Sodium-Glucose Co-Transporter-2 Inhibitor Empagliflozin Attenuates Sorafenib-Induced Myocardial Inflammation and Toxicity.

Environmental antineoplastics such as sorafenib may pose a risk to humans through water recycling, and the increased risk of cardiotoxicity is a clinical issue in sorafenib users. Thus, developing strategies to prevent sorafenib cardiotoxicity is an urgent work. Empagliflozin, as a sodium-glucose co-transporter-2 (SGLT2) inhibitor for type 2 diabetes control, has been approved for heart failure therapy. Still, its cardioprotective effect in the experimental model of sorafenib cardiotoxicity has not yet been reported. Real-time quantitative RT-PCR (qRT-PCR), immunoblot, and immunohistochemical analyses were applied to study the effect of sorafenib exposure on cardiac SGLT2 expression. The impact of empagliflozin on cell viability was investigated in the sorafenib-treated cardiomyocytes using Alamar blue assay. Immunoblot analysis was employed to delineate the effect of sorafenib and empagliflozin on ferroptosis/proinflammatory signaling in cardiomyocytes. Ferroptosis/DNA damage/fibrosis/inflammation of myocardial tissues was studied in mice with a 28-day sorafenib ± empagliflozin treatment using histological analyses. Sorafenib exposure significantly promoted SGLT2 upregulation in cardiomyocytes and mouse hearts. Empagliflozin treatment significantly attenuated the sorafenib-induced cytotoxicity/DNA damage/fibrosis in cardiomyocytes and mouse hearts. Moreover, GPX4/xCT-dependent ferroptosis as an inducer for releasing high mobility group box 1 (HMGB1) was also blocked by empagliflozin administration in the sorafenib-treated cardiomyocytes and myocardial tissues. Furthermore, empagliflozin treatment significantly inhibited the sorafenib-promoted NFκB/HMGB1 axis in cardiomyocytes and myocardial tissues, and sorafenib-stimulated proinflammatory signaling (TNF-α/IL-1ß/IL-6) was repressed by empagliflozin administration. Finally, empagliflozin treatment significantly attenuated the sorafenib-promoted macrophage recruitments in mouse hearts. In conclusion, empagliflozin may act as a cardioprotective agent for humans under sorafenib exposure by modulating ferroptosis/DNA damage/fibrosis/inflammation. However, further clinical evidence is required to support this preclinical finding.

HDAC1 is Involved in Neuroinflammation and Blood-Brain Barrier Damage in Stroke Pathogenesis.

Background: Stroke is a common cause of disability and mortality worldwide; however, effective therapy remains limited. In stroke pathogenesis, ischemia/reperfusion injury triggers gliosis and neuroinflammation that further activates matrix metalloproteinases (MMPs), thereby damaging the blood-brain barrier (BBB). Increased BBB permeability promotes macrophage infiltration and brain edema, thereby worsening behavioral outcomes and prognosis. Histone deacetylase 1 (HDAC1) is a repressor of epigenomic gene transcription and participates in DNA damage and cell cycle regulation. Although HDAC1 is deregulated after stroke and is involved in neuronal loss and DNA repair, its role in neuroinflammation and BBB damage remains unknown. Methods: The rats with cerebral ischemia were evaluated in behavioral outcomes, levels of inflammation in gliosis and cytokines, and BBB damage by using an endothelin-1-induced rat model with cerebral ischemia/reperfusion injury. Results: The results revealed that HDAC1 dysfunction could promote BBB damage through the destruction of tight junction proteins, such as ZO-1 and occludin, after stroke in rats. HDAC1 inhibition also increased the levels of astrocyte and microglial gliosis, tumor necrosis factor-alpha, interleukin-1 beta, lactate dehydrogenase, and reactive oxygen species, further triggering MMP-2 and MMP-9 activity. Moreover, modified neurological severity scores for the cylinder test revealed that HDAC1 inhibition deteriorated behavioral outcomes in rats with cerebral ischemia. Discussion: HDAC1 plays a crucial role in ischemia/reperfusion-induced neuroinflammation and BBB damage, thus indicating its potential as a therapeutic target.

Impaired Ventrolateral Periaqueductal Gray-Ventral Tegmental area Pathway Contributes to Chronic Pain-Induced Depression-Like Behavior in Mice.

