Macrophage/microglia-producing transient increase of platelet-activating factor is involved in neuropathic pain.

Peripheral nerve injury (PNI) induces debilitating neuropathic pain symptoms, such as tactile allodynia. Accumulating evidence suggests that the expression levels of various transcripts and proteins are drastically changed after PNI. Recent lipidome analysis demonstrates increased levels of diverse lipids in chronic pain conditions. We show that PNI transiently increases platelet-activating factor (PAF) levels, a potent inflammatory phospholipid mediator, in the dorsal root ganglia (DRG) and spinal cord. We revealed that macrophage and microglia-specific PAF-producing enzyme LPLAT9/LPCAT2 knockout mice (Cx3cr1CreERT2;Lpcat2flox/flox) failed to develop mechanical allodynia and to increase PAF levels in the DRG and spinal cord after PNI. Moreover, we observed the suppression of PNI-induced PAF increase in the spinal cord of PAF receptor knockout mice, indicating a self-amplification loop of PAF production. In conclusion, macrophages and microglia enhance PAF production, contributing to PNI-induced neuropathic pain. Additionally, PAF-PAF receptor signaling is a potential target of neuropathic pain control.

Text and image generation from intracranial electroencephalography using an embedding space for text and images.

Objective.Invasive brain-computer interfaces (BCIs) are promising communication devices for severely paralyzed patients. Recent advances in intracranial electroencephalography (iEEG) coupled with natural language processing have enhanced communication speed and accuracy. It should be noted that such a speech BCI uses signals from the motor cortex. However, BCIs based on motor cortical activities may experience signal deterioration in users with motor cortical degenerative diseases such as amyotrophic lateral sclerosis. An alternative approach to using iEEG of the motor cortex is necessary to support patients with such conditions.Approach. In this study, a multimodal embedding of text and images was used to decode visual semantic information from iEEG signals of the visual cortex to generate text and images. We used contrastive language-image pretraining (CLIP) embedding to represent images presented to 17 patients implanted with electrodes in the occipital and temporal cortices. A CLIP image vector was inferred from the high-γpower of the iEEG signals recorded while viewing the images.Main results.Text was generated by CLIPCAP from the inferred CLIP vector with better-than-chance accuracy. Then, an image was created from the generated text using StableDiffusion with significant accuracy.Significance.The text and images generated from iEEG through the CLIP embedding vector can be used for improved communication.

Medial Meniscus Posterior Root Reconstruction and Open-Wedge High-Tibial Osteotomy for Medial Meniscus Posterior Root Tear With Varus Knee Alignment: A Retrospective Study on Short-Term Outcomes.

PURPOSE: We describe 13 cases of medial meniscus posterior root tear (MMPRT) with varus knee alignment treated with medial meniscus posterior root reconstruction (MMPR-R) and open-wedge high-tibial osteotomy (OWHTO) to identify an optimal MMPRT treatment. METHODS: We retrospectively reviewed 13 patients (mean age: 66.3 ± 8.0 years) who underwent MMPR-R and OWHTO. The Knee Injury and Osteoarthritis Outcome Score (KOOS), femorotibial angle (FTA), percentage mechanical axis (%MA) on radiography, and medial meniscus extrusion (MME) on magnetic resonance imaging (MRI) between the preoperative period and last follow-up were compared. Moreover, meniscus healing status and the International Cartilage Repair Society (ICRS) classification of the medial femoral condyle and medial tibial plateau on arthroscopy between the initial surgery and second-look arthroscopy were compared. RESULTS: The mean follow-up duration was 12.8 ± 2.2 months. At the last follow-up, the KOOS significantly improved (P < 0.01). Based on the FTA and %MA, the varus alignment was predominantly corrected at the last follow-up (P < 0.01). The MME was increased in nine (62.9%) patients, and the mean MME significantly increased at the last follow-up (P = 0.04). Second-look arthroscopy revealed improvements in the ICRS grade for the medial femoral condyle and medial tibial plateau in six (46.2%) patients. However, the results did not significantly differ. Regarding meniscus healing, four (30.8%) patients presented with complete healing, eight (57.1%) with partial healing, and one (7.7%) with failed healing. CONCLUSIONS: The MMPRT with varus knee alignment significantly improved with MMPR-R and OWHTO. However, the MME and meniscus healing were unsatisfactory.

