Effect of a novel nasal oxytocin spray with enhanced bioavailability on autism: a randomized trial.

Although intranasal oxytocin is expected to be a novel therapy for the core symptoms of autism spectrum disorder, which has currently no approved medication, the efficacy of repeated administrations was inconsistent, suggesting that the optimal dose for a single administration of oxytocin is not optimal for repeated administration. The current double-blind, placebo-controlled, multicentre, crossover trial (ClinicalTrials.gov Identifier: NCT03466671) was aimed to test the effect of TTA-121, a new formulation of intranasal oxytocin spray with an enhanced bioavailability (3.6 times higher than Syntocinon® spray, as assessed by area under the concentration-time curve in rabbit brains), which enabled us to test a wide range of multiple doses, on autism spectrum disorder core symptoms and to determine the dose-response relationship. Four-week administrations of TTA-121, at low dose once per day (3 U/day), low dose twice per day (6 U/day), high dose once per day (10 U/day), or high dose twice per day (20 U/day), and 4-week placebo were administered in a crossover manner. The primary outcome was the mean difference in the reciprocity score (range: 0-14, higher values represent worse outcomes) on the Autism Diagnostic Observation Schedule between the baseline and end point of each administration period. This trial with two administration periods and eight groups was conducted at seven university hospitals in Japan, enrolling adult males with high-functioning autism spectrum disorder. Enrolment began from June 2018 and ended December 2019. Follow-up ended March 2020. Of 109 males with high-functioning autism spectrum disorder who were randomized, 103 completed the trial. The smallest P-value, judged as the dose-response relationship, was the contrast with the peak at TTA-121 6 U/day, with inverted U-shape for both the full analysis set (P = 0.182) and per protocol set (P = 0.073). The Autism Diagnostic Observation Schedule reciprocity score, the primary outcome, was reduced in the TTA-121 6 U/day administration period compared with the placebo (full analysis set: P = 0.118, mean difference = -0.5; 95% CI: -1.1 to 0.1; per protocol set: P = 0.012, mean difference = -0.8; 95% CI: -1.3 to -0.2). The per protocol set was the analysis target population, consisting of all full analysis set participants except those who deviated from the protocol. Most dropouts from the full analysis set to the per protocol set occurred because of poor adherence to the test drug (9 of 12 in the first period and 8 of 15 in the second period). None of the secondary clinical and behavioural outcomes were significantly improved with the TTA-121 compared with the placebo in the full analysis set. A novel intranasal spray of oxytocin with enhanced bioavailability enabled us to test a wide range of multiple doses, revealing an inverted U-shape dose-response curve, with the peak at a dose that was lower than expected from previous studies. The efficacy of TTA-121 shown in the current exploratory study should be verified in a future large-scale, parallel-group trial.

Robust sensing of approaching vehicles relying on acoustic cues.

The latest developments in automobile design have allowed them to be equipped with various sensing devices. Multiple sensors such as cameras and radar systems can be simultaneously used for active safety systems in order to overcome blind spots of individual sensors. This paper proposes a novel sensing technique for catching up and tracking an approaching vehicle relying on an acoustic cue. First, it is necessary to extract a robust spatial feature from noisy acoustical observations. In this paper, the spatio-temporal gradient method is employed for the feature extraction. Then, the spatial feature is filtered out through sequential state estimation. A particle filter is employed to cope with a highly non-linear problem. Feasibility of the proposed method has been confirmed with real acoustical observations, which are obtained by microphones outside a cruising vehicle.

Objective assessment of autism spectrum disorder based on performance in structured interpersonal acting-out tasks with prosodic stability and variability.

In this study, we sought to objectively and quantitatively characterize the prosodic features of autism spectrum disorder (ASD) via the characteristics of prosody in a newly developed structured speech experiment. Male adults with high-functioning ASD and age/intelligence-matched men with typical development (TD) were asked to read 29 brief scripts aloud in response to preceding auditory stimuli. To investigate whether (1) highly structured acting-out tasks can uncover the prosodic of difference between those with ASD and TD, and (2) the prosodic stableness and flexibleness can be used for objective automatic assessment of ASD, we compared prosodic features such as fundamental frequency, intensity, and mora duration. The results indicate that individuals with ASD exhibit stable pitch registers or volume levels in some affective vocal-expression scenarios, such as those involving anger or sadness, compared with TD and those with TD. However, unstable prosody was observed in some timing control or emphasis tasks in the participants with ASD. Automatic classification of the ASD and TD groups using a support vector machine (SVM) with speech features exhibited an accuracy of 90.4%. A machine learning-based assessment of the degree of ASD core symptoms using support vector regression (SVR) also had good performance. These results may inform the development of a new easy-to-use assessment tool for ASD core symptoms using recorded audio signals.