Chronic pain conditions within clinical populations are correlated with a high incidence of depression, and researchers have reported their high rate of comorbidity. Clinically, chronic pain worsens the prevalence of depression, and depression increases the risk of chronic pain. Individuals suffering from chronic pain and depression respond poorly to available medications, and the mechanisms underlying the comorbidity of chronic pain and depression remain unknown. We used spinal nerve ligation (SNL) in a mouse model to induce comorbid pain and depression. We combined behavioral tests, electrophysiological recordings, pharmacological manipulation, and chemogenetic approaches to investigate the neurocircuitry mechanisms of comorbid pain and depression. SNL elicited tactile hypersensitivity and depression-like behavior, accompanied by increased and decreased glutamatergic transmission in dorsal horn neurons and midbrain ventrolateral periaqueductal gray (vlPAG) neurons, respectively. Intrathecal injection of lidocaine, a sodium channel blocker, and gabapentin ameliorated SNL-induced tactile hypersensitivity and neuroplastic changes in the dorsal horn but not depression-like behavior and neuroplastic alterations in the vlPAG. Pharmacological lesion of vlPAG glutamatergic neurons induced tactile hypersensitivity and depression-like behavior. Chemogenetic activation of the vlPAG-rostral ventromedial medulla (RVM) pathway ameliorated SNL-induced tactile hypersensitivity but not SNL-elicited depression-like behavior. However, chemogenetic activation of the vlPAG-ventral tegmental area (VTA) pathway alleviated SNL-produced depression-like behavior but not SNL-induced tactile hypersensitivity. Our study demonstrated that the underlying mechanisms of comorbidity in which the vlPAG acts as a gating hub for transferring pain to depression. Tactile hypersensitivity could be attributed to dysfunction of the vlPAG-RVM pathway, while impairment of the vlPAG-VTA pathway contributed to depression-like behavior.

Risk factors for pressure ulcer recurrence following surgical reconstruction: A cross-sectional retrospective analysis.

Many studies on the recurrence of pressure ulcers after surgical reconstruction have focused on surgical techniques and socioeconomic factors. Herein, we aimed to identify the risk factors of the associated comorbidities for pressure ulcer recurrence. We enrolled 147 patients who underwent pressure ulcer reconstruction and were followed up for more than three years. The recurrence of pressure ulcers was defined as recurrent pressure ulcers with stage 3/4 pressure ulcers. We reviewed and analyzed systematic records of medical histories, including sex, age, associated comorbidities such as spinal cord injury (SCI), diabetes mellitus (DM), coronary artery disease, cerebral vascular accident, end-stage renal disease, scoliosis, dementia, Parkinson's disease, psychosis, autoimmune diseases, hip surgery, and locations of the primary pressure ulcer. Patients with recurrent pressure ulcers were younger than those without. Patients with SCI and scoliosis had higher odds, while those with Parkinson's disease had lower odds of recurrence of pressure ulcers than those without these comorbidities. Moreover, the decision tree algorithm identified that SCI, DM, and age < 34 years could be risk factor classifiers for predicting recurrent pressure ulcers. This study demonstrated that age and SCI are the two most important risk factors associated with recurrent pressure ulcers following surgical reconstruction.

Slow skeletal muscle troponin T acts as a potential prognostic biomarker and therapeutic target for hepatocellular carcinoma.

Slow skeletal muscle troponin T (TNNT1) as a poor prognostic indicator is upregulated in colon and breast cancers. However, the role of TNNT1 in the disease prognosis and biological functions of hepatocellular carcinoma (HCC) is still unclear. The Cancer Genome Atlas (TCGA), real-time quantitative RT-PCR (qRT-PCR), immunoblot, and immunohistochemical analyses were applied to evaluate the TNNT1 expression of human HCC. The impact of TNNT1 levels on disease progression and survival outcome was studied using TCGA analysis. Moreover, the bioinformatics analysis and HCC cell culture were used to investigate the biological functions of TNNT1. Besides, the immunoblot analysis and enzyme-linked immunosorbent assay (ELISA) were used to detect the extracellular TNNT1 of HCC cells and circulating TNNT1 of HCC patients, respectively. The effect of TNNT1 neutralization on oncogenic behaviors and signaling was further validated in the cultured hepatoma cells. In this study, tumoral and blood TNNT1 was upregulated in HCC patients based on the analyses using bioinformatics, fresh tissues, paraffin sections, and serum. From the multiple bioinformatics tools, the TNNT1 overexpression was associated with advanced stage, high grade, metastasis, vascular invasion, recurrence, and poor survival outcome in HCC patients. By the cell culture and TCGA analyses, TNNT1 expression and release were positively correlated with epithelial-mesenchymal transition (EMT) processes in HCC tissues and cells. Moreover, TNNT1 neutralization suppressed oncogenic behaviors and EMT in hepatoma cells. In conclusion, TNNT1 may serve as a non-invasive biomarker and drug target for HCC management. This research finding may provide a new insight for HCC diagnosis and treatment.

Direct Effects of Mifepristone on Mice Embryogenesis: An In Vitro Evaluation by Single-Embryo RNA Sequencing Analysis.