Stress responses to bacterial and viral mimetics in polycystic ovary syndrome model rats.

Polycystic ovary syndrome (PCOS) is associated with an increased risk of psychological distress as well as enhanced responses to psychosocial stress. Recently, it was hypothesized that PCOS patients may be at high risk of novel COVID-19 infections and worse clinical presentations during such infections. Here, we evaluated the effects of PCOS on stress responses to bacterial and viral mimetics using dihydrotestosterone-induced PCOS model rats. Lipopolysaccharide (LPS; a bacterial mimetic) or polyinosinic-polycytidylic acid (Poly-IC; a viral mimetic) was injected into PCOS model rats (PCOS) and non-PCOS rats (control), and the rats' stress responses were evaluated. In the PCOS group, the rats' anorectic and febrile responses to LPS injection were enhanced, whereas their anorectic and febrile responses to Poly-IC injection were unaltered. The PCOS group also exhibited greater changes in peripheral cytokine levels in response to LPS, but not Poly-IC. On the contrary, after the injection of Poly-IC depressed locomotor activity was more evident in the PCOS group, whereas no such changes were observed after LPS injection. These findings indicate that although the stress responses of PCOS model rats to infection may be enhanced, the patterns of change in stress responses and their underlying mechanisms may differ between bacterial and viral infections.

Kisspeptin administration may promote precopulatory behavior in male rats independently or supplementally to testosterone and contribute to proceptive behavior in female partners, reducing mating failure.

Kisspeptin is a peptide that plays an important role through its effects on the hypothalamus-pituitary-gonadal (HPG) axis. It has also been implicated in sexual behavior. The present study investigated whether the relationship between kisspeptin and sexual behavior is independent of the HPG axis, i.e., testosterone. Sexual behavior was examined after the administration of kisspeptin to gonadally intact male rats and gonadectomized male rats that received testosterone supplementation. Other male rats were also observed for sexual behavior once a week from 2 to 5 weeks after gonadectomy and receiving kisspeptin for the sixth postoperative week. Sexual behavior in female rats serving as the partner for each male was also observed. Female rats were not administered kisspeptin in the present study. The results obtained showed that the administration of kisspeptin increased precopulatory behavior in gonadally intact male rats and gonadectomized male rats that received testosterone supplementation and proceptive behavior in their female partners. Precopulatory behavior in males and receptive behavior in females increased, while copulatory behavior in males and receptive behavior in females remained unchanged. Furthermore, the administration of kisspeptin increased precopulatory behavior in gonadectomized males, but did not affect receptive behavior in females. These results suggest that kisspeptin affected males independently and/or supplementally to testosterone, and also that changes in the presence of testosterone in males had an impact on proceptive behavior in their female partners. In conclusion, kisspeptin may involve an as-yet-unidentified neural pathway in sexual desire independently of the HPG axis.

Expression of SMADs in orthotopic human endometrium, ovarian endometriosis, and endometriotic lesions in a murine model.

Activin A promotes the development of endometriotic lesions in a murine model of endometriosis, and the immunohistochemical localization of phosphorylated suppressor of mothers against decapentaplegic homolog 2/3 (pSMAD2/3) complex in endometriotic lesions has been reported. Activin may therefore be involved in the development and proliferation of endometriotic cells via the SMAD signaling pathway. However, few detailed reports exist on SMAD7 expression in endometriosis. The purpose of this study was to investigate the expression of pSMAD2/3 or pSMAD3 and SMAD7 in the orthotopic human endometrium, ovarian endometriosis, and endometriotic lesions in a murine model and the effect of activin A on pSMAD2/3 and SMAD7 expression. We established an endometriosis murine model via the intraperitoneal administration of endometrial tissue and blood from donor mice. Activin A was intraperitoneally administered to the activin group. We immunohistochemically evaluated orthotopic endometria, ovarian endometriotic tissues, and endometriotic lesions in the murine model followed by western blotting. We found that pSMAD3 and SMAD7 were expressed in ovarian endometriosis and orthotopic endometria from patients with and without endometriosis. In the murine model, endometriotic lesions expressed pSMAD2/3 and SMAD7 in the activin and control groups, and higher SMAD7 expression was found in the activin group. To the best of our knowledge, this study is the first to show that SMAD7 expression is upregulated in endometriosis. In conclusion, these results suggest that activin A activates the SMAD signaling pathway and promotes the development of endometriotic lesions, thus identifying SMAD7 as a potential therapeutic target for endometriosis.

