Acute acalculous cholecystitis following extended administration of nirmatrelvir/ritonavir for persistent SARS-CoV-2 infection.

Immunocompromised patients with hematologic malignancies, particularly those treated with anti-CD20 antibodies such as rituximab and obinutuzumab, are known to be at risk of prolonged infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Prolonged administration or combination therapy with antiviral medications reportedly yields favorable outcomes in these patients. However, knowledge regarding the adverse events associated with such therapeutic approaches is limited. Herein, we report a case of acute acalculous cholecystitis (AAC) following extended administration of nirmatrelvir/ritonavir (NMV/r) in a 68-year-old Japanese man with persistent SARS-CoV-2 infection. The patient had received obinutuzumab and bendamustine for follicular lymphoma and was diagnosed with coronavirus disease 2019 (COVID-19) approximately one year after treatment initiation with these drugs. Subsequently, he was admitted to a different hospital, where he received antiviral drugs, monoclonal antibodies, and steroids. Despite these interventions, the patient relapsed and was subsequently transferred to our hospital due to persistent SARS-CoV-2 infection. Remdesivir administration was ineffective, leading to the initiation of extended NMV/r therapy. One week later, he exhibited elevated gamma-glutamyl transpeptidase (GGT) levels, and one month later, he developed AAC. Cholecystitis was successfully resolved via percutaneous transhepatic gallbladder drainage and administration of antibiotics. We speculate that extended NMV/r administration, in addition to COVID-19, may have contributed to the elevated GGT and AAC. During treatment of persistent SARS-CoV-2 infection with extended NMV/r therapy, patients should be carefully monitored for the appearance of findings suggestive of biliary stasis and the development of AAC.

Effect of Arch Height Flexibility in Individuals With Flatfoot on Abductor Hallucis Muscle Activity and Medial Longitudinal Arch Angle During Short Foot Exercises.

Flatfoot presents decreased medial longitudinal arch (MLA), and such foot deformity involves intrinsic foot muscles dysfunction. Flatfoot can be classified into flexible and stiff types according to arch height flexibility (AHF). Short foot exercise (SFE) is an intrinsic foot muscle strengthening exercise, which is reportedly effective against flatfoot. However, its effectiveness against flexible or stiff types in flatfoot is unclear. We examined the effect of AHF in individuals with flatfoot during abductor hallucis muscle (AbH) activity and medial longitudinal arch during SFE. Foot alignment was assessed using the arch height index during standing, and individuals with flatfoot (N = 16) were recruited. The AbH activity and MLA angle during SFE while maintaining single-leg standing were assessed. The relationship between AHF and AbH activity and between AHF and MLA angle ratio was analyzed using correlation coefficients. Additional correlations between AHF and AbH activity were observed with the outliers removed. There were no correlations between AHF and AbH muscle activity and between AHF and MLA angle ratio. However, with the 2 outliers removed, moderate correlations between AHF and AbH activity were significant (r = 0.64, p = .01). AbH activity during SFE increased in individuals with flatfoot for high AHF (flexible type). Thus, SFE may be more effective for individuals with flatfoot having a high AHF. These findings may be helpful when making decisions for surgery and rehabilitation.

The Effect of Ankle Position on Peak Eccentric Force during The Nordic Hamstring Exercise.

Peak eccentric force during the Nordic hamstring exercise (NHE) is recognized as a predictive factor for hamstring strain injury (HSI). During the NHE, the knee flexor muscles are eccentrically contracting to resist the knee joint extension. Therefore, it is thought that the action of the gastrocnemius muscle, and thus the ankle position, influences peak eccentric force during the NHE. However, the effect of ankle position on peak eccentric force during the NHE remains unclear. Therefore, we investigated the effect of ankle position on peak eccentric force during the NHE in a cohort of 50 healthy young male rugby players (mean age, 18.7 ± 1.2 years; mean body mass, 81.7 ± 15.2 kg; height, 1.72 ± 0.06 m) with no history of HSI. Each participant performed NHE strength testing with the ankle dorsiflexed or plantarflexed position and was instructed to fall forward as far as possible within 3 s. Peak eccentric force, reported relative to body mass (N/kg), of both legs was recorded, and the mean values of both legs were compared in both ankle positions. The mean peak eccentric force was significantly greater with the ankle plantarflexed position than the dorsiflexed position (3.8 ± 1.1 vs. 3.5 ± 1.1 N/kg, respectively, p = 0.049). These results indicate that ankle position should be carefully considered when measuring peak eccentric force during the NHE and performing NHE training.

