Treatment selection in the clinical practice of systemic lupus erythematosus: results from the Kyushu Collagen Disease Network for Systemic Lupus Erythematosus (KCDN-SLE) registry.

OBJECTIVES: This study aimed to describe the treatment selection for systemic lupus erythematosus (SLE) using data from the Kyushu Collagen Disease Network for SLE (KCDN-SLE) registry, a multicenter prospective registry in Japan. METHODS: This study used data from patients registered between August 2022 and November 2023. Clinical characteristics, purpose of agent initiation, other candidate agents, and short-term efficacy and safety were evaluated. RESULTS: We analyzed 69 previously treated patients with SLE (mean age 43.7 years; 62 females, 7 males). Hydroxychloroquine, biological agents, and immunosuppressive agents were initiated during the maintenance phase in 12, 41, and 16 patients, respectively. In patients with active organ involvement, hydroxychloroquine and biological agents were widely used for initiation. In those who already achieved treatment goals, biological agents alone were predominantly selected. The SLE Disease Activity Index 2000 score and prednisolone dose declined significantly over a 6-month follow-up period. Among 48 patients with active disease, 22 achieved a lupus low disease activity state, but this had no evident association with the initiation of a biological agent. In total, 14 adverse events, predominantly infections, were observed. CONCLUSIONS: Biological agents were used preferentially, and the therapeutic agents were appropriately effective and mostly achieved the purpose of agent initiation.

Mycobacterial mycolic acids trigger inhibitory receptor Clec12A to suppress host immune responses.

Mycobacteria often cause chronic infection. To establish persistence in the host, mycobacteria need to evade host immune responses. However, the molecular mechanisms underlying the evasion strategy are not fully understood. Here, we demonstrate that mycobacterial cell wall lipids trigger an inhibitory receptor to suppress host immune responses. Mycolic acids are major cell wall components and are essential for survival of mycobacteria. By screening inhibitory receptors that react with mycobacterial lipids, we found that mycolic acids from various mycobacterial species bind to mouse Clec12A, and more potently to human Clec12A. Clec12A is a conserved inhibitory C-type lectin receptor containing immunoreceptor tyrosine-based inhibitory motif (ITIM). Innate immune responses, such as MCP-1 production, and PPD-specific recall T cell responses were augmented in Clec12A-deficient mice after infection. In contrast, human Clec12A transgenic mice were susceptible to infection with M. tuberculosis. These results suggest that mycobacteria dampen host immune responses by hijacking an inhibitory host receptor through their specific and essential lipids, mycolic acids. The blockade of this interaction might provide a therapeutic option for the treatment or prevention of mycobacterial infection.

IgA vasculitis following COVID-19 vaccination.

Immunoglobulin A (IgA) vasculitis is generally triggered by infectious causes, but it has also been reported after immunisation with various vaccines. Herein, we report two cases of IgA vasculitis after receiving the first or second dose of the Pfizer-BioNTech BNT16B2b2 mRNA vaccine. Two men, aged 22 and 30 years, developed palpable purpura on the extremities and arthritis. One patient also complained of fever and gastrointestinal symptoms. Laboratory findings revealed mild leucocytosis and slightly elevated C-reactive protein levels, although the platelet count and coagulation profile were within normal levels in both cases. Proteinuria and microhaematuria were seen in one patient. Skin biopsies were performed in both patients and revealed leucocytoclastic vasculitis. The deposits of IgA and C3 were shown in immunofluorescence studies in one patient. Both patients were diagnosed with IgA vasculitis and treated with prednisolone, and their symptoms resolved within 1 week after initiation of treatment. The coronavirus disease 2019 mRNA vaccine could trigger IgA vasculitis; however, a coincidence cannot be ruled out.

A fatal case of diffuse alveolar hemorrhage complicated by rheumatoid arthritis.