Prediction of MGMT promotor methylation status in glioblastoma by contrast-enhanced T1-weighted intensity image.

Background: The study aims to explore MRI phenotypes that predict glioblastoma's (GBM) methylation status of the promoter region of MGMT gene (pMGMT) by qualitatively assessing contrast-enhanced T1-weighted intensity images. Methods: A total of 193 histologically and molecularly confirmed GBMs at the Kansai Network for Molecular Diagnosis of Central Nervous Tumors (KANSAI) were used as an exploratory cohort. From the Cancer Imaging Archive/Cancer Genome Atlas (TCGA) 93 patients were used as validation cohorts. "Thickened structure" was defined as the solid tumor component presenting circumferential extension or occupying >50% of the tumor volume. "Methylated contrast phenotype" was defined as indistinct enhancing circumferential border, heterogenous enhancement, or nodular enhancement. Inter-rater agreement was assessed, followed by an investigation of the relationship between radiological findings and pMGMT methylation status. Results: Fleiss's Kappa coefficient for "Thickened structure" was 0.68 for the exploratory and 0.55 for the validation cohort, and for "Methylated contrast phenotype," 0.30 and 0.39, respectively. The imaging feature, the presence of "Thickened structure" and absence of "Methylated contrast phenotype," was significantly predictive of pMGMT unmethylation both for the exploratory (p = .015, odds ratio = 2.44) and for the validation cohort (p = .006, odds ratio = 7.83). The sensitivities and specificities of the imaging feature, the presence of "Thickened structure," and the absence of "Methylated contrast phenotype" for predicting pMGMT unmethylation were 0.29 and 0.86 for the exploratory and 0.25 and 0.96 for the validation cohort. Conclusions: The present study showed that qualitative assessment of contrast-enhanced T1-weighted intensity images helps predict GBM's pMGMT methylation status.

Ionic Liquid Interface as a Cell Scaffold.

In sharp contrast to conventional solid/hydrogel platforms, water-immiscible liquids, such as perfluorocarbons and silicones, allow the adhesion of mammalian cells via protein nanolayers (PNLs) formed at the interface. However, fluorocarbons and silicones, which are typically used for liquid cell culture, possess only narrow ranges of physicochemical parameters and have not allowed for a wide variety of cell culturing environments. In this paper, it is proposed that water-immiscible ionic liquids (ILs) are a new family of liquid substrates with tunable physicochemical properties and high solvation capabilities. Tetraalkylphosphonium-based ILs are identified as non-cytotoxic ILs, whereon human mesenchymal stem cells are successfully cultured. By reducing the cation charge distribution, or ionicity, via alkyl chain elongation, the interface allows cell spreading with matured focal contacts. High-speed atomic force microscopy observations of the PNL formation process suggest that the cation charge distribution significantly altered the protein adsorption dynamics, which are associated with the degree of protein denaturation and the PNL mechanics. Moreover, by exploiting dissolution capability of ILs, an ion-gel cell scaffold is fabricated. This enables to further identify the significant contribution of bulk subphase mechanics to cellular mechanosensing in liquid-based culture scaffolds.

Progesterone treatment reduces food intake and body weight in ovariectomized female rats.