Spinal reciprocal inhibition in the co-contraction of the lower leg depends on muscle activity ratio.

The spinal reciprocal inhibition during co-contraction remains unclear. Reports on the reciprocal Ia and D1 inhibitions in the co-contraction are lacking, and a point about the muscle activity amount during co-contraction is unclear. This study aimed to clarify the influence of changes in the ratio of soleus (Sol) and tibialis anterior (TA) muscle activities in co-contraction on reciprocal Ia and D1 inhibitions. Twenty healthy adults were subjected to four stimulatory conditions: a conditioning stimulus-test stimulation interval (CTI) of - 2, 2, or 20 ms or a test stimulus without a conditioning stimulus (single). Co-contraction [change in (Sol)/(TA) activity] was examined at task A, 0%/0% maximal voluntary contraction (MVC); task B, 5%/5% MVC; task C, 15%/15% MVC; task D, 5%/15% MVC; and task E, 15%/5% MVC. At 2-ms CTI, the H-reflex amplitude value was significantly lower in tasks A, B, C, and D than in the single condition. Among the tasks, the H-reflex amplitude values were lower for A, B, C, and D than for E. At 20-ms CTI, the H-reflex amplitude was significantly lower in tasks A, B, C, D, and E. Among the tasks, the H-reflex amplitude was significantly lower from task A and B to task E. The change in the muscle activity ratio during co-contraction could modulate reciprocal Ia inhibition depending on the Sol/TA muscle activity ratio. D1 inhibition at rest did not differ significantly when the Sol/TA ratio was equal or when TA muscle activity was high. During co-contraction with high Sol muscle activity, D1 inhibition decreased from rest.

Relationships between differences in the number of fiber bundles of the anterior talofibular ligament and differences in the angle of the calcaneofibular ligament and their effects on ankle-braking function.

PURPOSE: The aim was to clarify the relationships between differences in the number of fiber bundles of the anterior talofibular ligament (ATFL) and differences in the angle of the calcaneofibular ligament (CFL) with respect to the long axis of the fibula and their effects on ankle braking function. METHODS: The study sample included 110 Japanese cadavers. ATFLs were categorized as: Type I with one fiber bundle; Type II with two fiber bundles with incomplete separation and complete separation; and Type III with three fiber bundles. The CFLs were categorized according to the angles of the CFLs with respect to the long axis of the fibula and the number of fiber bundles. Six categories were established: CFL10° (angle of the CFL with respect to the long axis of the fibula from 10° to 19°); CFL20° (range 20°-29°); CFL30° (range 30°-39°); CFL40° (range 40°-49°); CFL50° (range 50°-59°); and CFL2 (CFLs with two crossing fiber bundles). RESULTS: ATFL was Type I in 34 legs (31%), Type II in 66 legs (60%), and Type III in 10 legs (9%). Five CFL categories were identified: CFL10° in 4 feet (3.7%); CFL20° in 23 feet (20.9%); CFL30° in 34 feet (30.9%); CFL40° in 33 feet (30%); CFL50° in 15 feet (13.6%); and CFL2 in one foot (0.9%). Type III contained mainly CFL40° and CFL50° (7 of 10 feet). CONCLUSIONS: ATFL and CFL appear to cooperate in the ankle joint braking function.

The relationships between the quadratus plantae and the flexor digitorum longus and the flexor hallucis longus.

