Tyrosine kinase 2 (Tyk2) is a nonreceptor tyrosine kinase that belongs to the Janus kinase (Jak) family. Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed with hyper-IgE syndrome. This patient showed unusual susceptibility to various microorganisms including virus, fungi, and mycobacteria and suffered from atopic dermatitis with elevated serum IgE. The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23. The cytokine signals were successfully restored by transducing the intact Tyk2 gene. Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation. This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially from Tyk2 function in mice.

Medication-related osteonecrosis of the jaw (MRONJ) is an adverse event that may inhibit the treatment of primary disease and remarkably influence the patient's quality of life. The treatment methods for MRONJ, nonsurgical and surgical, are controversial, with no agreement as to which method provides the best outcome and should therefore be recommended. This multicenter retrospective study aimed to investigate the treatment methods and outcome in a large number of patients with MRONJ in Japan, utilizing propensity score matching analysis. A total of 361 patients with MRONJ, at eight hospitals, were registered in this study retrospectively. Various demographic and treatment-related variables were examined and analyzed to determine their correlation with the treatment outcome. After propensity score matching for treatment methods (nonsurgical versus surgical treatment), 176 patients were analyzed by logistic regression. It was shown that those with low-dose administration of an antiresorptive agent and surgical treatment had better outcomes. Furthermore, in 159 patients who underwent surgical treatment, those who underwent extensive surgery experienced significantly better treatment outcomes than those who underwent conservative surgery. This is the first study to compare treatment methods for MRONJ using propensity score matching analysis. The results indicated that extensive surgical treatment should be performed as first-choice therapy for patients with MRONJ. © 2017 American Society for Bone and Mineral Research.

Porcine embryonic fibroblasts (PEF) are important as donor cells for nuclear transfer for generation of genetically modified pigs. In this study, we determined an optimal protocol for transfection of PEF with the Amaxa Nucleofection system, which directly transfers DNA into the nucleus of cells, and compared its efficiency with conventional lipofection and electroporation. Cell survival and transfection efficiency were assessed using dye-exclusion assay and a green fluorescent protein (GFP) reporter construct, respectively. Our optimized nucleofection parameters yielded survival rates above 60%. Under these conditions, FACS analysis demonstrated that 79% of surviving cells exhibited transgene expression 48 h after nucleofection when program U23 was used. This efficiency was higher than that of transfection of PEFs with electroporation (ca. 3-53%) or lipofection (ca. 3-8%). Transfected cells could be expanded as stably transgene-expressing clones over a month. When porcine nuclear transfer (NT) was performed using stable transformant expressing GFP as a donor cell, 5-6% of reconstituted embryos developed to blastocysts, from which 30-50% of embryos exhibited NT-embryo-derived green fluorescence. Under the conditions evaluated, nucleofection exhibited higher efficiency than conventional electroporation and lipofection, and may be a useful alternative for generation of genetically engineered pigs through nuclear transfer.

This study evaluated the effect of oral cancer surgery on masticatory efficiency. Masticatory efficiency was measured using the ATP absorption method. Eating ability was measured using a questionnaire. Two groups were employed as controls: The "normal occlusion group" consisted of subjects who had a complete set of natural maxillary teeth opposed to mandibular teeth, and the "unilateral occlusion group" consisted of subjects who had lost their molar and premolar teeth on one side of the mandible as a result of caries or periodontal diseases. Three treatment groups, each of 6 patients, were studied: a glossectomy group, a marginal mandibulectomy group and a segmental mandibulectomy group. There were no differences in masticatory efficiency between two control groups. Masticatory efficiencies of the three oral cancer treatment groups were lower than in the unilateral occlusion group, even 12 months after surgery. Masticatory efficiency of the glossectomy group was significantly higher 12 months after surgery compared with pre-surgery. Masticatory and eating abilities of the marginal mandibulectomy group and the segmental mandibulectomy were reduced at 3 and 6 months after surgery. The masticatory efficiency 12 months after surgery was higher in the marginal mandibulectomy group than the segmental mandibulectomy group, although the difference was not statistically significant. The self assessed eating ability 12 months after surgery was significantly higher in the marginal mandibulectomy group than the segmental mandibulectomy group. These results suggest that discontinuation of the mandible may lead patients to eat only foods that do not require a substantial amount of chewing. Hence, the quality of life of patients in the marginal mandibulectomy group was considered to be better than that in the segmental mandibulectomy group.

SummaryThe prevalence of allergic diseases is high in Japan, even in infants. Their risk for developing allergies is influenced by the antigens in the mother's diet during pregnancy. We hypothesized that, apart from the antigens, hypersensitivity induced through high en ergy and nutrient intake by mothers during pregnancy may be a factor for allergic diseases in their babies. In this study, we tried to confirm our hypothesis. Allergy histories of parents and their infants, body characteristics and food and nutrient intake were measured by a questionnaire and a food frequency questionnaire, respectively. A total of 2,642 responses were obtained (return rate, 94.7%). The major allergic diseases in the infants were atopic dermatitis (6.0%), food allergy (3.7%) and bronchial asthma or asthmatic bronchitis (3.2%). About 60% of the infants with allergies had a family history of allergies. Family his tory of allergy, age of infant, order of birth, head and chest circumferences of infants, BMI of mothers before pregnancy and delivery and intake of lipids (fat and vegetable oil) and veg etables by mothers related positively, and the intake of protein, carbohydrates and milk and its products correlated negatively with allergic diseases in the infants (p<0.05). The results, together with previous reports, suggest that a high intake of energy and lipids (fat and veg etable oil) during pregnancy may accelerate allergic diseases in infants.