While the effects of progesterone on body weight and appetite in pre-menopausal conditions have been well elucidated, its effects in post-menopausal conditions have not been clarified. On the contrary, the effects of estrogen on body weight and appetite in post-menopausal conditions have been well established. In this study, the effects of progesterone treatment on body weight, appetite, and fat mass in ovariectomized rats were evaluated. In addition, the central and/or peripheral levels of oxytocin (OT), leptin, and their receptors, which are potent anorectic factors, were examined. Female rats were ovariectomized and divided into control, progesterone-treated, and estrogen-treated groups. Body weight, food intake, and subcutaneous fat mass were lower in both the progesterone and estrogen groups than in the control group. The estrogen group exhibited higher serum OT levels than the control group, whereas the OT levels of the progesterone and control groups did not differ. The serum leptin levels of both the progesterone and estrogen groups were lower than those of the control group. Gene expression analysis of OT, leptin, and their receptors in the hypothalamus and adipose tissue found few significant differences among the groups. Hypothalamic neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) mRNA levels involved in appetite regulation were slightly altered in the progesterone and estrogen groups. These findings suggest that progesterone treatment may have favorable effects on body weight, appetite, and fat mass regulation in post-menopausal conditions and that the mechanisms underlying these effects of progesterone differ from those underlying the effects of estrogen.

Age-Dependent Changes in the Effects of Androgens on Female Metabolic and Body Weight Regulation Systems in Humans and Laboratory Animals.

In recent years, the effects of androgens on metabolic and body weight regulation systems and their underlying mechanisms have been gradually revealed in females. In women and experimental animals of reproductive age, androgen excess can adversely affect metabolic functioning, appetite, and body weight regulation. In addition, excess androgens can increase the risk of metabolic disorders, such as obesity, insulin resistance, and diabetes. These unfavorable effects of androgens are induced by alterations in the actions of hypothalamic appetite-regulatory factors, reductions in energy expenditure, insulin resistance in skeletal muscle, and ß-cell dysfunction. Interestingly, these unfavorable effects of androgens on metabolic and body-weight regulation systems are neither observed nor evident in ovariectomized animals and post-menopausal women, indicating that the adverse effects of androgens might be dependent on the estrogen milieu. Recent findings may provide novel sex- and age-specific strategies for treating metabolic diseases.

Effects of activation with a Ca ionophore and roscovitine on the development of human oocytes that failed to fertilize after ICSI.

OBJECTIVE: The effects of oocyte activation with a Ca ionophore and roscovitine (Ca+R), a selective inhibitor of M-phase promoting factor, on unfertilized oocytes after intracytoplasmic sperm injection (ICSI) or testicular sperm extraction (TESE)-ICSI were evaluated. METHOD: Oocytes without pronuclei at 18 hours after ICSI were judged to be unfertilized and were exposed to the Ca ionophore A23187 (5 ?M) with or without roscovitine (50 ?M). The activation rate was measured 3, 7, and 18 hours later. Oocytes with two polar bodies and two pronuclei with a sperm tail were judged to have been activated. RESULTS: At 18 hours, the activation rates in the control, Ca ionophore, and Ca+R groups were 3.5% (4/112), 26.9% (7/26), and 32.1% (17/53), respectively. The activation rate of the Ca+R group was significantly higher than that of the control and similar to that of the Ca ionophore group. Among the oocytes that remained unfertilized after TESE-ICSI, the activation rates of the Ca ionophore and Ca+R groups were 22.2% (2/9) and 43.8% (7/16), respectively. CONCLUSIONS: Sequential treatment with an Ca ionophore and roscovitine activates oocytes that remain unfertilized after ICSI. In TESE-ICSI, the activation rate tended to be increased by the co-administration of roscovitine with a Ca ionophore. J. Med. Invest. 70 : 321-324, August, 2023.

Qualitative MR features to identify non-enhancing tumors within glioblastoma's T2-FLAIR hyperintense lesions.