PURPOSE: The purpose of this research was to clarify the relationships between quadratus plantae (QP) and flexor digitorum longus (FDL) and flexor hallucis longus (FHL) using large-scale specimens. METHODS: This study examined 116 legs from 62 Japanese cadavers. The QP was classified as: Type I, formed by the lateral and medial heads; Type II, the lateral head is absent; and Type III, the medial head is absent. The FHL branches to the lesser toes were classified as: Type A, connection from FHL to toe 2; Type B, connection from FHL to toes 2 and 3; Type C, connection from FHL to toes 2-4. Next, the relationships between QP and FHL and FDL were observed. RESULTS: Type I accounted for 87%, Type II for 10%, and Type III for 3%. Type A accounted for 33%, Type B for 53%, and Type C for 14%. Regarding the relationship between QP and FDL, regardless of the classification of the connections of the FHL tendon slip to the lesser toes, QP attachments to FDL branching to toes 2, 3, and 4 were seen in 47-59%. Furthermore, QP attachments to FDL branching to toes 2, 3, 4, and 5 were seen in 41-47%. CONCLUSIONS: QP appears to function strongly to counter the oblique pull of FDL and FHL and as a lesser digit plantar flexor.

The effect of differences in the number of fiber bundles of the anterior tibial ligament on ankle braking function: a simulation study.

PURPOSE: The aim was to clarify the effect of differences in the number of fiber bundles of the anterior tibial ligament (ATFL) on ankle braking function. METHODS: The study sample included 81Japanese cadavers. ATFLs were categorized as: Type I with one fiber bundle; Type II with two fiber bundles that were completely separated; and Type III with three fiber bundles. Three-dimensional reconstructions of a single specimen from each category were then created. These were used to simulate and calculate ATFL strain during dorsiflexion (20°) and plantarflexion (30°) on the talocrural joint axis and inversion (20°) on the subtalar joint axis. RESULTS: Almost all types of superior fiber lines were stretched with dorsiflexion and plantarflexion. Regardless of Type, the inferior fiber line was shortened with plantarflexion and stretched with dorsiflexion. The inferior fiber bundle of Type III was shortened only at plantarflexion 30° and inversion 20°, but in all others it was stretched. CONCLUSIONS: The results suggest that Type III was weaker than Type I and Type II in terms of ankle plantarflexion and inversion braking function.

Differences in the strain applied to Achilles tendon fibers when the subtalar joint is overpronated: a simulation study.

PURPOSE: The purpose of this study was to investigate the strain applied to each of the tendon fiber bundles of the medial head of the gastrocnemius (MG), the lateral head of the gastrocnemius (LG), and the soleus muscle (Sol) that compose the Achilles tendon (AT) when the subtalar joint is pronated and supinated. METHODS: Three AT twist types (least, moderate, extreme) were investigated. Using the MicroScribe system, the AT and the talocrural and subtalar joints were digitized to reconstruct three-dimensional models. Using this system, subtalar joint rotations in the pronation (20°) and supination (20°) directions were simulated, and the degrees of strain (%) on each tendon were calculated. RESULTS: For all twist types, when the subtalar joint was pronated, MG, LG, and Sol stretched, and when supinated, MG, LG, and Sol shortened. In particular, the least and severe twist types had large degrees of strain of Sol when the subtalar joint was pronated, and furthermore, each tendon fiber composing Sol had different degrees of strain. CONCLUSIONS: The study results suggest that the degree of strain applied within the AT with subtalar joint pronation is not constant, and that, especially in least and extreme twist types, the risk of developing AT disorders may increase.

Morphological characteristics of the lateral talocalcaneal ligament: a large-scale anatomical study.

PURPOSE: The purpose of this study is to clarify the morphological characteristics of the lateral talocalcaneal ligament (LTCL). METHODS: This study examined 100 legs from 54 Japanese cadavers. The LTCL was classified into three types: Type I, the LTCL branches from the calcaneofibular ligament (CFL); Type II, the LTCL is independent of the CFL and runs parallel to the calcaneus; and Type III, the LTCL is absent. The morphological features measured were fiber bundle length, fiber bundle width, and fiber bundle thickness. RESULTS: The LTCL was classified as Type I in 18 feet (18%), Type II in 24 feet (24%), and Type III in 58 feet (58%). All LTCLs were associated with the anterior talofibular ligament at the talus. There was no significant difference in morphological characteristics by Type for each ligament. CONCLUSIONS: The LTCL was similar to the CFL in terms of fiber bundle width and fiber bundle thickness.

