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Patients with psoriasis are frequently complicated with metabolic syndrome; however, it is not fully understood how obesity and dyslipidemia contribute to the pathogenesis of psoriasis. To investigate the mechanisms by which obesity and dyslipidemia exacerbate psoriasis using murine models and neonatal human epidermal keratinocytes (NHEKs), we used wild-type and Apoe-deficient dyslipidemic mice, and administered a high-fat diet for 10 weeks to induce obesity. Imiquimod was applied to the ear for 5 days to induce psoriatic dermatitis. To examine the innate immune responses of NHEKs, we cultured and stimulated NHEKs using IL-17A, TNF-α, palmitic acid, and leptin. We found that obesity and dyslipidemia synergistically aggravated psoriatic dermatitis associated with increased gene expression of pro-inflammatory cytokines and chemokines. Treatment of NHEKs with palmitic acid and leptin amplified pro-inflammatory responses in combination with TNF-α and IL-17A. Additionally, pretreatment with palmitic acid and leptin enhanced IL-17A-mediated c-Jun N-terminal kinase phosphorylation. These results revealed that obesity and dyslipidemia synergistically exacerbate psoriatic skin inflammation, and that metabolic-disorder-associated inflammatory factors, palmitic acid, and leptin augment the activation of epidermal keratinocytes. Our results emphasize that management of concomitant metabolic disorders is essential for preventing disease exacerbation in patients with psoriasis.

IntroductionClinical studies have suggested a bidirectional association between non-alcoholic steatohepatitis (NASH) and psoriasis, affecting each other’s development and severity. Here, we explored bidirectional causal linkages between NASH and psoriasis using a murine model.MethodsNASH was induced in mice by streptozotocin injection at 2 days of age and by high-fat diet feeding (STAM™ model). Psoriasis was induced by topical application of imiquimod (IMQ) on the ear. The severities of liver damage and psoriatic skin changes were determined using histological analysis. Gene expression in the skin tissues was evaluated using quantitative PCR analysis. Serum cytokine levels were determined using enzyme-linked immunosorbent assay. To examine the innate immune responses of normal human epidermal keratinocytes (NHEKs), the cells were treated with interleukin (IL)-17A, tumor necrosis factor (TNF)-α, and AdipoRon, an adiponectin receptor agonist.Results and DiscussionThere were no differences in the degree of liver tissue damage (fat deposition, inflammation, and fibrosis) between NASH mice with and those without psoriasis. Conversely, the co-occurrence of NASH significantly augmented psoriatic skin changes, represented by epidermal hyperplasia, in psoriatic mice. Pro-inflammatory cytokines were expressed in the inflamed skin of psoriatic mice, and the expression of genes, especially Il23a , Il1b , Il36g , and Mip2 , was significantly upregulated by the co-occurrence of NASH. The expression of keratinocyte activation marker genes Defb4b and Krt16 was also upregulated by the co-occurrence of NASH. The serum TNF-α and IL-17 levels were increased by the co-occurrence of NASH and psoriasis. The serum adiponectin levels decreased in NASH mice compared with that in non-NASH mice. In NHEK culture, TNF-α and IL-17A synergistically upregulated CXCL1 , CXCL8 , and IL1B expression. The upregulated pro-inflammatory gene expression was suppressed by AdipoRon treatment, reflecting the anti-inflammatory capacity of adiponectin.ConclusionThe co-occurrence of NASH exacerbated psoriatic skin changes associated with increased serum inflammatory cytokine levels and decreased serum adiponectin levels. Combined with in vitro findings, increased inflammatory cytokine levels and decreased adiponectin levels likely promote innate immune responses in epidermal keratinocytes in psoriatic skin lesions. Overall, therapeutic intervention for co-occurring NASH is essential to achieve a favorable prognosis of psoriasis in clinical practice.

Patch granuloma annulare is a rare type of granuloma annulare. Histopathologically, patch granuloma annulare shows interstitial infiltration of histiocytes. In our case, immunohistochemical analyses demonstrated CD68‐negative, CD163‐positive M2 macrophages infiltration in an interstitial pattern.