We describe a fatal case of diffuse alveolar hemorrhage (DAH) complicated by rheumatoid arthritis (RA). A female patient was diagnosed with RA two months earlier and was treated with prednisolone and tacrolimus due to abnormalities in chest images. The patient was admitted to Hamanomachi Hospital for exertional dyspnea and was treated for exacerbation of chronic heart failure. Even after treatment for heart failure, exertional dyspnea remained. Chest CT imaging revealed contractile, patchy consolidations and ground-glass opacities (GGO) with a peribronchial distribution, suggesting an organizing pneumonia (OP) pattern. She was then treated with an additional 25 mg/day of prednisolone following a clinical diagnosis of OP. When the prednisolone dose was tapered, chest imaging showed worsening infiltration. A bronchoscopy was conducted, and bronchoalveolar lavage fluid was sanguineous, indicating DAH. Given that additional workup for the other etiology of DAH was negative, DAH was thought to be related to RA. Intensive treatment, including pulse dose methylprednisolone, failed to halt progression of respiratory failure, leading to a fatal outcome. The clinical presentation proved challenging due to its rarity. DAH might be a differential diagnosis in RA patients with consolidations and GGO in chest CT images. We review past cases of RA-associated DAH and assess potential treatment choices for future cases.

Neuronal degeneration and cognitive impairment can be prevented via the normalization of mitochondrial dynamics.

Neuronal cells possess a certain degree of plasticity to recover from cell damage. When the stress levels are higher than their plasticity capabilities, neuronal degeneration is triggered. However, the factors correlated to the plasticity capabilities need to be investigated. In this study, we generated a novel mouse model that able to express in an inducible manner a dominant-negative form of MFN2, a mitochondrial fusion factor. We then compared the phenotype of the mice continuously expressing the mutated MFN2 with that of the mice only transiently expressing it. Remarkably, the phenotypes of the group transiently expressing mutant MFN2 could be divided into 3 types: equivalent to what was observed in the continuous expression group, intermediate between the continuous expression group and the control group, and equivalent to the control group. In particular, in the continuous expression group, we observed remarkable hyperactivity and marked cognitive impairments, which were not seen, or were very mild in the transient expression group. These results indicate that abnormal mitochondrial dynamics lead to stress, triggering neuron degeneration; therefore, the neurodegeneration progression can be prevented via the normalization of the mitochondrial dynamics. Since the availability of mouse models suitable for the reproduction of both neurodegeneration and recovery at least partially is very limited, our mouse model can be a useful tool to investigate neuronal plasticity mechanisms and neurodegeneration.

Discovery of Self-Assembling Small Molecules as Vaccine Adjuvants.

Immune potentiators, termed adjuvants, trigger early innate immune responses to ensure the generation of robust and long-lasting adaptive immune responses of vaccines. Presented here is a study that takes advantage of a self-assembling small-molecule library for the development of a novel vaccine adjuvant. Cell-based screening of the library and subsequent structural optimization led to the discovery of a simple, chemically tractable deoxycholate derivative (molecule 6, also named cholicamide) whose well-defined nanoassembly potently elicits innate immune responses in macrophages and dendritic cells. Functional and mechanistic analyses indicate that the virus-like assembly enters the cells and stimulates the innate immune response through Toll-like receptor 7 (TLR7), an endosomal TLR that detects single-stranded viral RNA. As an influenza vaccine adjuvant in mice, molecule 6 was as potent as Alum, a clinically used adjuvant. The studies described here pave the way for a new approach to discovering and designing self-assembling small-molecule adjuvants against pathogens, including emerging viruses.

Rituximab maintenance therapy for patients with antineutrophil cytoplasmic antibody-associated vasculitis in Japan.