5-HT3a Receptors Modulate Hippocampal Gamma Oscillations by Regulating Synchrony of Parvalbumin-Positive Interneurons.

Gamma-frequency oscillatory activity plays an important role in information integration across brain areas. Disruption in gamma oscillations is implicated in cognitive impairments in psychiatric disorders, and 5-HT3 receptors (5-HT3Rs) are suggested as therapeutic targets for cognitive dysfunction in psychiatric disorders. Using a 5-HT3aR-EGFP transgenic mouse line and inducing gamma oscillations by carbachol in hippocampal slices, we show that activation of 5-HT3aRs, which are exclusively expressed in cholecystokinin (CCK)-containing interneurons, selectively suppressed and desynchronized firings in these interneurons by enhancing spike-frequency accommodation in a small conductance potassium (SK)-channel-dependent manner. Parvalbumin-positive interneurons therefore received diminished inhibitory input leading to increased but desynchronized firings of PV cells. As a consequence, the firing of pyramidal neurons was desynchronized and gamma oscillations were impaired. These effects were independent of 5-HT3aR-mediated CCK release. Our results therefore revealed an important role of 5-HT3aRs in gamma oscillations and identified a novel crosstalk among different types of interneurons for regulation of network oscillations. The functional link between 5-HT3aR and gamma oscillations may have implications for understanding the cognitive impairments in psychiatric disorders.

The effect of hepatocyte growth factor on secretory functions in human eosinophils.

Hepatocyte growth factor (HGF), originally identified as a potent mitogen for mature hepatocytes, is now recognized as a humoral mediator in inflammatory and immune responses. Previous studies indicated that HGF negatively regulated allergic airway inflammation. In view of eosinophils playing a role in the pathogenesis of asthma, especially in airway remodeling as a rich source of pro-fibrogenic mediators, the effects of HGF on the different types of eosinophil secretory functions were examined in this study. We found that HGF significantly inhibited IL-5-induced secretion of TGF-ß and VEGF from human eosinophils. The inhibitory effect is not associated with TGF-ß transcription; rather, it is associated with ultrastructural granule emptying and loss of intracellular TGF-ß contents, indicating HGF inhibits the process of piecemeal degranulation. The effect of HGF on extracellular trap cell death (ETosis) that mediates cytolytic degranulation was also investigated; however, immobilized IgG- or phorbol myristate acetate-induced ETosis was only minimally attenuated by HGF. These results reveal the effect of HGF on the distinct pathways of eosinophil secretory functions and also provide novel insights into the role of HGF in the pathogenesis of allergic inflammation.

Synthesis and anti-HCV determinant motif identification in pyranone carboxamide scaffold.

Hepatitis C Virus exhibits high genetic diversity. The current treatment for genotype-1 with ∼80% sustained virologic responses is a combination of pegylated interferon, ribavirin and boceprevir/telaprevir/simeprevir which is associated with several side effects and need close monitoring. Therefore, novel therapies are invited for safer and more efficient treatment. This study was designed for synthesis of new α-pyranone carboxamide analogs for evaluation of anti-HCV activity to delineate structure-activity relationship (SAR) and to identify anti-HCV determinant motif on this new scaffold. Forty four new α-pyranone carboxamide analogs were synthesized. Six potential anti-HCV candidates 11a (EC50=0.35 µM), 11e (EC50=0.48 µM), 12f (EC50=0.47 µM), 12g (EC50=0.39 µM), 12h (EC50=0.20 µM) and 12j (EC50=0.25 µM) with lower cytotoxicity (CC50>20 µM) were discovered through cell based HCV replicon system. The activity profile of forty four new α-pyranone carboxamide analogs suggests the role of an aromatic motif in the B region to add a synergistic effect to NHOH motif at 4-position and revels an anti-HCV activity determinants motif under this scaffold. The biochemical assay against most promising HCV target protein 'NS3 protease and NS5B polymerase' showed no activity and open a scope to explore new mechanism inhibitor.