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autoinflammatory periodic fever syndrome associated with heterozygous mutations in TNFRSF1A , which encodes TNF receptor type I (TNFR1). Although possible proinflammatory mechanisms have been proposed, most previous studies were performed using in vitro overexpression models, which could lead to undesirable inflammatory responses due to artificial overexpression. It is crucial to reproduce heterozygous mutations at physiological expression levels; however, such studies remain limited. In this study, we generated TRAPS mutant mice and analyzed their phenotypes. Three Tnfrsf1a mutant strains were generated by introducing T79M, G87V, or T90I mutation. T79M is a known mutation responsible for TRAPS, whereas G87V is a TRAPS mutation that we have reported, and T90I is a variant of unknown significance. Using these murine models, we investigated whether TRAPS mutations could affect the inflammatory responses in vivo and in vitro . We found that none of the mutant mice exhibited detectable inflammatory phenotypes under standard housing conditions for 1 year. Interestingly, TRAPS mutant (T79M and G87V) mice had reduced mortality rates after the administration of lipopolysaccharide (LPS) and D-galactosamine, which induce TNFα-dependent lethal hepatitis. Moreover, TRAPS mutations strongly suppressed the development of TNFα-mediated arthritis when crossed with human TNFα transgenic mice. In in vitro primary bone marrow-derived macrophage cultures, the T79M and G87V mutations attenuated the inflammatory responses to TNFα compared with the wild-type, whereas these mutations did not alter the responsiveness of these cells to LPS. The T90I mutant macrophages behaved similarly to wild type in response to LPS and TNFα. The TNFR1 levels were increased in whole-cell lysates of TRAPS mutant macrophages, whereas the cell surface expression of TNFR1 was significantly decreased in TRAPS mutant macrophages. Taken together, TRAPS mutations did not augment the inflammatory responses to TNFα and LPS; instead, they suppressed the response to TNFα via decreased cell surface expression of TNFR1. The stimulation of lymphotoxin-α, adenosine triphosphate, and norepinephrine in primary macrophages or various stimuli in murine splenocytes did not induce detectable inflammatory responses. In conclusion, TRAPS mutations suppressed responsiveness to TNFα, and TRAPS-associated inflammation is likely induced by unconfirmed disease-specific proinflammatory factors.

We report a rare case of Campylobacter fetus meningitis and pyogenic spondylodiscitis in a healthy young woman. A 35-year-old woman without significant medical history presented with fever, headache, and low back pain. C. fetus was detected from the blood culture. Cerebrospinal fluid analysis showed bacterial meningitis 2 days after onset. Although initial magnetic resonance imaging (MRI) did not reveal abnormal findings, repeated MRI showed a low-signal-intensity lesion on T1-weighted image (T1WI) and a high-signal-intensity lesion on T2WI between the L5 and S1 vertebral bodies 11 days after onset. The mode of infection was considered to be the consumption of raw chicken meat. After antibiotic treatment with 12 g/day ampicillin following 6 g/day meropenem, she was discharged 51 days after onset. As the inflammatory signs on MRI improved, oral antibiotic therapy was discontinued 85 days after onset. Although the initial MRI showed no abnormal findings, repeat MRI should be performed for patients who have persistent low back pain and fever.

Objective To identify the incidence and characteristics of airway diseases in very low birth weight infants (VLBWIs). Methods A retrospective study of 214 inborn VLBWIs admitted to our NICU between April 2009 and March 2022 (approval no: 2023-0008). Neonatologists ourselves performed bronchoscopy to diagnose airway diseases. Results Symptomatic airway diseases were present in 36/214 (16.8%) of VLBWIs. Common airway diseases were tracheobronchomalacia (TBM) and pharyngomalacia. Infants with airway diseases had shorter gestational age, lower birth weight, more boys, and more moderate/severe bronchopulmonary dysplasia (BPD). Regarding treatment, more infants with airway diseases required intubation were intubated longer, used more dexamethasone, were on ventilators and oxygen longer, and were hospitalized longer. Conclusion We found that VLBWIs were more frequently complicated with airway diseases, especially TBM. We also observed many pharyngeal lesions, which have not been previously reported. Intensity of prematurity, BPD, and the need for stronger respiratory management were risks for airway diseases. In VLBWIs, bronchoscopy should be actively performed because airway diseases are important complications.