PURPOSE: To identify qualitative MRI features of non-(contrast)-enhancing tumor (nCET) in glioblastoma's T2-FLAIR hyperintense lesion. METHODS: Thirty-three histologically confirmed glioblastoma patients whose T1-, T2- and contrast-enhanced T1-weighted MRI and 11C-methionine positron emission tomography (Met-PET) were available were included in this study. Met-PET was utilized as a surrogate for tumor burden. Imaging features for identifying nCET were searched by qualitative examination of 156 targets. A new scoring system to identify nCET was established and validated by two independent observers. RESULTS: Three imaging features were found helpful for identifying nCET; "Bulky gray matter involvement", "Around the rim of contrast-enhancement (Around-rim)," and "High-intensity on T1WI and low-intensity on T2WI (HighT1LowT2)" resulting in an nCET score = 2 × Bulky gray matter involvement - 2 × Around-rim + HighT1LowT2 + 2. The nCET score's classification performances of two independent observers measured by AUC were 0.78 and 0.80, with sensitivities and specificities using a threshold of four being 0.443 and 0.771, and 0.916 and 0.768, respectively. The weighted kappa coefficient for the nCET score was 0.946. CONCLUSION: The current investigation demonstrated that qualitative assessments of glioblastoma's MRI might help identify nCET in T2/FLAIR high-intensity lesions. The novel nCET score is expected to aid in expanding treatment targets within the T2/FLAIR high-intensity lesions.

Vibegron shows high selectivity and potent agonist activity for ß3-adrenoceptors, irrespective of receptor density.

ß3-Adrenoceptor (AR) agonists are used to treat patients with an overactive bladder (OAB). Clinical proof-of-concept data have been obtained for the ß3-AR agonists vibegron, mirabegron, solabegron, and ritobegron; however, the selectivities of these agents have not been compared directly under the same experimental conditions. Moreover, the bladders of some patients express lower ß3-AR densities than those of healthy individuals, and the ß3-AR density might be expected to affect agonist activity. This study assessed the ß3-AR selectivities of four ß3-AR agonists and examined the effects of ß-AR density on their pharmacological profiles. Functional cellular assays were performed using Chinese hamster ovary-K1 cells expressing three human ß-AR subtypes transfected with different amounts of plasmid DNA (0.1, 0.05, 0.025 µg/well). The half-maximal effective concentration values, intrinsic activities (IAs), and ß3-AR selectivities of vibegron, mirabegron, solabegron, and ritobegron were calculated to assess their pharmacological profiles. The ß3-AR selectivities of vibegron, mirabegron, solabegron, and ritobegron were >7937-, 517-, 21.3-, and >124-fold higher than for ß1-ARs, and >7937-, 496-, >362- and 28.1-fold higher than for ß2-ARs, respectively, under the same experimental conditions. The IAs of mirabegron, solabegron, and ritobegron decreased in line with decreasing receptor density, while the IA of vibegron was maintained at the same level as that of the full agonist isoproterenol at various ß3-AR densities. Vibegron has high ß3-AR selectivity and exhibits full agonist activity, regardless of the ß3-AR density. These results suggest that vibegron is a highly effective and safe drug for treating OAB.

Guidelines for the Management of Respiratory Infectious Diseases in Children in Japan 2022.

The members of the Japanese Society for Pediatric Infectious Diseases and the Japanese Society of Pediatric Pulmonology have developed Guidelines for the Management of Respiratory Infectious Diseases in Children with the objective of facilitating appropriate diagnosis, treatment and prevention of respiratory infections in children. The first edition was published in 2004 and the fifth edition was published in 2022. The Guideline 2022 consists of 2 parts, clinical questions and commentary, and includes general respiratory infections and specific infections in children with underlying diseases and severe infections. This executive summary outlines the clinical questions in the Guidelines 2022, with reference to the Japanese Medical Information Distribution Service Manual. All recommendations are supported by a systematic search for relevant evidence and are followed by the strength of the recommendation and the quality of the evidence statements.

Lipid in microglial biology - from material to mediator.