The effect of pharmacological PI3Kγ inhibitor on eotaxin-induced human eosinophil functions.

BACKGROUND: Asthma is characterized by chronic inflammation caused by activation of immune cells including Th2 lymphocytes and eosinophils. Phosphoinositide 3-kinase (PI3K) γ deficient asthmatic mice did not develop lung eosinophilia, although the detailed mechanisms are not well known. A CC chemokine eotaxin (CCL11) plays a prominent role in developing eosinophilic inflammation through CCR3. In this study, we tested the roles of PI3Kγ in eotaxin-induced eosinophil functions using a pharmacological inhibitor. METHOD: Human peripheral blood eosinophils were isolated by CD16-negative selection method. The effect of AS605240, synthetic PI3Kγ inhibitor on eotaxin-induced adhesion, chemotaxis, and degranulation were studied using intracellular adhesion molecule-1 (ICAM-1)-coated plates, Boyden chamber system, ELISA for eosinophil-derived neurotoxin (EDN) levels in the culture supernatant, respectively. CCR3 expression levels and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation were assessed by flowcytometry. Involvement of PI3Kγ in spontaneous apoptosis was studied using flowcytometry. RESULTS: Although AS605240 did not affect the eosinophil spontaneous apoptosis, eotaxin-induced chemotaxis, adhesion to ICAM-1 coated plate, and EDN release were inhibited by AS605240. AS605240 also inhibited the eotaxin-induced ERK1/2 phosphorylation without down-regulation of surface CCR3 expression. CONCLUSION: These results indicate that PI3Kγ inhibitor attenuates eotaxin-induced eosinophil functions by suppressing the downstream signaling of CCR3 without significant cytotoxicity. PI3Kγ plays an important role in the development of eosinophilic inflammation and blockade of PI3Kγ might be a therapeutic strategy for treatment of eosinophil-related diseases including asthma.

Sex and stress interactions in fear synchrony of mouse dyads.

Socially coordinated threat responses support the survival of animal groups. Given their distinct social roles, males and females must differ in such coordination. Here, we report such differences during the synchronization of auditory-conditioned freezing in mouse dyads. To study the interaction of emotional states with social cues underlying synchronization, we modulated emotional states with prior stress or modified the social cues by pairing unfamiliar or opposite-sex mice. In same-sex dyads, males exhibited more robust synchrony than females. Stress disrupted male synchrony in a prefrontal cortex-dependent manner but enhanced it in females. Unfamiliarity moderately reduced synchrony in males but not in females. In dyads with opposite-sex partners, fear synchrony was resilient to both stress and unfamiliarity. Decomposing the synchronization process in the same-sex dyads revealed sex-specific behavioral strategies correlated with synchrony magnitude: following partners' state transitions in males and retroacting synchrony-breaking actions in females. Those were altered by stress and unfamiliarity. The opposite-sex dyads exhibited no synchrony-correlated strategy. These findings reveal sex-specific adaptations of socio-emotional integration defining coordinated behavior and suggest that sex-recognition circuits confer resilience to stress and unfamiliarity in opposite-sex dyads.

Predicting exacerbation of renal function by DNA methylation clock and DNA damage of urinary shedding cells: a pilot study.

Recent reports have shown the feasibility of measuring biological age from DNA methylation levels in blood cells from specific regions identified by machine learning, collectively known as the epigenetic clock or DNA methylation clock. While extensive research has explored the association of the DNA methylation clock with cardiovascular diseases, cancer, and Alzheimer's disease, its relationship with kidney diseases remains largely unexplored. In particular, it is unclear whether the DNA methylation clock could serve as a predictor of worsening kidney function. In this pilot study involving 20 subjects, we investigated the association between the DNA methylation clock and subsequent deterioration of renal function. Additionally, we noninvasively evaluated DNA damage in urinary shedding cells using a previously reported method to examine the correlation with the DNA methylation clock and worsening kidney function. Our findings revealed that patients with an accelerated DNA methylation clock exhibited increased DNA damage in urinary shedding cells, along with a higher rate of eGFR decline. Moreover, in cases of advanced CKD (G4-5), the DNA damage in urinary shedding cells was significantly increased, highlighting the interplay between elevated DNA damage and eGFR decline. This study suggests the potential role of the DNA methylation clock and urinary DNA damage as predictive markers for the progression of chronic kidney disease.

