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.

These data demonstrate genetic heterogeneity in LVNC, with mutation of a novel gene, alpha-dystrobrevin, identified in LVNC associated with CHD. In addition, these results confirm that mutations in G4.5 result in a wide phenotypic spectrum of cardiomyopathies.

Various materials have been proposed for cranial reconstruction. Bone autograft and alloplasts such as polymethylmethacrylate (PMMA) and hydroxyapatite (HA) cement are most commonly used at the present time. Patients submitted for cranioplasty were evaluated. The prognostic factors influencing the results and the outcome were analyzed. Three hundred twelve patients who had 449 procedures performed by a single surgeon to reconstruct a calvarial deformity between 1981 and 2001 were studied. Post-tumor resection deformity was the main reason for cranioplasty (32.4%). Bone graft was the material of choice (69.5%). The main surgical site was the frontal bone (53.2%). Complications were observed in 23.6% of cases and were responsible for the least satisfactory results (P > 0.001), with infection and material exposure being the most critical complications. The eventual outcome was considered good in 91.8% of cases. The use of HA cement was associated with the worst results (P > 0.001). Bone grafts showed a high grade of partial resorption and required further surgery for correction. Multiple surgical procedures were correlated with a high rate of complications and an unsatisfactory outcome. Bone graft and PMMA are still the best materials in calvarial reconstruction. Even though HA cement is an osteoconductive material, it seems to induce what appears to be an immunoguided delayed inflammatory reaction that leads to thinning of the skin and exposure of the material, making secondary repair difficult. Before deciding which reconstructive option to use, a careful evaluation of the patient in terms of diagnosis, number of previous surgeries, and surgical site should be undertaken. If this is adopted, good results and a satisfactory outcome can be achieved on long-term follow-up.

In Japanese children, INVM can be found by screening examinations at asymptomatic stage, and it might have a longer dinical course with gradually depressed left ventricular function and restrictive hemodynamics. The pattern of familial recurrence we observed implies that INVM is a distinctive clinical entity with a heterogeneous genetic background.

D-Serine is the endogenous ligand for the glycine binding site of the N-methyl-D-aspartate (NMDA)-type glutamate receptor (GluR) channel and is involved in the regulation of synaptic plasticity, neural network formation, and neurodegenerative disorders. D-Serine is synthesized from L-serine by serine racemase (SR), which was first reported to be localized in astrocytes. However, recently, SR mRNA and its protein have been detected in neurons. In this study, we examined the SR distribution in the brain during postnatal development and in cultured cells by using novel SR knockout mice as negative controls. We found that SR is predominantly localized in pyramidal neurons in the cerebral cortex and hippocampal CA1 region. Double immunofluorescence staining revealed that SR signals colocalized with those of the neuron-specific nuclear protein, but not with the astrocytic markers glial fibrillary acid protein and 3-phosphoglycerate dehydrogenase. In the striatum, we observed SR expression in gamma-aminobutyric acid (GABA)ergic medium-spiny neurons. Furthermore, in the adult cerebellum, we detected weak but significant SR signals in GABAergic Purkinje cells. From these findings, we conclude that SR is expressed predominantly in many types of neuron in the brain and plays a key role in the regulation of brain functions under physiological and pathological conditions via the production of the neuromodulator D-serine.