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SummaryTooth extraction in patients receiving bisphosphonates is thought to be a risk factor for osteonecrosis of the jaw (ONJ); however, ONJ did not develop, even when tooth extraction was performed with continued oral bisphosphonate therapy. A drug holiday from bisphosphonates before tooth extraction may not be necessary.IntroductionIt is controversial whether bisphosphonate withdrawal is necessary prior to invasive procedures such as tooth extraction in order to prevent bisphosphonate-related osteonecrosis of the jaw (BRONJ). This study aimed to evaluate the clinical safety of continuing oral bisphosphonate therapy in patients undergoing tooth extraction.MethodsWe prospectively enrolled 132 patients (20 men, 112 women) who were receiving oral bisphosphonates for the prevention or treatment of osteoporosis and required tooth extraction. All patients were managed using an identical protocol, which included preoperative antibiotic prophylaxis and did not necessarily require complete wound closure. The patients were classified into groups according to the duration of bisphosphonate administration: < 2 years (n = 51), 2–5 years (n = 41), 5–10 years (n = 28), and > 10 years (n = 12). The groups were compared regarding the time taken for the extraction socket to heal, and the occurrence of BRONJ. Follow-up duration was at least 3 months.ResultsA total of 274 teeth were removed. Long-term oral bisphosphonate therapy for > 5 years significantly delayed the healing of the extraction socket in comparison with administration for < 5 years; however, BRONJ did not develop in any group. There was no prolongation of wound healing due to systemic risk factors such as glucocorticoid administration and diabetes mellitus. There were no adverse skeletal events such as bone fracture.ConclusionsPatients who underwent tooth extraction with continued oral bisphosphonate therapy showed delayed healing of the extraction socket as the cumulative administration period prolonged, but BRONJ did not develop.

Successful pluripotent stem cell differentiation methods have been developed for several endoderm-derived cells, including hepatocytes, β-cells and intestinal cells. However, stomach lineage commitment from pluripotent stem cells has remained a challenge, and only antrum specification has been demonstrated. We established a method for stomach differentiation from embryonic stem cells by inducing mesenchymal Barx1 , an essential gene for in vivo stomach specification from gut endoderm. Barx1 -inducing culture conditions generated stomach primordium-like spheroids, which differentiated into mature stomach tissue cells in both the corpus and antrum by three-dimensional culture. This embryonic stem cell-derived stomach tissue (e-ST) shared a similar gene expression profile with adult stomach, and secreted pepsinogen as well as gastric acid. Furthermore, TGFA overexpression in e-ST caused hypertrophic mucus and gastric anacidity, which mimicked Ménétrier disease in vitro . Thus, in vitro stomach tissue derived from pluripotent stem cells mimics in vivo development and can be used for stomach disease models. Noguchi and colleagues report the generation of stomach-like tissue from mouse embryonic stem cells. They show that the tissue contains all stomach-specific cell types and secretes acid and digestive enzyme.

Mutations reducing the function of MYT1L, a neuron-specific transcription factor, are associated with a syndromic neurodevelopmental disorder. MYT1L is used as a pro-neural factor in fibroblast-to-neuron transdifferentiation and is hypothesized to influence neuronal specification and maturation, but it is not clear which neuron types are most impacted by MYT1L loss. In this study, we profile 412,132 nuclei from the forebrains of wild-type and MYT1L-deficient mice at three developmental stages: E14 at the peak of neurogenesis, P1 when cortical neurons have been born, and P21 when neurons are maturing, to examine the role of MYT1L levels on neuronal development. MYT1L deficiency disrupts cortical neuron proportions and gene expression, primarily affecting neuronal maturation programs. Effects are mostly cell autonomous and persistent through development. While MYT1L can both activate and repress gene expression, the repressive effects are most sensitive to haploinsufficiency, likely mediating MYT1L syndrome. These findings illuminate MYT1L’s role in orchestrating gene expression during neuronal development, providing insights into the molecular underpinnings of MYT1L syndrome. Mutations reducing the function of MYT1L, a neuron-specific transcription factor, are associated with a syndromic neurodevelopmental disorder, yet it remains unclear which cell types are most impacted by MYT1L loss. Here authors use single-nuclei RNA sequencing to profile the forebrains of MYT1L-deficient mice at three developmental stages and reveal MYT1L deficiency disrupts cortical neuron proportions and gene expression, primarily affecting excitatory neuron maturation programs.