Viral uptake and pathophysiology of the lung endothelial cells in age-associated severe SARS-CoV-2 infection models.

Thrombosis is the major cause of death in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the pathology of vascular endothelial cells (ECs) has received much attention. Although there is evidence of the infection of ECs in human autopsy tissues, their detailed pathophysiology remains unclear due to the lack of animal model to study it. We used a mouse-adapted SARS-CoV-2 virus strain in young and mid-aged mice. Only mid-aged mice developed fatal pneumonia with thrombosis. Pulmonary ECs were isolated from these infected mice and RNA-Seq was performed. The pulmonary EC transcriptome revealed that significantly higher levels of viral genes were detected in ECs from mid-aged mice with upregulation of viral response genes such as DDX58 and IRF7. In addition, the thrombogenesis-related genes encoding PLAT, PF4, F3 PAI-1, and P-selectin were upregulated. In addition, the inflammation-related molecules such as CXCL2 and CXCL10 were upregulated in the mid-aged ECs upon viral infection. Our mouse model demonstrated that SARS-CoV-2 virus entry into aged vascular ECs upregulated thrombogenesis and inflammation-related genes and led to fatal pneumonia with thrombosis. Current results of EC transcriptome showed that EC uptake virus and become thrombogenic by activating neutrophils and platelets in the aged mice, suggesting age-associated EC response as a novel finding in human severe COVID-19.

Target-specific suppression of GABA release from parvalbumin interneurons in the basolateral amygdala by dopamine.

Dopamine (DA) in the basolateral amygdala (BLA) promotes fear learning by disinhibiting principal neurons (PNs) and enabling synaptic plasticity in their sensory inputs. While BLA interneurons (INs) are heterogeneous, it is unclear which interneuron subtypes decrease GABAergic input to PNs in the presence of DA. Here, using cell type-selective photostimulation by channelrhodopsin 2 in BLA slices from mouse brain, we examined the role of parvalbumin-positive INs (PV-INs), the major interneuronal subpopulation in BLA, in the disinhibitory effect of DA. We found that DA selectively suppressed GABAergic transmission from PV-INs to PNs by acting on presynaptic D(2) receptors, and this effect was mimicked by Rp-cAMP, an inhibitor of cAMP-dependent signaling. In contrast, DA did not alter GABA release from PV-INs to INs. Furthermore, neither suppressing cAMP-dependent signaling by Rp-cAMP nor enhancing it by forskolin altered GABA release from PV-INs to BLA INs. Overall, DA disinhibits BLA, at least in part, by suppressing GABA release from PV-INs in the target cell-specific manner that results from differential control of this release by cAMP-dependent signaling.

Adiponectin attenuates human eosinophil adhesion and chemotaxis: implications in allergic inflammation.

