in the 300 IR group. Most adverse events (AEs) were mild, and 16 serious AEs (SAEs) were reported; however, none of them were drug-related. CONCLUSIONS: One-year treatment with 300 IR and 500 IR HDM tablets was effective without major safety concerns. The recommended therapeutic dose for AR is 300 IR.

Effects of behavioural activation on the neural basis of other perspective self-referential processing in subthreshold depression: a functional magnetic resonance imaging study.

BACKGROUND: It has been demonstrated that negatively distorted self-referential processing, in which individuals evaluate one's own self, is a pathogenic mechanism in subthreshold depression that has a considerable impact on the quality of life and carries an elevated risk of developing major depression. Behavioural activation (BA) is an effective intervention for depression, including subthreshold depression. However, brain mechanisms underlying BA are not fully understood. We sought to examine the effect of BA on neural activation during other perspective self-referential processing in subthreshold depression. METHOD: A total of 56 subjects underwent functional magnetic resonance imaging scans during a self-referential task with two viewpoints (self/other) and two emotional valences (positive/negative) on two occasions. Between scans, while the intervention group (n = 27) received BA therapy, the control group (n = 29) did not. RESULTS: The intervention group showed improvement in depressive symptoms, increased activation in the dorsal medial prefrontal cortex (dmPFC), and increased reaction times during other perspective self-referential processing for positive words after the intervention. Also, there was a positive correlation between increased activation in the dmPFC and improvement of depressive symptoms. Additionally, there was a positive correlation between improvement of depressive symptoms and increased reaction times. CONCLUSIONS: BA increased dmPFC activation during other perspective self-referential processing with improvement of depressive symptoms and increased reaction times which were associated with improvement of self-monitoring function. Our results suggest that BA improved depressive symptoms and objective monitoring function for subthreshold depression.

Antimelanoma differentiation-associated protein 5 antibody level is a novel tool for monitoring disease activity in rapidly progressive interstitial lung disease with dermatomyositis.

BACKGROUND: Antimelanoma differentiation-associated protein (anti-MDA)5 antibodies are associated with rapidly progressive interstitial lung disease (RP-ILD) in patients with clinically amyopathic dermatomyositis (CADM) or dermatomyositis (DM). OBJECTIVES: We aimed to evaluate the relevance of monitoring anti-MDA5 antibody levels for the management of RP-ILD in patients with CADM or DM. METHODS: Twelve patients with CADM (n = 10) or DM (n = 2) accompanied by RP-ILD were included. Baseline characteristics and outcomes were recorded. Serial measurements of anti-MDA5 antibody levels were measured. All patients were treated with corticosteroids, tacrolimus and intravenous cyclophosphamide. RESULTS: All patients achieved RP-ILD remission after combined immunosuppressive therapy for a mean of 6·8 months, with significant decreases noted in the mean anti-MDA5 antibody levels at remission. Six (50%) patients became anti-MDA5 antibody negative after therapy. After a mean follow-up of 31 months, RP-ILD relapse was observed in four (33%) patients in both the anti-MDA5 antibody sustained positive group and the negative conversion group. However, relapsed patients in the sustained positive group relapsed earlier than those in the negative conversion group. Thus, a decrease in anti-MDA5 antibody levels during remission was associated with longer remission. Relapses were associated with a reincrease of anti-MDA5 antibody levels in four of four (100%) patients. In contrast, none of the patients without reincrease in anti-MDA5 antibody exhibited symptoms of relapse during follow-up. Therefore, reincrease in anti-MDA5 antibody levels was associated with relapse. CONCLUSIONS: The anti-MDA5 antibody level is a novel parameter for monitoring and a good predictor of RP-ILD relapse in patients with CADM or DM.

Clinical and mutational spectrum of Charcot-Marie-Tooth disease type 2Z caused by MORC2 variants in Japan.

BACKGROUND AND PURPOSE: The microrchidia family CW-type zinc finger 2 gene (MORC2) was newly identified as a causative gene of Charcot-Marie-Tooth disease (CMT) type 2Z in 2016. We aimed to describe the clinical and mutational spectrum of patients with CMT harboring MORC2 mutations in Japan. METHODS: We analyzed samples from 781 unrelated patients clinically diagnosed with CMT using deoxyribonucleic acid microarray or targeted resequencing by next-generation sequencing, and samples from 434 mutation-negative patients were subjected to whole-exome sequencing. We extracted MORC2 variants from these whole-exome sequencing data and classified them according to American College of Medical Genetics standards and guidelines. RESULTS: We identified MORC2 variants in 13 patients. As the second most common causative gene of CMT type 2 after MFN2, MORC2 variants were detected in 2.7% of patients with CMT type 2. The mean age of onset was 10.3 ± 8.7 years, and the inheritance pattern was mostly sporadic (11/13 patients, 84.6%). The clinical phenotype was typically length-dependent polyneuropathy, and electrophysiological studies revealed sensory-dominant axonal neuropathy. Mental retardation was identified in 4/13 patients (30.8%). p.Arg190Trp, as a mutational hotspot, was observed in eight unrelated families. We also identified two novel probably pathogenic variants, p.Cys345Tyr and p.Ala369Val, and one novel uncertain significance variant, p.Tyr332Cys. CONCLUSIONS: Our study is the largest report of patients harboring MORC2 variants. We revealed a clinical and mutational spectrum of Japanese patients with MORC2 variants. More attention should be paid to cognitive impairment, and the responsible mechanism requires further research for elucidation.