Background:Hemophilic arthropathy (HA), is characterized by synovitis and cartilage and bony destruction, which ultimately results from repeated joint bleeding episodes in patients with hemophilia (PwH).Early detection of HA is crucial to prevent joint damage. In daily clinical practice, the standard of joint evaluation is based on the patient’s symptoms and physical examination such as tender joint, swollen joint, and the specific scales as Hemophilia Joint Health Score (HJHS).Synovitis can be asymptomatic, going unnoticed on physical examination, especially in patients on prophylaxis. Therefore, the use of imaging tools such as magnetic resonance imaging (MRI) and musculoskeletal ultrasound (MSKUS) for the assessment of the most frequently affected joints in PWH is increasingly being promoted.For polyarticular and repeated assessment, performing MSKUS seems the most practical option among patients with Hemophilia (PwH).Recently, HEAD-US (Hemophilia Early Arthropathy Detection with Ultrasound) protocol has been established as a simplified US scale used to evaluate joint health and could be useful to individualize treatment.It is underexploring about the efficacy of MSKUS in assessing asymptomatic joint damage by joint level among PwH.Objectives:This study aimed to explore the value of MSKUS beyond clinical joint parameters in assessing asymptomatic joints in PwH.Methods:We analyzed PwH under 35 years of age with mild joint damage who had examined MSKUS at our department.Prior to the MSKUS examination, clinical joint parameters such as an episode of joint bleeding within a month, tender joint, swollen joint, and HJHS, radiographic assessment (Petterson score) were evaluated.MSKUS was performed according to HEAD-US protocol, with bilateral ankle, knee joints, and elbow joints.Synovial hypertrophy, disease damage of cartilage and bone surface were independently scored and each HEAD-US score ≧1 was defined as the presence of synovitis, cartilage damage, and bone damage.Additionally, the presence of joint effusion and positive rate of the power doppler signal in synovitis were assessed.For each joint with synovitis, clinical joint parameters were compared independently.We compared the differences of clinical joint parameters and MSKUS findings between the asymptomatic joints with synovitis and without synovitis.Results:Of the total 168 joints in 28 PwH (median age 15 years), 147 (88%) asymptomatic joints were enrolled.The frequency of synovitis/cartilage damage/bone damage/joint effusion in each joint is shown below: Elbow (51 joints);33%/6%/8%/27%, Knee (53 joints); 40%/8%/8%/38%, Foot (43 joints);19%/51%/49%/7%. The score of HEAD-US synovial hypertrophy in each joint was shown in Figure 1.A comparison of joint parameters and US findings between asymptomatic joints with synovitis and without synovitis is shown in Table 1. Peterson’s score was significantly higher in the synovitis group.Of the 45 asymptomatic joints with synovitis, 2% had tenderness, 2% had swelling, 13% had HJHS score ≥1, and 11% had Petterson score ≥1.Conclusion:Among asymptomatic joints, synovitis was more common in elbow and knee joints, and cartilage and bone damage were more common in ankle joints. Although the frequency of bone damage detected by XR or MSKUS was higher in the joint with synovitis, even in cases where radiographic bone damage was absent, synovitis was confirmed in approximately 90% of instances. From these findings, we conclude that predicting synovitis solely based on the presence of bone damage is challenging. Therefore, when considering early diagnosis for synovitis, a more comprehensive MSKUS approach beyond the presence of joint parameters is deemed necessary.REFERENCES: NIL.Figure 1.Table 1.Acknowledgements:NIL.Disclosure of Interests:None declared.