OBJECTIVES: We examined the efficacy and safety of rituximab (RTX) maintenance therapy for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan. METHODS: We conducted a retrospective study using a multi-center cohort database of vasculitis patients. All maintenance treatment courses were divided into three groups: a RTX group, a group treated with other immunosuppressant drugs (IS) and a group receiving glucocorticoid monotherapy (GC). The primary endpoint was the comparison of relapse-free survival after 1 year. We also analyzed the occurrence of severe adverse events (SAEs) to assess safety. RESULTS: We included 123 courses of 107 patients (RTX n = 14, IS n = 64, GC n = 45). Twelve of 14 in the RTX group patients were diagnosed with granulomatosis with polyangiitis (GPA). The relapse-free survival of RTX maintenance therapy was comparable to that in the other groups (p = .122). After 1 year of treatment, the RTX group was administered lower steroid doses and one-third of them could withdraw corticosteroid. The overall incidence of SAE was 0.54/patient-year in the RTX group, 0.39/patient-year in the IS group and 0.34/patient-year in the GC group. CONCLUSION: RTX maintenance therapy could be effective and safe in Japanese GPA patients.

Diapause influenced oviposition behavior and physical egg hatch cues of Aedes atropalpus (Diptera: Culicidae): traits that may influence successful colonization of riverine rock pools.

Mosquitoes have developed specialized oviposition strategies that allow them to develop in a wide variety of aquatic habitats. Environmentally cued hatching traits may also play an important role in the successful colonization of some larval habitats, but this subject has remained largely unexplored in Culicidae. Aedes atropalpus (Coquillett) is an autogenous rock pool specialist that may maintain unique adaptations for oviposition and egg hatching. We investigated the egg-laying strategies of Ae. atropalpus exposed to standard (non-diapausing) rearing conditions and diapause-inducing conditions and tested the impact of physical agitation on egg hatch rates by exposing floating and submerged eggs to physical agitation treatments. The results of the oviposition experiment indicate that Ae. atropalpus females primarily lay non-diapausing eggs directly onto the water surface and lay diapausing eggs directly on solid surfaces. The egg-hatching experiment demonstrated that physical agitation significantly increases Ae. atropalpus hatch rates. Floating and submerged eggs responded similarly to the agitation treatment. These data suggest that oviposition behaviors based on both egg diapause status and environmentally-cued hatching strategies may be important adaptations for Ae. atropalpus in riverine rock pools.

Clozapine-induced antineutrophil cytoplasmic antibody-associated vasculitis: a case report.

Clozapine is the most effective antipsychotic medication for refractory schizophrenia, but it has many possible serious side effects, including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, the rare case reports available have not presented sufficient characteristic features of drug-induced AAV. Herein, we report a case of a 48-year-old Japanese woman with schizophrenia who presented with fever, arthralgia, myalgia and skin rash after 2 years of clozapine treatment. Her C-reactive protein (CRP) level increased, myeloperoxidase ANCA was positive and skin biopsy revealed leukocytoclastic vasculitis. Initially, steroid administration achieved remission, but her symptoms and high CRP levels relapsed every time the steroid dosage was tapered down. Upon discontinuation of clozapine, her symptoms and elevated CRP level immediately improved and the steroid was successfully tapered and discontinued. This outcome suggested that clozapine was the main cause of AAV.

Demonstration of on-chip quantum dot microcavity lasers in a molecularly engineered annular groove.

The on-chip quantum dot (QD) microcavity laser engineered on an annular groove made of fused silica was demonstrated based on the external quasi-cavity configuration. By incorporating an appropriate dose of polymer into QD film, the spectral purity of the lasing spectrum was significantly enhanced. In contrast to the dye microcavity laser embedded on the same trench profile, a QD laser possesses a lifetime that is over 10 times longer. We have introduced a unique two-step quantum gain deposition process that has remarkably reduced the wavelength drifts of laser emissions in an aqueous environment by approximately 400%. The reconfigurable cavity platform in combination with an appropriately engineered quantum gain medium embedded onto it promises to enable photostable chip-scale coherent light sources for various photonic, chemical, and biochemical sensing applications.

Acquired Expression of Mutant Mitofusin 2 Causes Progressive Neurodegeneration and Abnormal Behavior.