Vaccination-induced systemic autoimmunity in farmed Atlantic salmon.

Over half of the salmon consumed globally are farm-raised. The introduction of oil-adjuvanted vaccines into salmon aquaculture made large-scale production feasible by preventing infections. The vaccines that are given i.p. contain oil adjuvant such as mineral oil. However, in rodents, a single i.p. injection of adjuvant hydrocarbon oil induces lupus-like systemic autoimmune syndrome, characterized by autoantibodies, immune complex glomerulonephritis, and arthritis. In the present study, whether the farmed salmon that received oil-adjuvanted vaccine have autoimmune syndrome similar to adjuvant oil-injected rodents was examined. Sera and tissues were collected from vaccinated or unvaccinated Atlantic salmon (experimental, seven farms) and wild salmon. Autoantibodies (immunofluorescence, ELISA, and immunoprecipitation) and IgM levels (ELISA) in sera were measured. Kidneys and livers were examined for pathology. Autoantibodies were common in vaccinated fish vs unvaccinated controls and they reacted with salmon cells/Ags in addition to their reactivity with mammalian Ags. Diffuse nuclear/cytoplasmic staining was common in immunofluorescence but some had more specific patterns. Serum total IgM levels were also increased in vaccinated fish; however, the fold increase of autoantibodies was much more than that of total IgM. Sera from vaccinated fish immunoprecipitated ferritin and approximately 50% also reacted with other unique proteins. Thrombosis and granulomatous inflammation in liver, and immune-complex glomerulonephritis were common in vaccinated fish. Autoimmunity similar to the mouse model of adjuvant oil-induced lupus is common in vaccinated farmed Atlantic salmon. This may have a significant impact on production loss, disease of previously unknown etiology, and future strategies of vaccines and salmon farming.

Quantification of speech and synchrony in the conversation of adults with autism spectrum disorder.

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by impairments in social reciprocity and communication together with restricted interest and stereotyped behaviors. The Autism Diagnostic Observation Schedule (ADOS) is considered a 'gold standard' instrument for diagnosis of ASD and mainly depends on subjective assessments made by trained clinicians. To develop a quantitative and objective surrogate marker for ASD symptoms, we investigated speech features including F0, speech rate, speaking time, and turn-taking gaps, extracted from footage recorded during a semi-structured socially interactive situation from ADOS. We calculated not only the statistic values in a whole session of the ADOS activity but also conducted a block analysis, computing the statistical values of the prosodic features in each 8s sliding window. The block analysis identified whether participants changed volume or pitch according to the flow of the conversation. We also measured the synchrony between the participant and the ADOS administrator. Participants with high-functioning ASD showed significantly longer turn-taking gaps and a greater proportion of pause time, less variability and less synchronous changes in blockwise mean of intensity compared with those with typical development (TD) (p<0.05 corrected). In addition, the ASD group had significantly wider distribution than the TD group in the within-participant variability of blockwise mean of log F0 (p<0.05 corrected). The clinical diagnosis could be discriminated using the speech features with 89% accuracy. The features of turn-taking and pausing were significantly correlated with deficits of ASD in reciprocity (p<0.05 corrected). Additionally, regression analysis provided 1.35 of mean absolute error in the prediction of deficits in reciprocity, to which the synchrony of intensity especially contributed. The findings suggest that considering variance of speech features, interaction and synchrony with conversation partner are critical to characterize atypical features in the conversation of people with ASD.

Induction of lupus-related specific autoantibodies by non-specific inflammation caused by an intraperitoneal injection of n-hexadecane in BALB/c mice.