This study aimed to propose appropriate management for odontogenic chronic rhinosinusitis. Thirty-one adult patients with odontogenic chronic rhinosinusitis undergoing maxillary extraction were retrospectively analysed. Patients with (n = 21) and without (n = 10) oroantral fistula on computed tomography were classified. Functional endoscopic sinus surgery was performed when sinusitis did not improve after extraction. The critical indicators for surgical requirement in the management of odontogenic chronic rhinosinusitis were analysed. Sinusitis significantly improved after extraction in both groups. Patients without oroantral fistula had significantly more severe remnant sinusitis than those with oroantral fistula after extraction on computed tomography (p = 0.0037). The requirement for functional endoscopic sinus surgery was statistically significant for patients without orofacial fistula over those with orofacial fistula (p < 0.0001). The surgical improvement ratio was 93 per cent. The absence of oroantral fistula and severe sinusitis can be critical indicators for the requirement of functional endoscopic sinus surgery after extraction in the management of odontogenic chronic rhinosinusitis.

The pluripotent state of embryonic stem (ES) cells is controlled by a network of specific transcription factors. Recent studies also suggested the significant contribution of mitochondria on the regulation of pluripotent stem cells. However, the molecules involved in these regulations are still unknown. In this study, we found that prohibitin 2 (PHB2), a pleiotrophic factor mainly localized in mitochondria, is a crucial regulatory factor for the homeostasis and differentiation of ES cells. PHB2 was highly expressed in undifferentiated mouse ES cells, and the expression was decreased during the differentiation of ES cells. Knockdown of PHB2 induced significant apoptosis in pluripotent ES cells, whereas enhanced expression of PHB2 contributed to the proliferation of ES cells. However, enhanced expression of PHB2 strongly inhibited ES cell differentiation into neuronal and endodermal cells. Interestingly, only PHB2 with intact mitochondrial targeting signal showed these specific effects on ES cells. Moreover, overexpression of PHB2 enhanced the processing of a dynamin-like GTPase (OPA1) that regulates mitochondrial fusion and cristae remodeling, which could induce partial dysfunction of mitochondria. Our results suggest that PHB2 is a crucial mitochondrial regulator for homeostasis and lineage-specific differentiation of ES cells.

Background:Transient receptor potential (TRP)A1, a member of the TRP family of ion channels, has been proposed to function in diverse sensory processes, including thermosensation and pain. However, TRPA1 has not been directly implicated in stomach mechanosensation, and its contribution to acute visceral pain from this organ is unknown. Here, we investigated the expression of TRPA1 in primary sensory afferents and its involvement in visceral hypersensitivity in rats.Methods:We examined TRPA1 expression in the dorsal root ganglion (DRG), nodose ganglion (NG), and stomach of rats by using immunohistochemistry. Electromyographic responses to gastric distention (GD) were recorded from the acromiotrapezius muscle in TRPA1 knockdown rats and in control rats.Results:TRPA1 was predominantly expressed with sensory neuropeptides in DRG and NG neurons, and in nerve fibres in the rat stomach. Gastric distention induced the activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) in DRG and NG neurons 2 min after stimulation, and most of the phosphorylated-ERK1/2-labelled DRG neurons were TRPA1-positive neurons. Intrathecal injection of TRPA1 antisense attenuated the visceromotor response, and suppressed ERK1/2 activation in the DRG, but not NG, neurons produced by GD. Furthermore, intrathecal and intraperitoneal injections of the TRPA1 inhibitor HC-03003 suppressed the response to noxious GD.Conclusions:The activation of TRPA1 in DRG neurons by noxious GD may be involved in acute visceral pain. Our findings point to the potential blockade of TRPA1 in primary afferents as a new therapeutic target for the reduction of visceral hypersensitivity.