OBJECTIVE: Growing evidence has shown an association between obesity and asthma. Adiponectin, an adipocyte-derived cytokine, is known to have anti-inflammatory effects with reduced concentrations in obese subjects. Recent findings raised the intriguing possibility that adiponectin might play a role in allergic inflammation, although the mechanistic basis for their relationship remains unclear. The purpose of this study was to examine whether adiponectin might affect functions of eosinophils, which play an important role in the pathogenesis of asthma. METHODS: Human peripheral blood eosinophils were purified to study expression of adiponectin receptors AdipoR1 and AdipoR2 using RT-PCR and flow cytometry. The effect of adiponectin on eosinophil survival was investigated using annexin V and propidium iodide staining. Eotaxin-induced cell adhesion was investigated using ICAM-1-coated plates. A Boyden chamber and real-time horizontal migration system were used for eotaxin-directed chemotaxis assay. Expression of eotaxin receptor CCR3 and intracellular calcium influx were assessed by flow cytometry. RESULTS: AdipoR1 and AdipoR2 were expressed in human eosinophils. Adiponectin did not affect eosinophil survival or CCR3 expression; however, eotaxin-enhanced adhesion was inhibited by pretreatment with adiponectin. Adiponectin also diminished eotaxin-directed chemotactic responses by disturbing both velocity and directionality. Calcium influx in response to eotaxin was attenuated by adiponectin. CONCLUSIONS: These results indicate that adiponectin attenuates the eosinophil functions induced by eotaxin without affecting cell viability. The inhibitory effect was associated with diminished calcium signaling rather than altering of surface receptor expression. Increasing circulating adiponectin might be a novel therapeutic modality for treatment of asthma, especially in obese asthmatics.

Gender difference in allergic airway remodelling and immunoglobulin production in mouse model of asthma.

BACKGROUND AND OBJECTIVE: Epidemiological studies have shown that the prevalence of adult asthma and severe asthma is higher in women. It has also been reported that female mice are more susceptible than males to the development of allergic airway inflammation and airway hyperresponsiveness (AHR). The influence of gender difference in the pathogenesis of severe asthma, especially airway remodelling in an animal model, has been studied rarely. We investigated gender difference in the development of airway remodelling using a long-term antigen-challenged mouse asthma model. METHODS: Following ovalbumin (OVA)/alum intraperitoneal injection, male or female mice (BALB/c) were challenged with aerosolized 1% OVA on 3 days/week for 5 weeks, and differences in AHR, airway inflammation and airway remodelling between the sexes were investigated. RESULTS: In OVA-sensitized and OVA-challenged (OVA/OVA) female mice, eosinophils, lymphocytes, T-helper type 2 cytokines and growth factors in bronchoalveolar lavage fluid were increased compared with OVA/OVA male mice. Histological features of airway remodelling were also increased in OVA/OVA female mice. Serum total and OVA-specific immunoglobulin E (IgE) and serum IgA were significantly elevated in OVA/OVA female mice. CONCLUSIONS: These results indicate that female mice experience more airway remodelling compared with male mice. These results suggest the involvement of sex hormones and gender differences in cellular functions in airway remodelling.

Social Synchronization of Conditioned Fear in Mice Requires Ventral Hippocampus Input to the Amygdala.

BACKGROUND: Social organisms synchronize behaviors as an evolutionary-conserved means of thriving. Synchronization under threat, in particular, benefits survival and occurs across species, including humans, but the underlying mechanisms remain unknown because of the scarcity of relevant animal models. Here, we developed a rodent paradigm in which mice synchronized a classically conditioned fear response and identified an underlying neuronal circuit. METHODS: Male and female mice were trained individually using auditory fear conditioning and then tested 24 hours later as dyads while allowing unrestricted social interaction during exposure to the conditioned stimulus under visible or infrared illumination to eliminate visual cues. The synchronization of the immobility or freezing bouts was quantified by calculating the effect size Cohen's d for the difference between the actual freezing time overlap and the overlap by chance. The inactivation of the dorsomedial prefrontal cortex, dorsal hippocampus, or ventral hippocampus was achieved by local infusions of muscimol. The chemogenetic disconnection of the hippocampus-amygdala pathway was performed by expressing hM4D(Gi) in the ventral hippocampal neurons and infusing clozapine N-oxide in the amygdala. RESULTS: Mice synchronized cued but not contextual fear. It was higher in males than in females and attenuated in the absence of visible light. Inactivation of the ventral but not dorsal hippocampus or dorsomedial prefrontal cortex abolished fear synchronization. Finally, the disconnection of the hippocampus-amygdala pathway diminished fear synchronization. CONCLUSIONS: Mice synchronize expression of conditioned fear relying on the ventral hippocampus-amygdala pathway, suggesting that the hippocampus transmits social information to the amygdala to synchronize threat response.