A single intraperitoneal (i.p.) injection of pristane, incomplete Freund's adjuvant (IFA), or the adjuvant oil squalene, but not high molecular weight medicinal mineral oils, induces lupus-related autoantibodies to nRNP/Sm and -Su in non-autoimmune strains of mice. This ability appears to be associated with the low molecular weight and adjuvanticity of hydrocarbon. n-Hexadecane (C(16)H(34)), which is present in petroleum, has adjuvant activity and induces arthritis in rodents like other lupus-inducing oils. In addition to dietary exposure to n-hexadecane in mineral oils, exposure also occurs via inhalation of oil mist, jet fuel, or diesel exhaust or by absorption through the skin. Since n-hexadecane is a low molecular weight adjuvant hydrocarbon oil similar to other lupus-inducing hydrocarbons, the present study examined whether it can also induce lupus-related autoantibodies in mice. Female BALB/cJ mice received a single i.p. injection of 0.5 ml of n-hexadecane, pristane, or saline (control). Pathology and serology (immunoglobulin levels, autoantibodies by immunofluorescence, immunoprecipitation, and ELISA) were examined 3 months later. Unexpectedly, all n-hexadecane-treated mice, but none in the other groups, developed inflammatory ascites within 2.5 months. n-Hexadecane induced hypergammaglobulinemia (IgG1, IgG2a), antinuclear (titer>1:160, 67%) and -cytoplasmic antibodies (58%) and autoantibodies to nRNP/Sm (25%), Su (33%), ssDNA (83%), and chromatin (100%). Therefore, non-specific inflammation caused by n-hexadecane resulted in the production of a limited set of specific autoantibodies. These previously unrecognized immunological effects of n-hexadecane may have implications in monitoring human exposure to hydrocarbons and in the pathogenesis of autoimmune diseases.

Scintigraphic assessment of the effects of bone marrow-derived mononuclear cell transplantation combined with off-pump coronary artery bypass surgery in patients with ischemic heart disease.

UNLABELLED: Myocardial SPECT may be useful for assessment of the therapeutic effects and the mechanisms of cardiac regeneration medicine. We aimed to assess first the feasibility and the short-term safety of autologous bone marrow-derived mononuclear cell transplantation (BMCT) into the ischemic myocardium in patients who undergo off-pump coronary artery bypass surgery (OPCAB). In addition, we aimed to assess our hypothesis that the BMCT may help ameliorate myocardial perfusion in patients with ischemic heart disease (IHD) using myocardial perfusion scintigraphy. METHODS: We performed BMCT in 10 patients with IHD during OPCAB. Cells for BMCT were collected by intraoperative bone marrow aspiration or by preoperative cellular apheresis after pretreatment with granulocyte colony-stimulating factor. After OPCAB was performed in all graftable ischemic areas, a total of 3.4 +/- 1.2 x 10(9) mononuclear cells, including 5.2 +/- 1.6 x 10(6) CD34-positive (CD34(+)) cells, were injected into ungraftable ischemic myocardial areas. Dipyridamole-stress and resting (99m)Tc myocardial SPECT was performed before and 1 mo after the procedures. RESULTS: BMCT was performed safely in all patients. Compared with before treatment, myocardial (99m)Tc tracer uptake on the dipyridamole-stress image increased similarly in BMCT- and OPCAB-treated areas, whereas tracer accumulation at rest did not change in all myocardial areas. The improvement of myocardial perfusion was not correlated with the total number of mononuclear cells transplanted. However, it was positively correlated with the number of transplanted CD34(+) cells: (99m)Tc tracer uptake after/before BMCT (ratio) = 1.091 x (CD34(+) cell number [x10(6)])(0.074) (r(2) = 0.48, P < 0.05), although new development of coronary vessels was not documented cineangiographically. Myocardial histopathology in 2 of 3 autopsy cases revealed coronary angiogenesis in the areas corresponding to the sites of BMCT. CONCLUSION: The present study demonstrates the feasibility of BMCT combined with OPCAB. This therapy improves myocardial perfusion possibly via CD34-related development of coronary microvessels.

Fine-needle aspiration cytology of bronchial acinic cell carcinoma: a case report.

Salivary gland-type carcinomas of the lung are rare but well-known tumors. Among them, acinic cell carcinoma (ACC) is extremely rare and its cytological features have not been reported. We present a case of bronchial ACC and describe its cytological characteristics. The tumor occurred in a 58-yr-old man as a 15-mm polypoid lesion at the right middle lobar bronchus and filled its lumen. Transbronchial brush cytology and a biopsy failed to collect tumor cells but transbronchial fine-needle aspiration (FNA) cytology was successful. The smear obtained was richly cellular and a large number of thick-layered or monolayered sheet-like tumor cell clusters and dissociated tumor cells were observed. Cribriform globular spaces were common and a lobulated acinar structure was found focally. The tumor cells had a fine granular large polygonal cytoplasm and rather uniform round or ovoid nuclei. The nuclei were situated eccentrically or centrally and the nuclear/cytoplasmic ratio was consistently low. These cytological features were essentially similar to those of ACC of the head and neck region. The patient underwent a lobectomy and the tumor was resected completely. Transbronchial FNA cytology was useful for diagnosing bronchial ACC and differentiating it from other conventional and salivary gland type carcinomas.

Pristane-induced autoimmunity in germ-free mice.

