A Critical Temporal Window for Selectin-dependent CD4+ Lymphocyte Homing and Initiation of Late-Phase Inflammation in Contact Sensitivity

Contact sensitivity (CS) is an inflammatory disorder characterized by early and late phases of leukocyte recruitment. We used a noninvasive intravital microscopy technique allowing for the direct visualization of leukocyte rolling and adhesion on blood vessel endothelium. By blocking specific adhesion molecules, we elucidated the molecular mechanisms mediating early leukocyte recruitment to be E- and P-selectin and demonstrated that leukocyte recruitment in the late phase had a different adhesive profile (mainly α4-integrin). Complete blockade of E- and P-selectin within the first 2 h of leukocyte–endothelial cell interactions (but not later) eliminated selectin-independent leukocyte recruitment at 24 h. Despite the predominance of neutrophils in the early phase, specific elimination of CD4+ lymphocytes in the early phase eliminated the late response. CD4+ lymphocytes homed to skin via E- and P-selectin within the early phase and induced the late phase response. Addition of these same CD4+ lymphocytes 2 h after antigen challenge was too late for these cells to home to the skin and induce late phase responses. Our data clearly demonstrate that the antigen-challenged microenvironment is only accessible to CD4+ lymphocytes for the first 2 h, and that this process is essential for the subsequent recruitment of other leukocyte populations in late phase responses

Therapy for pneumonitis and sialadenitis by accumulation of CCR2-expressing CD4(+)CD25(+ )regulatory T cells in MRL/lpr mice

Adoptive transfer of CD4(+)CD25(+ )regulatory T cells has been shown to have therapeutic effects in animal models of autoimmune diseases. Chemokines play an important role in the development of autoimmune diseases in animal models and humans. The present study was performed to investigate whether the progression of organ-specific autoimmune diseases could be reduced more markedly by accumulating chemokine receptor-expressing CD4(+)CD25(+ )regulatory T cells efficiently in target organs in MRL/MpJ-lpr/lpr (MRL/lpr) mice. CD4(+)CD25(+)Foxp3(+ )T cells (Treg cells) and CD4(+)CD25(+)Foxp3(+ )CCR2-transfected T cells (CCR2-Treg cells) were transferred via retro-orbital injection into 12-week-old MRL/lpr mice at the early stage of pneumonitis and sialadenitis, and the pathological changes were evaluated. Expression of monocyte chemoattractant protein-1 (MCP-1)/CCL2 was observed in the lung and submandibular gland of the mice and increased age-dependently. The level of CCR2 expression and MCP-1 chemotactic activity of CCR2-Treg cells were much higher than those of Treg cells. MRL/lpr mice to which CCR2-Treg cells had been transferred showed significantly reduced progression of pneumonitis and sialadenitis in comparison with MRL/lpr mice that had received Treg cells. This was due to more pronounced migration of CCR2-Treg cells and their localization for a longer time in MCP-1-expressing lung and submandibular gland, resulting in stronger suppressive activity. We prepared chemokine receptor-expressing Treg cells and demonstrated their ability to ameliorate disease progression by accumulating in target organs. This method may provide a new therapeutic approach for organ-specific autoimmune diseases in which the target antigens remain undefined

A Randomized Phase 2 Trial of Antibiotic Prophylaxis Versus No Intervention for Muscle Biopsy in A Neurology Department

Muscle biopsy can be used to confirm the diagnosis of neuromuscular diseases. However, it is unclear whether antibiotic prophylaxis prior to muscle biopsy is needed to prevent surgical site infection (SSI). We are conducting a phase 2, single-center, open-labeled, prospective randomized trial to clarify the need for antibiotic prophylaxis in patients at low risk for SSI undergoing muscle biopsy. Patients will be randomized to an antibiotic prophylaxis group or a control group, and the incidence of SSI will be compared between the groups. Our findings will clarify the need for antibiotic prophylaxis in this patient population

Suppression of a broad spectrum of liver autoimmune pathologies by single peptide-MHC-based nanomedicines