Acute flaccid myelitis (AFM) is an acute flaccid paralysis syndrome with spinal motor neuron involvement of unknown etiology. We investigated the characteristics and prognostic factors of AFM clusters coincident with an enterovirus D68 (EV-D68) outbreak in Japan during autumn 2015. An AFM case series study was conducted following a nationwide survey from August to December 2015. Radiographic and neurophysiologic data were subjected to centralized review, and virology studies were conducted for available specimens. Fifty-nine AFM cases (58 definite, 1 probable) were identified, including 55 children and 4 adults (median age, 4.4 years). The AFM epidemic curve showed strong temporal correlation with EV-D68 detection from pathogen surveillance, but not with other pathogens. EV-D68 was detected in 9 patients: 5 in nasopharyngeal, 2 in stool, 1 in cerebrospinal fluid (adult case), and 1 in tracheal aspiration, nasopharyngeal, and serum samples (a pediatric case with preceding steroid usage). Cases exhibited heterogeneous paralysis patterns from 1- to 4-limb involvement, but all definite cases had longitudinal spinal gray matter lesions on magnetic resonance imaging (median, 20 spinal segments). Cerebrospinal fluid pleocytosis was observed in 50 of 59 cases (85%), and 8 of 29 (28%) were positive for antiganglioside antibodies, as frequently observed in Guillain-Barré syndrome. Fifty-two patients showed variable residual weakness at follow-up. Good prognostic factors included a pretreatment manual muscle strength test unit score >3, normal F-wave persistence, and EV-D68-negative status. EV-D68 may be one of the causative agents for AFM, while host susceptibility factors such as immune response could contribute to AFM development.

Estrogen is an essential sex steroid hormone that functions primarily in female reproductive system, as well as in a variety of tissues and organs with pleiotropic effects, such as in cardiovascular, nervous, immune, and musculoskeletal systems. Women with low estrogen, as exemplified by those in postmenopause, are therefore prone to suffer from various disorders, i.e., cardiovascular disease, dementia, metabolic syndrome, osteoporosis, sarcopenia, frailty, and so on. Estrogen regulates the expression of its target genes by binding to its cognate receptors, estrogen receptors (ERs) α and β. Notably, the estrogen-related receptors (ERRs) α, β, and γ are originally identified as orphan receptors that share substantial structural homology and common transcriptional targets with ERs. Accumulating evidence suggests that ERs and ERRs play crucial roles in skeletal muscles, such as muscle mass maintenance, muscle exercise physiology, and muscle regeneration. In this article, we review potential regulatory roles of ERs and ERRs in muscle physiology, particularly with regard to mitochondrial function and metabolism.

In Pseudomonas aeruginosa , MexAB–OprM plays a central role in multidrug resistance by ejecting various drug compounds, which is one of the causes of serious nosocomial infections. Although the structures of the components of MexAB–OprM have been solved individually by X-ray crystallography, no structural information for fully assembled pumps from P. aeruginosa were previously available. In this study, we present the structure of wild-type MexAB–OprM in the presence or absence of drugs at near-atomic resolution. The structure reveals that OprM does not interact with MexB directly, and that it opens its periplasmic gate by forming a complex. Furthermore, we confirm the residues essential for complex formation and observed a movement of the drug entrance gate. Based on these results, we propose mechanisms for complex formation and drug efflux. In Pseudomonas aeruginosa , MexAB–OprM plays a central role in multidrug resistance by ejecting various drug compounds. Here the authors present the structure of wild-type MexAB–OprM in the presence or absence of drugs and propose mechanisms for complex formation and drug efflux.

A major obstacle to improving prognoses in ovarian cancer is the lack of effective screening methods for early detection. Circulating microRNAs (miRNAs) have been recognized as promising biomarkers that could lead to clinical applications. Here, to develop an optimal detection method, we use microarrays to obtain comprehensive miRNA profiles from 4046 serum samples, including 428 patients with ovarian tumors. A diagnostic model based on expression levels of ten miRNAs is constructed in the discovery set. Validation in an independent cohort reveals that the model is very accurate (sensitivity, 0.99; specificity, 1.00), and the diagnostic accuracy is maintained even in early-stage ovarian cancers. Furthermore, we construct two additional models, each using 9–10 serum miRNAs, aimed at discriminating ovarian cancers from the other types of solid tumors or benign ovarian tumors. Our findings provide robust evidence that the serum miRNA profile represents a promising diagnostic biomarker for ovarian cancer. Screening methods for early detection of ovarian cancer is technically difficult. Here, the authors investigated circulating microRNA in human blood serum and developed a model using 10 microRNAs to discern between ovarian cancer and being ovarian tumors, solid tumors, and non-cancer patients.