Hypergammaglobulinemia and autoantibodies are reduced in pristane-treated specific pathogen-free mice vs. conventionally housed controls, consistent with the role of microbial stimulation in this model. To determine whether microbial stimulation is required, BALB/c mice housed under germ-free conditions were treated i.p. with sterile PBS or pristane and examined 6 months later. As in conventional mice, pristane-treated germ-free mice developed peritoneal granulomas and hypergammaglobulinemia with increased IgG2a/IgG1 ratios. LPS stimulation induced more IL-6, IL-12, and TNF-alpha, and anti-CD3 induced more IFN-gamma and IL-4 by peritoneal cells from pristane-treated mice vs. control. Anti-nRNP/Sm and -Su autoantibodies were found in 40% and 43%, respectively, of pristane-treated germ-free mice by immunoprecipitation. Thus, bacterial stimulation was not required for lupus autoantibodies, peritoneal granuloma formation, hypergammaglobulinemia, or cytokine overproduction. Although microbial stimulation acts synergistically with pristane, these results clearly indicate that pristane does not act merely by increasing exposure to microbial products such as LPS.

Gammadelta T-cell large granular lymphocyte (LGL) leukemia with spontaneous remission.

T-cell large granular lymphocyte (LGL) leukemia is a clonal disorder with an indolent clinical course. In July 1995, a 46-year-old Japanese man was admitted to our hospital because his anemia had progressed. He had a white blood cell count of 3.9 x 10(9)/L with 75% lymphocytes, which were intermediate to large and had almost round nuclei and azurophilic granules, and anemia with a red blood cell count (RBC) of 2.69 x 10(12)/L, hemoglobin (Hb) of 9.5 g/dL, and hematocrit (Hct) of 28.3%. Electron microscopic examination showed that most of the lymphocytes had a parallel tubular array and dense core granules in their cytoplasm. Flow cytometry and Southern blotting of the T-cell antigen receptor (TCR) genes using the peripheral blood species showed monoclonal proliferation of LGLs with a CD3+, TCRgammadelta+, CD4-, CD8-, CD16+, CD56-, CD57-, HLA-DR+ phenotype, and a TCR gamma gene rearrangement, respectively, suggesting that the patient was diagnosed as having gammadelta T-cell LGL leukemia. He had no symptoms, organomegaly, or skin lesions. About 1.5 years after diagnosis, the anemia gradually improved with disappearance and appearance of a rearranged band in the TCR-gamma gene and TCR-beta gene, respectively. About 7 years after diagnosis, the anemia improved completely with a RBC of 5.01 x 10(12)/L, Hb of 14.8 g/dL, and Hct of 44.3%, and he was in complete remission without TCR-beta and -gamma gene rearrangements. He had received no therapy. This is the first report of spontaneous remission of gammadelta T-cell LGL leukemia.

X-linked immunodeficient mice spontaneously produce lupus-related anti-RNA helicase A autoantibodies, but are resistant to pristane-induced lupus.

Murine lupus can occur spontaneously or be induced by hydrocarbons, such as pristane. Spontaneous disease in MRL and NZB/W F1 mice is suppressed by the xid (X-linked immunodeficiency) mutation, which greatly diminishes T cell-independent type 2 responses as well as the number of peritoneal B1 cells. The present study asked whether lupus induced by i.p. injection of pristane likewise is inhibited by the xid defect. Male CBA/N (xid) mice were refractory to the induction of autoantibodies by pristane, whereas 23% of pristane-treated male CBA/CaJ controls produced anti-nRNP/Sm, -Su and/or -OJ (isoleucyl tRNA synthetase) antibodies. Unexpectedly, 43% (12 of 28) of the xid mice spontaneously produced anti-nuclear antibodies that proved highly specific for the lupus antigen RNA helicase A (RHA). Strikingly, this specificity was absent in CBA/CaJ mice (none of 51). Moreover, pristane treatment suppressed the production of anti-RHA antibodies when administered prior to the onset of autoantibody production, but enhanced anti-RHA levels when given after the onset of autoantibody production, suggesting that pristane interferes with anti-RHA production at an early stage. Large amounts of IgG1 anti-RHA autoantibodies were detected in the sera of xid mice, whereas pristane-induced anti-nRNP/Sm and -Su autoantibodies were almost exclusively IgG2a. Cytokine production within the peritoneal cavity reflected the predominant isotypes: IL-12 and IFN-gamma predominated in pristane-treated mice, whereas IL-4 and IL-6 were more predominant in untreated xid mice. The spontaneous production of anti-RHA by xid mice and its suppression by pristane treatment at the level of autoantibody induction supports the idea that lupus autoantibodies may be generated through a variety of mechanisms.