Two genetic variants of CD38 in subjects with autism spectrum disorder and controls

金沢大学医薬保健研究域医学系The neurobiological basis of autism spectrum disorder (ASD) remains poorly understood. Given the role of CD38 in social recognition through oxytocin (OT) release, we hypothesized that CD38 may play a role in the etiology of ASD. Here, we first examined the immunohistochemical expression of CD38 in the hypothalamus of post-mortem brains of non-ASD subjects and found that CD38 was colocalized with OT in secretory neurons. In studies of the association between CD38 and autism, we analyzed 10 single nucleotide polymorphisms (SNPs) and mutations of CD38 by re-sequencing DNAs mainly from a case-control study in Japan, and Caucasian cases mainly recruited to the Autism Genetic Resource Exchange (AGRE). The SNPs of CD38, rs6449197 (p 70; designated as high-functioning autism (HFA)) in the U.S. 104 AGRE family trios, but not with Japanese 188 HFA subjects. A mutation that caused tryptophan to replace arginine at amino acid residue 140 (R140W; (rs1800561, 4693C>T)) was found in 0.6-4.6% of the Japanese population and was associated with ASD in the smaller case-control study. The SNP was clustered in pedigrees in which the fathers and brothers of T-allele-carrier probands had ASD or ASD traits. In this cohort OT plasma levels were lower in subjects with the T allele than in those without. One proband with the T allele who was taking nasal OT spray showed relief of symptoms. The two variant CD38 poloymorphysms tested may be of interest with regard of the pathophysiology of ASD. © 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society

Laser ultrasonics measurement of ferrite formation during stepped cooling

Dual phase steels consist of soft ferrite and hard martensite phases and have been the most used advanced high strength steels in automotive design. The control of the phase transformations during processing is essential to achieve their optimal mechanical properties. Thus, sensor technology which can in-situ monitor phase transformation is of great interest. Recently, laser ultrasonics (LUS) has been gaining attention as an in-situ monitoring technique for the microstructure evolution. In this work, phase transformation kinetics of two low carbon steels with potential dual phase chemistries has been investigated using LUS for thermal treatments conditions relevant for run-out table cooling in hot strip mills. Comparing the ultrasound velocity changes during continuous cooling with conventional dilatometry, it was confirmed that LUS can successfully monitor the phase transformation in the present steels. For the industrially relevant stepped cooling transformation tests, the fraction transformed concluded from ultrasound velocity agrees well with the ferrite phase fraction in the final microstructure as obtained from ex-situ metallography. The hardness has a linear relationship with the fraction transformed, which is consistent with literature data for dual phase steels. The evolution of the normalized velocity change for a given isothermal holding temperature can be described by the JMAK approach with the exponent and the rate parameters being consistent with the literature data for the austenite-to-ferrite transformation. Depending on the heat treatment conditions, banded or non-banded microstructures were observed. FEM analysis confirmed that the geometric configuration of phases has a negligible effect on the LUS phase transformation measurement, indicating the robustness of the LUS method.Applied Science, Faculty ofMaterials Engineering, Department ofGraduat

Berberine-induced activation of 5'-adenosine monophosphate-activated protein kinase and glucose transport in rat skeletal muscles.

Berberine (BBR) is the main alkaloid of Coptis chinensis, which has been used as a folk medicine to treat diabetes mellitus in Asian countries. We explored the possibility that 5'-adenosine monophosphate-activated protein kinase (AMPK) is involved in metabolic enhancement by BBR in skeletal muscle, the important tissue for glucose metabolism. Isolated rat epitrochlearis and soleus muscles were incubated in a buffer containing BBR, and activation of AMPK and related events were examined. In response to BBR treatment, the Thr(172) phosphorylation of the catalytic α-subunit of AMPK, an essential step for full kinase activation, increased in a dose- and time-dependent manner. Ser(79) phosphorylation of acetyl-coenzyme A carboxylase, an intracellular substrate of AMPK, increased correspondingly. Analysis of isoform-specific AMPK activity revealed that BBR activated both the α1 and α2 isoforms of the catalytic subunit. This increase in enzyme activity was associated with an increased rate of 3-O-methyl-d-glucose transport in the absence of insulin and with phosphorylation of AS160, a signaling intermediary leading to glucose transporter 4 translocation. The intracellular energy status estimated from the phosphocreatine concentration was decreased by BBR. These results suggest that BBR acutely stimulates both AMPKα1 and AMPKα2 and insulin-independent glucose transport in skeletal muscle with a reduction of the intracellular energy status

Vision Improvement after Osimertinib Treatment in Paraneoplastic Optic Neuropathy Associated with Lung Adenocarcinoma