Countermeasures against Zika virus (ZIKV), including vaccines, are frequently tested in nonhuman primates (NHP). Macaque models are important for understanding how ZIKV infections impact human pregnancy due to similarities in placental development. The lack of consistent adverse pregnancy outcomes in ZIKV-affected pregnancies poses a challenge in macaque studies where group sizes are often small (4–8 animals). Studies in small animal models suggest that African-lineage Zika viruses can cause more frequent and severe fetal outcomes. No adverse outcomes were observed in macaques exposed to 1x10 4 PFU (low dose) of African-lineage ZIKV at gestational day (GD) 45. Here, we exposed eight pregnant rhesus macaques to 1x10 8 PFU (high dose) of African-lineage ZIKV at GD 45 to test the hypothesis that adverse pregnancy outcomes are dose-dependent. Three of eight pregnancies ended prematurely with fetal death. ZIKV was detected in both fetal and placental tissues from all cases of early fetal loss. Further refinements of this exposure system (e.g., varying the dose and timing of infection) could lead to an even more consistent, unambiguous fetal loss phenotype for assessing ZIKV countermeasures in pregnancy. These data demonstrate that high-dose exposure to African-lineage ZIKV causes pregnancy loss in macaques and also suggest that ZIKV-induced first trimester pregnancy loss could be strain-specific.

Objectives To examine the radiological patterns specifically associated with hypoxemic respiratory failure in patients with coronavirus disease (COVID-19). Methods We enrolled patients with COVID-19 confirmed by qPCR in this prospective observational cohort study. We explored the association of clinical, radiological, and microbiological data with the development of hypoxemic respiratory failure after COVID-19 onset. Semi-quantitative CT scores and dominant CT patterns were retrospectively determined for each patient. The microbiological evaluation included checking the SARS-CoV-2 viral load by qPCR using nasal swab and serum specimens. Results Of the 214 eligible patients, 75 developed hypoxemic respiratory failure and 139 did not. The CT score was significantly higher in patients who developed hypoxemic respiratory failure than in those did not (median [interquartile range]: 9 [6–14] vs 0 [0–3]; p  < 0.001). The dominant CT patterns were subpleural ground-glass opacities (GGOs) extending beyond the segmental area ( n  = 44); defined as “extended GGOs.” Multivariable analysis showed that hypoxemic respiratory failure was significantly associated with extended GGOs (odds ratio [OR] 29.6; 95% confidence interval [CI], 9.3–120; p  < 0.001), and a CT score  > 4 (OR 12.7; 95% CI, 5.3–33; p  < 0.001). The incidence of RNAemia was significantly higher in patients with extended GGOs (58.3%) than in those without any pulmonary lesion (14.7%; p  < 0.001). Conclusions Extended GGOs along the subpleural area were strongly associated with hypoxemia and viremia in patients with COVID-19. Key Points • Extended ground-glass opacities (GGOs) along the subpleural area and a CT score  > 4, in the early phase of COVID-19, were independently associated with the development of hypoxemic respiratory failure. • The absence of pulmonary lesions on CT in the early phase of COVID-19 was associated with a lower risk of developing hypoxemic respiratory failure. • Compared to patients with other CT findings, the extended GGOs and a higher CT score were also associated with a higher incidence of RNAemia.

BackgroundPelizaeus Merzbacher disease (PMD) is a dysmyelinating disorder of the central nervous system caused by impaired differentiation of oligodendrocytes. This study was prompted by findings that antimuscarinic compounds enhance oligodendrocyte differentiation and remyelination in vitro. One of these compounds, clemastine fumarate, is licensed for treatment of allergic conditions. We tested whether clemastine fumarate can promote myelination in two rodent PMD models, the myelin-deficient and the PLP transgenic rat.MethodsPups were treated with daily injections of clemastine (10-30 mg/kg/day) on postnatal days 1-21. Neurologic phenotypes and myelination patterns in the brain, optic nerves, and spinal cords were assessed using histological techniques.ResultsNo changes in neurological phenotype or survival were observed even at the highest dose of clemastine. Postmortem staining with Luxol fast blue and myelin basic protein immunohistochemistry revealed no evidence for improved myelination in the CNS of treated rats compared to vehicle-treated littermates. Populations of mature oligodendrocytes were unaffected by the treatment.ConclusionThese results demonstrate lack of therapeutic effect of clemastine in two rat PMD models. Both models have rapid disease progression consistent with the connatal form of the disease. Further studies are necessary to determine whether clemastine bears a therapeutic potential in milder forms of PMD.