Neurons have high plasticity in developmental and juvenile stages that decreases in adulthood. Mitochondrial dynamics are highly important in neurons to maintain normal function. To compare dependency on mitochondrial dynamics in juvenile and adult stages, we generated a mouse model capable of selective timing of the expression of a mutant of the mitochondrial fusion factor Mitofusin 2 (MFN2). Mutant expression in the juvenile stage had lethal effects. Contrastingly, abnormalities did not manifest until 150 d after mutant expression during adulthood. After this silent 150 d period, progressive neurodegeneration, abnormal behaviors, and learning and memory deficits similar to those seen in human neurodegenerative diseases were observed. This indicates that abnormal neuronal mitochondrial dynamics seriously affect survival during early life stages and can also significantly damage brain function after maturation. Our findings highlight the need to consider the timing of disease onset in mimicking human neurodegenerative diseases.SIGNIFICANCE STATEMENT To compare the dependency on mitochondrial dynamics in neurons in juvenile and adult stages, we generated a mouse model expressing a mutant of the mitochondrial fusion factor MFN2 in an arbitrary timing. Juvenile expression of the mutant showed acute and severe phenotypes and had lethal effects; however, post-adult expression induced delayed but progressive phenotypes resembling those found in human neurodegenerative diseases. Our results indicate that abnormal neuronal mitochondrial dynamics seriously affect survival during early life stages and can also significantly damage brain function after maturation. This strongly suggests that the timing of expression should be considered when establishing an animal model that closely resembles human neurodegenerative diseases.

Synthesis of Branched Trehalose Glycolipids and Their Mincle Agonist Activity.

The macrophage inducible C-type lectin (Mincle) is a pattern recognition receptor that recognizes trehalose dimycolate (TDM), and trehalose dibehenate (TDB) and related trehalose diesters, and thus represents a promising target for the development of vaccine adjuvants based on the trehalose glycolipid scaffold. To this end, we report on the synthesis of a series of long-chain α-branched, ß-modified trehalose monoesters and diesters to explore how glycolipid structure affects signaling through Mincle. Key steps in our synthetic strategy include a Fráter-Seebach α-alkylation to install the C20 aliphatic lipid on a malic acid derivative, and the formation of a ß,γ-epoxide as an intermediate from which modifications to the ß-position of the lipid can be made. Biological evaluation of the derivatives using nuclear factor of activated T cells (NFAT)-green fluorescent protein (GFP) reporter cell lines expressing mMincle or hMincle revealed that the hMincle agonist activity of all diesters was superior to that of the current lead trehalose glycolipid adjuvant TDB, while the activity of several monoesters was similar to that of their diester counterparts for mMincle, but all showed reduced hMincle agonist activity. Taken together, diesters 2d-g are thus potent Mincle agonists and promising vaccine adjuvants.

Organic-inorganic hybrid microdisk laser with dye and silica mixed doping prepared by ink-jet printing method.

We developed an ink-jet printing method for fabricating inorganic microdisks at room temperature, which is much lower than the melting point of solid-state inorganic oxide, and have fabricated an organic-inorganic hybrid microdisk laser. Silica was used as the inorganic disk material, and microdisk-shaped aggregates were formed by the ink-jet printing method using a solution in which nanosilica particles were dispersed in propylene glycol monomethylether (PGME) solvent. Then, a microdisk capable of laser oscillation was also prepared by preliminarily adding the laser dye rhodamine 6G to the ink to form a mixed organic material. The structural evaluation of the printed microdisk was first conducted using an optical microscope, a scanning electron microscope (SEM), and an atomic force microscope (AFM). The results of laser oscillation evaluation by optical excitation showed that the printed microdisk sufficiently functions as an optical resonator with a low optical loss. In these evaluations, excellent values such as a surface roughness of 5.83 nm from root mean square (R. M. S.) which is one forth smaller than the particle diameter, and a laser oscillation threshold of 4.76 µJ/mm2 at a wavelength of 601.4 nm were obtained. To the best of our knowledge, this is the first time that an inorganic microdisk has been fabricated at room temperature to realize an organic-inorganic hybrid microdisk laser.

Demonstration of versatile whispering-gallery micro-lasers for remote refractive index sensing.