Peptide-major histocompatibility complex class II (pMHCII)-based nanomedicines displaying tissue-specific autoantigenic epitopes can blunt specific autoimmune conditions by re-programming cognate antigen-experienced CD4+ T-cells into disease-suppressing T-regulatory type 1 (TR1) cells. Here, we show that single pMHCII-based nanomedicines displaying epitopes from mitochondrial, endoplasmic reticulum or cytoplasmic antigens associated with primary biliary cholangitis (PBC) or autoimmune hepatitis (AIH) can broadly blunt PBC, AIH and Primary Sclerosing Cholangitis in various murine models in an organ- rather than disease-specific manner, without suppressing general or local immunity against infection or metastatic tumors. Therapeutic activity is associated with cognate TR1 cell formation and expansion, TR1 cell recruitment to the liver and draining lymph nodes, local B-regulatory cell formation and profound suppression of the pro-inflammatory capacity of liver and liver-proximal myeloid dendritic cells and Kupffer cells. Thus, autoreactivity against liver-enriched autoantigens in liver autoimmunity is not disease-specific and can be harnessed to treat various liver autoimmune diseases broadly

Current-induced magnetization switching in MgO barrier magnetic tunnel junctions with CoFeB based synthetic ferrimagnetic free layers

We investigated the effect of using a synthetic ferrimagnetic (SyF) free layer in MgO-based magnetic tunnel junctions (MTJs) on current-induced magnetization switching (CIMS), particularly for application to spin-transfer torque random access memory (SPRAM). The employed SyF free layer had a Co40Fe40B20/ Ru/ Co40Fe40B20 and Co20Fe60B20/Ru/Co20Fe60B20 structures, and the MTJs(100x(150-300) nm^2) were annealed at 300oC. The use of SyF free layer resulted in low intrinsic critical current density (Jc0) without degrading the thermal-stability factor (E/kBT, where E, kB, and T are the energy potential, the Boltzmann constant, and temperature,respectively). When the two CoFeB layers of a strongly antiferromagnetically coupled SyF free layer had the same thickness, Jc0 was reduced to 2-4x10^6 A/cm^2. This low Jc0 may be due to the decreased effective volume under the large spin accumulation at the CoFeB/Ru. The E/kBT was over 60, resulting in a retention time of over ten years and suppression of the write current dispersion for SPRAM. The use of the SyF free layer also resulted in a bistable (parallel/antiparallel) magnetization configuration at zero field, enabling the realization of CIMS without the need to apply external fields to compensate for the offset field.Comment: 6 page

Efficacy and safety of micafungin in empiric and D-index-guided early antifungal therapy for febrile neutropenia ; A subgroup analysis of the CEDMIC trial

Objectives: The D-index is defined as the area over the neutrophil curve during neutropenia. The CEDMIC trial confirmed the noninferiority of D-index-guided early antifungal therapy (DET) using micafungin to empirical antifungal therapy (EAT). In this study, we evaluated the efficacy and safety of micafungin in these settings. Methods: From the CEDMIC trial, we extracted 67 and 113 patients who received micafungin in the DET and EAT groups, respectively. Treatment success was defined as the fulfilment of all components of a five-part composite end point. Fever resolution was evaluated at seven days after the completion of therapy. Results: The proportion of high-risk treatments including induction chemotherapy for acute leukemia and allogeneic hematopoietic stem cell transplantation was significantly higher in the DET group than in the EAT group (82.1% vs. 52.2%). The efficacy of micafungin was 68.7% (95%CI: 56.2–79.4) and 79.6% (71.0–86.6) in the DET and EAT groups, respectively. When we focused on high-risk treatments, the efficacy was 69.1% (55.2–80.9%) and 78.0% (65.3–87.7%), respectively (P = 0.30). There was no significant difference in any of the 5 components between the two groups. Conclusions: The efficacy of micafungin in patients undergoing high-risk treatment was not strongly impaired in DET compared to that in EAT

Transcriptional re-programming of insulin B-chain epitope-specific T-follicular helper cells into anti-diabetogenic T-regulatory type-1 cells

Systemic delivery of nanoparticles (NPs) coated with mono-specific autoimmune disease-relevant peptide-major histocompatibility complex class II (pMHCII) molecules can resolve organ inflammation in various disease models in a disease-specific manner without impairing normal immunity. These compounds invariably trigger the formation and systemic expansion of cognate pMHCII-specific T-regulatory type 1 (TR1) cells. By focusing on type 1 diabetes (T1D)-relevant pMHCII-NP types that display an epitope from the insulin B-chain bound to the same MHCII molecule (IAg7) on three different registers, we show that pMHCII-NP-induced TR1 cells invariably co-exist with cognate T-Follicular Helper (TFH)-like cells of quasi-identical clonotypic composition and are oligoclonal, yet transcriptionally homogeneous. Furthermore, these three different TR1 specificities have similar diabetes reversal properties in vivo despite being uniquely reactive against the peptide MHCII-binding register displayed on the NPs. Thus, pMHCII-NP treatment using nanomedicines displaying different epitope specificities results in the simultaneous differentiation of multiple antigen-specific TFH-like cell clones into TR1-like cells that inherit the fine antigenic specificity of their precursors while acquiring a defined transcriptional immunoregulatory program