Treatments for paraneoplastic optic neuropathy (PON), a tumor-related autoimmune disease, include immunosuppression, plasma exchange, and immunoglobulin therapies, as well as treatment of the underlying disease. Herein, we describe the clinical course of an older adult patient with PON whose loss of vision improved after switching between epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatments for cancer. A 76-year-old woman, who had been treated with gefitinib for lung adenocarcinoma for two years, presented with acute bilateral visual disturbances. Her decimal best-corrected visual acuity (BCVA) was 0.3 in the right eye (RE) and 0.7 in the left eye (LE). Slit-lamp examination and funduscopy showed no abnormal findings. Two weeks later, her BCVA decreased to 0.2 in the RE and 0.01 in the LE. Goldman’s perimetry showed a defect in the lower nasal RE and extensive visual-field loss in the LE. Single-flash electroretinograms showed normal amplitudes. Magnetic resonance imaging revealed left optic neuritis and showed neither metastatic cancer nor multiple sclerosis. Pattern-reversal visual evoked potentials showed decreased P100 amplitudes in both eyes (BE). Based on a diagnosis of PON from clinical findings, methylprednisolone pulse treatment was administered. However, her BCVA became no light perception in BE two months after the first visit. Because the tumor tissue was found to be positive for the EGFR T790M resistance mutation by bronchoscopy, the EGFR-TKI treatment was changed to osimertinib, decreasing the size of the lung cancer lesions. Her BCVA improved to hand motion in BE. Her final BCVA was 0.01 in the RE, counting fingers 10 cm in the LE. She died at the age of 79 years. To our knowledge, no reports have shown improvement in BCVA in patients with PON after changing EGFR-TKI treatments. This report indicates that some patients may develop severe visual dysfunction without early treatment for the primary tumor

Caffeine acutely activates 5'adenosine monophosphate-activated protein kinase and increases insulin-independent glucose transport in rat skeletal muscles

Caffeine (1, 3, 7-trimethylxanthine) has been implicated in the regulation of glucose and lipid metabolism including actions such as insulin-independent glucose transport, glucose transporter 4 expression, and fatty acid utilization in skeletal muscle. These effects are similar to the exercise-induced and 5′adenosine monophosphate–activated protein kinase (AMPK)–mediated metabolic changes in skeletal muscle, suggesting that caffeine is involved in the regulation of muscle metabolism through AMPK activation. We explored whether caffeine acts on skeletal muscle to stimulate AMPK. Incubation of rat epitrochlearis and soleus muscles with Krebs buffer containing caffeine (≥3 mmol/L, ≥15 minutes) increased the phosphorylation of AMPKα Thr[172], an essential step for full kinase activation, and acetyl–coenzyme A carboxylase Ser79, a downstream target of AMPK, in dose- and time-dependent manners. Analysis of isoform-specific AMPK activity revealed that both AMPKα1 and α2 activities increased significantly. This enzyme activation was associated with a reduction in phosphocreatine content and an increased rate of 3-O-methyl-d-glucose transport activity in the absence of insulin. These results suggest that caffeine has similar actions to exercise by acutely stimulating skeletal muscle AMPK activity and insulin-independent glucose transport with a reduction of the intracellular energy status

Concentrated protein body product derived from rice endosperm as an oral tolerogen for allergen-specific immunotherapy--a new mucosal vaccine formulation against Japanese cedar pollen allergy.

The endoplasmic reticulum-derived type-I protein body (PB-I) from rice endosperm cells is an ideal candidate formulation for the oral delivery of bioencapsulated peptides as tolerogens for allergen-specific immunotherapy. In the present study, PBs containing the deconstructed Japanese cedar pollen allergens Cryptomeria japonica 1 (Cry j 1) and Cry j 2 were concentrated by treatment with thermostable α-amylase at 90°C to remove the starch from milled rice powder, which resulted in a 12.5-fold reduction of dry weight compared to the starting material. The modified Cry j 1 and Cry j 2 antigens in this concentrated PB product were more resistant to enzymatic digestion than those in the milled seed powder despite the absence of intact cell wall and starch, and remained stable for at least 10 months at room temperature without detectable loss or degradation. The high resistance of these allergens could be attributed to changes in protein physicochemical properties induced by the high temperature concentration process, as suggested by the decreased solubility of the antigens and seed proteins in PBs in step-wise-extraction experiments. Confocal microscopy showed that the morphology of antigen-containing PB-Is was preserved in the concentrated PB product. The concentrated PB product induced specific immune tolerance against Cry j 1 and Cry j 2 in mice when orally administered, supporting its potential use as a novel oral tolerogen formulation