We developed chip-scale remote refractive index sensors based on Rhodamine 6G (R6G)-doped polymer micro-ring lasers. The chemical, temperature, and mechanical sturdiness of the fused-silica host guaranteed a flexible deployment of dye-doped polymers for refractive index sensing. The introduction of the dye as gain medium demonstrated the feasibility of remote sensing based on the free-space optics measurement setup. Compared to the R6G-doped TZ-001, the lasing behavior of R6G-doped SU-8 polymer micro-ring laser under an aqueous environment had a narrower spectrum linewidth, producing the minimum detectable refractive index change of 4 × 10-4 RIU. The maximum bulk refractive index sensitivity (BRIS) of 75 nm/RIU was obtained for SU-8 laser-based refractive index sensors. The economical, rapid, and simple realization of polymeric micro-scale whispering-gallery-mode (WGM) laser-based refractive index sensors will further expand pathways of static and dynamic remote environmental, chemical, biological, and bio-chemical sensing.

Effects of edge inclination angles on whispering-gallery modes in printable wedge microdisk lasers.

The ink-jet technique was developed to print the wedge polymer microdisk lasers. The characterization of these lasers was implemented using a free-space optics measurement setup. It was found that disks of larger edge inclination angles have a larger free spectral range (FSR) and a lower resonance wavelength difference between the fundamental transverse electric (TE) and transverse magnetic (TM) whispering-gallery modes (WGMs). This behavior was also confirmed with simulations based on the modified Oxborrow's model with perfectly matched layers (PMLs), which was adopted to accurately calculate the eigenfrequencies, electric field distributions, and quality parameters of modes in the axisymmetric microdisk resonators. Combined with the nearly equivalent quality factor (Q-factor) and finesse factor (F-factor) variations, the correlations between the TE and left adjacent TM modes were theoretically demonstrated. When the edge inclination angle is varied, the distinguishable mode distribution facilitates the precise estimation of a resonance wavelength shift. Therefore, the flexible and efficient nature of wedge polymer microdisk lasers extends their potential applications in precision sensing technology.

[A Case of Multiple Venous Thromboses Associated with Acute Cytomegalovirus Infection].

A previously healthy 44-year-old male presented with fever, abdominal pain, liver dysfunction and lymphadenopathy. He was diagnosed as having acute cytomegalovirus (CMV) infection with elevated CMV-IgG and IgM, and observed with supportive therapy. He was admitted to our hospital with prolonged fever lasting for a month. Enhanced CT revealed multiple thromboses in the right pulmonary artery and superior mesenteric vein. Follow-up CT after one week revealed new-onset thromboses in the left pulmonary artery and common iliac vein. Screening tests for thrombophilia were negative. His symptoms were improved with anticoagulant therapy with intravenous heparin, followed by oral warfarin. He was discharged on admission day 28 with good condition. Follow-up CT after 6 months revealed complete resolution of the thromboses. Anticoagulant therapy was stopped after 9 months, and he has been well without recurrence. Though vascular thrombosis is a rare complication, we must be alert to the signs and symptoms of thrombosis in patients with acute CMV infection.

Coexistence of Aedes aegypti and Aedes albopictus (Diptera: Culicidae) in Peninsular Florida Two Decades After Competitive Displacements.