Constitutive Expression of Insulin Receptor Substrate (IRS)-1 Inhibits Myogenic Differentiation through Nuclear Exclusion of Foxo1 in L6 Myoblasts

Insulin-like growth factors (IGFs) are well known to play essential roles in enhancement of myogenic differentiation. In this report we showed that initial IGF-I signal activation but long-term IGF-1 signal termination are required for myogenic differentiation. L6 myoblast stably transfected with myc-epitope tagged insulin receptor substrate-1, myc-IRS-1 (L6-mIRS1) was unable to differentiate into myotubes, indicating that IRS-1 constitutive expression inhibited myogenesis. To elucidate the molecular mechanisms underlying myogenic inhibition, IGF-I signaling was examined. IGF-I treatment of control L6 cells for 18 h resulted in a marked suppression of IGF-I stimulated IRS-1 association with the p85 PI 3-kinase and suppression of activation of Akt that correlated with a down regulation of IRS-1 protein. L6-mIRS1 cells, in contrast, had sustained high levels of IRS-1 protein following 18 h of IGF-I treatment with persistent p85 PI 3-kinase association with IRS-1, Akt phosphorylation and phosphorylation of the downstream Akt substrate, Foxo1. Consistent with Foxo1 phosphorylation, Foxo1 protein was excluded from the nuclei in L6-mIRS1 cells, whereas Foxo1 was localized in the nuclei in control L6 cells during induction of differentiation. In addition, L6 cells stably expressing a dominant-interfering form of Foxo1, Δ256Foxo1 (L6-Δ256Foxo1) were unable to differentiate into myotubes. Together, these data demonstrate that IGF-I regulation of Foxo1 nuclear localization is essential for the myogenic program in L6 cells but that persistent activation of IGF-1 signaling pathways results in a negative feedback to prevent myogenesis

Clustered Tonic Spasms Developed after Disappearance of Hypsarrythmia in West Syndrome

We report an infant case of West syndrome with clustered tonic spasms seen after the disappearance of hypsarrythmia. This time lag until the development of tonic spasms implies that their development is not directly related to hypsarrythmia. In other words, this clinical evidence suggests that the hypsarrythmia and tonic spasms did not directly originate from the same mechanism in West syndrome. In this report, we describe the patient\u27s demonstrable neuro-radiological imaging with CT, MRI, ^Tc-ECD SPECT, and EEG changes over her clinical course before and after low-dose ACTH therapy for West syndrome. In addition, the mechanisms of hypsarrythmia and infantile spasms are discussed with a literature review

Lissencephaly Type I Associated with Lennox-Gastaut Syndrome in a 20-Year-old man : a Case Report

Lissencephaly is associated with various types of intractable epilepsy. However, complication by Lennox-Gastaut syndrome is rare. We report an adult patient with Lissencephaly type I complicated by Lennox-Gastaut syndrome, along with a review of the literature. Although mild asphyxia was noted in the history of birth, there were no recognized multiple anomalies. His developmental milestones were severely delayed. Partial seizures frequently occurred at the age of 2 months. Brain CT revealed a smooth surface of the brain cortex, and so he was diagnosed with type I lissencephaly. He was treated with several kinds of oral administrations of anti-convulsants, such as phenobarbital, valproric acid, and clonazepam, but progressed into infantile spasms with West syndrome. At the age of 20, he was repeatedly hospitalized due to respiratory infection, and aspiration pneumonia with diffuse aspiration bronchitis. Deformity of the thorax and ventilation disorder associated with severe scoliosis and respiratory muscle atrophy were also noted. His epilepsy was intractable, and tonic and axial seizures repeatedly occurred for a prolonged period. On electroencephalography, a high-amplitude 1.5-Hz spike-and-slow wave complex was dominant in the frontal region, and a rapid rhythm also appeared, based on which Lennox-Gastaut syndrome was diagnosed. Epileptic surgery and tracheotomy were recommended to his parents, but they did not consent. The patient died of rapid aggravation of respiratory infection and the frequent occurrence of epileptic seizures, in addition to chronic respiratory disorder, at 20 years of age