Microglia are resident macrophages in the central nervous system (CNS) that play various roles during brain development and in the pathogenesis of CNS diseases. Recently, reprogramming of cellular energetic metabolism in microglia has drawn attention as a crucial mechanism for diversification of microglial functionality. Lipids are highly diverse materials and crucial components of cell membranes in every cell. Accumulating evidence has shown that lipid and its metabolism are tightly involved in microglial biology. In this review, we summarize the current knowledge about microglial lipid metabolism in health and disease.

Developmental Changes in Hypothalamic and Serum Oxytocin Levels in Prenatally Normally Nourished and Undernourished Rats.

Changes in the activities of some metabolic factors have been suggested to increase the risk of conditions associated with the Developmental Origins of Health and Disease (DOHaD). We examined changes in oxytocin (OT), a metabolic factor, and OT receptor (OTR) mRNA levels throughout the developmental period in rats of intrauterine undernutrition. Pregnant rats were divided into two groups: a maternal normal nutrition (mNN) and maternal undernutrition (mUN) group. Serum OT concentrations and hypothalamic mRNA levels of OT and OTR were measured in both offspring at various postnatal stages. Both offspring showed significant increases in serum OT concentrations during the neonatal period, significant reductions around the pubertal period, and significant increases in adulthood. Hypothalamic OT mRNA expression levels gradually increased from the neonatal to pubertal period and decreased in adulthood in both offspring. In the pre-weaning period, hypothalamic OT mRNA expression levels were significantly lower in the mUN offspring than in the mNN offspring. In the mUN offspring, hypothalamic OTR mRNA expression levels transiently increased during the neonatal period, decreased around the pubertal period, and increased again in adulthood, whereas transient changes were not detected in mNN offspring. These changes could affect nutritional and metabolic regulation systems in later life and play a role in the mechanisms underlying DOHaD.

Photoactivatable surfaces resolve the impact of gravity vector on collective cell migratory characteristics.

Despite considerable interest in the impact of space travel on human health, the influence of the gravity vector on collective cell migration remains unclear. This is primarily because of the difficulty in inducing collective migration, where cell clusters appear in an inverted position against gravity, without cellular damage. In this study, photoactivatable surfaces were used to overcome this challenge. Photoactivatable surfaces enable the formation of geometry-controlled cellular clusters and the remote induction of cellular migration via photoirradiation, thereby maintaining the cells in the inverted position. Substrate inversion preserved the circularity of cellular clusters compared to cells in the normal upright position, with less leader cell appearance. Furthermore, the inversion of cells against the gravity vector resulted in the remodeling of the cytoskeletal system via the strengthening of external actin bundles. Within the 3D cluster architecture, enhanced accumulation of active myosin was observed in the upper cell-cell junction, with a flattened apical surface. Depending on the gravity vector, attenuating actomyosin activity correlates with an increase in the number of leader cells, indicating the importance of cell contractility in collective migration phenotypes and cytoskeletal remodeling.

Polarity Does Not Matter: Molecular Weight Reverses the Photoisomerization-Induced Phase Separation of an Azobenzene-Bearing Polymer.

The non-canonical photoisomerization-induced phase separation of an azobenzene-bearing polymer is found. The polymer composed of acrylate-based azobenzene (AzoAA) and N,N-dimethylacrylamide (DMA), namely poly(AzoAA-r-DMA), phase separates under visible light-induced cis-to-trans isomerization at high molecular weight, whereas the phase separation is realized under UV light-induced trans-to-cis isomerization at low molecular weight. Conventionally, the origin of photoisomerization-induced phase separation is believed to arise from the difference in polarity between the apolar trans and polar cis states; thereby the direction of phase changes, either to separate or dissolute, is uniquely determined by the polarity changes during the isomerization of azobenzene. Contrary to this common perception, the poly(AzoAA-r-DMA) in this study phase separates through both trans and cis isomerization, depending on the molecular weight. The non-canonical phase separation of poly(AzoAA-r-DMA) reported herein suggests that molecular weight plays a significant role in determining the phase behavior of azobenzene-bearing polymers. This study provides a platform for the development of spatial-temporally controlled delivery vehicles and microreactors.