The spread of Aedes albopictus (Skuse) eastward in the mid-1980s from its initial establishment in Houston, TX, was associated with rapid declines and local disappearances of Aedes aegypti (L.) in Gulf Coast states and Florida where annual larval surveillance during the early 1990s described temporal and spatial patterns of competitive displacements in cemeteries and tire shops. Approximately 20 yr later in 2013-2014, we re-visited former collection sites and sampled aquatic immatures of these two species from tire shops in 10 cities on State Route 441 and from 9 cemeteries from Lakeland to Miami in southwest Florida. In the recent samples Ae. aegypti was recovered from three central Florida cities where it had not been detected in 1994, but its northern limit on Rte. 441, Apopka, did not change. Other evidence, such as trends at a few cemeteries, suggested a moderate resurgence of this species since 1994. Cage experiments that exposed female progeny of Ae. aegypti from recent Florida collection sites to interspecific mating by Ae. albopictus males showed that females from coexistence sites had evolved resistance to cross-mating, but Ae. aegypti from sites with no Ae. albopictus were relatively susceptible to satyrization. Habitat classifications of collection sites were reduced by principal component (PC) analysis to four variables that accounted for > 99% of variances; PCs with strong positive loadings for tree cover and ground vegetation were associated with collection sites yielding only Ae. albopictus Within the coexistence range of the two species, the numbers of Ae. aegypti among total Aedes collected were strongly correlated in stepwise logistic regression models with two habitat-derived PCs, distance from the coast, and annual rainfall and mean maximum temperatures at the nearest weather station. Subtle increases in the range of Ae. aegypti since its previous displacements are interpreted in the context of the evolution of resistance to mating interference, realized versus fundamental niches of the two species, and persisting competition with Ae. albopictus.

Nanoparticle-polymer composite volume holographic gratings dispersed with ultrahigh-refractive-index hyperbranched polymer as organic nanoparticles.

We report on volume holographic recording at a wavelength of 532 nm in photopolymerizable polymer nanocomposites that are incorporated with new hyperbranched polymers (HBPs) acting as transporting organic nanoparticles. Since HBPs possess an ultrahigh index of refraction of 1.82 due to the inclusion of triazine and aromatic ring units, high-contrast transmission volume holographic gratings with refractive index modulation amplitudes as large as 2.2×10(-2) are recorded. This value enables us to realize a 10 µm thick transmission volume grating with the diffraction efficiency near 100% in the green.

Efficient gene-targeting in rat embryonic stem cells by CRISPR/Cas and generation of human kynurenine aminotransferase II (KAT II) knock-in rat.

The relative proportion of kynurenine aminotransferase (KAT) I-IV activities in the brain is similar between humans and rats. Moreover, KAT II is considered to be the main enzyme for kynurenic acid production in the brain. Taken together, human KAT II knock-in (hKAT II KI) rats will become a valuable tool for the evaluation of KAT II targeted drugs as a human mimetic model. Although we initially tried the approach by conventional gene-targeting via embryonic stem cells (ESCs) to generate them, we had to give up the production because of no recombinant ESCs. Accordingly, we developed a method to improve the efficiency of homologous recombination (HR) in ESCs by the combination with the CRISPR/Cas system. Co-electroporation of Cas9 plasmid, single guide RNA plasmid and hKAT II KI vector increased the number of drug-resistant colonies and greatly enhanced the HR efficiency from 0 to 36 %. All the clones which we obtained showed the same sequence as designed. These recombinant clones resulted in chimeras that transmitted the hKAT II KI allele to their offspring. hKAT II KI rats showed no reduction of KATs mRNA expression and the amount of kynurenic acid was similar between the hKAT II KI rats and the wild type in their brains. These results indicate that the methodology presented in this report can overcome the problem encountered in conventional gene-targeting that prevented production of humanized rats.

Impact characteristics of a vehicle population in low speed front to rear collisions.

Rear impact collisions are mostly low severity, but carry a very high societal cost due to reported symptoms of whiplash and related soft tissue injuries. Given the difficulty in physiological measurement of damage in whiplash patients, there is a significant need to assess rear impact severity on the basis of vehicle damage. This paper presents fundamental impact equations on the basis of an equivalent single vehicle to rigid barrier collision in order to predict relationships between impact speed, maximum dynamic crush, mean and peak acceleration, time to common velocity and vehicle stiffness. These are then applied in regression analysis of published staged low speed rear impact tests. The equivalent mean and peak accelerations are linear functions of the collision closing speed, while the time to common velocity is independent of the collision closing speed. Furthermore, the time to common velocity can be used as a surrogate measure of the normalized vehicle stiffness, which provides opportunity for future accident reconstruction.