The clinical use of mifepristone for medical abortions has been established in 1987 in France and since 2000 in the United States. Mifepristone has a limited medical period that lasts <9 weeks of gestation, and the incidence of mifepristone treatment failure increases with gestation time. Mifepristone functions as an antagonist for progesterone and glucocorticoid receptors. Studies have confirmed that mifepristone treatments can directly contribute to endometrium disability by interfering with the endometrial receptivity of the embryo, thus causing decidual endometrial degeneration. However, whether mifepristone efficacy directly affects embryo survival and growth is still an open question. Some women choose to continue their pregnancy after mifepristone treatment fails, and some women express regret and seek medically unapproved mifepristone antagonization with high doses of progesterone. These unapproved treatments raise the potential risk of embryonic fatality and developmental anomalies. Accordingly, in the present study, we collected mouse blastocysts ex vivo and treated implanted blastocysts with mifepristone for 24 h. The embryos were further cultured to day 8 in vitro to finish their growth in the early somite stage, and the embryos were then collected for RNA sequencing (control n = 3, mifepristone n = 3). When we performed a gene set enrichment analysis, our data indicated that mifepristone treatment considerably altered the cellular pathways of embryos in terms of viability, proliferation, and development. The data indicated that mifepristone was involved in hallmark gene sets of protein secretion, mTORC1, fatty acid metabolism, IL-2-STAT5 signaling, adipogenesis, peroxisome, glycolysis, E2F targets, and heme metabolism. The data further revealed that mifepristone interfered with normal embryonic development. In sum, our data suggest that continuing a pregnancy after mifepristone treatment fails is inappropriate and infeasible. The results of our study reveal a high risk of fetus fatality and developmental problems when pregnancies are continued after mifepristone treatment fails.

Long-term DEHP/MEHP exposure promotes colorectal cancer stemness associated with glycosylation alterations.

Plasticizers are considered as environmental pollution released from medical devices and increased potential oncogenic risks in clinical therapy. Our previous studies have shown that long-term exposure to di-ethylhexyl phthalate (DEHP)/mono-ethylhexyl phthalate (MEHP) promotes chemotherapeutic drug resistance in colorectal cancer. In this study, we investigated the alteration of glycosylation in colorectal cancer following long-term plasticizers exposure. First, we determined the profiles of cell surface N-glycomes by using mass spectrometry and found out the alterations of α2,8-linkages glycans. Next, we analyzed the correlation between serum DEHP/MEHP levels and ST8SIA6 expression from matched tissues in total 110 colorectal cancer patients. Moreover, clinical specimens and TCGA database were used to analyze the expression of ST8SIA6 in advanced stage of cancer. Finally, we showed that ST8SIA6 regulated stemness in vitro and in vivo. Our results revealed long-term DEHP/MEHP exposure significantly caused cancer patients with poorer survival outcome and attenuated the expression of ST8SIA6 in cancer cells and tissue samples. As expected, silencing of ST8SIA6 promoted cancer stemness and tumorigenicity by upregulating stemness-associated proteins. In addition, the cell viability assay showed enhanced drug resistance in ST8SIA6 silencing cells treated with irinotecan. Besides, ST8SIA6 was downregulated in the advanced stage and positively correlated with tumor recurrence in colorectal cancer. Our results imply that ST8SIA6 potentially plays an important role in oncogenic effects with long-term phthalates exposure.

Evaluation of Bodily Pain Associated with Polycystic Ovary Syndrome: A Review of Health-Related Quality of Life and Potential Risk Factors.

Polycystic ovary syndrome (PCOS) is the most common reproductive disease affecting the hormone and metabolic status of women. Its associated symptoms are diverse among the patients, including hyperandrogenism, insulin resistance, anovulation, infertility, obesity, hirsutism, acne, and more. In addition, PCOS can potentially increase the risk of dysmenorrhea, endometriosis, endometrioma, and irritable bowel syndrome, which are highly related to pelvic pain and sexual difficulty. However, little known is whether PCOS exacerbates other chronic bodily pain or contributes to hyperalgesia. Health-related quality of Life (HRQoL) reflects the life satisfaction and quality derived by an individual from mental, physical, emotional, and social activities under specific conditions. In this study, we reviewed pain perception from HRQoL of PCOS patients (SF-36). The review data evidently indicated that pain perception is significantly more prevalent in patients with PCOS than in healthy controls, and obesity and infertile status could be the rationales associated with pain development. Nevertheless, underlying causes remain undetermined due to the limited information from SF-36. Furthermore, we reviewed pathophysiologic factors to pain development or exacerbation, such as the deregulation of inflammation levels, adipokines, and insulin resistance. Although current evidence of pain perception and pathophysiologic risk factors are solid in PCOS, patients' pain perception is often ignored in clinical settings. Clinicians should note the perception and treatment of pain in PCOS patients. The correlation or causality between pain and PCOS warrants further clinical examination and basic studies, thereby providing new insights into this topic in the context of clinical diagnosis and health care.

Long-term mortality rates of young stroke in Taiwan: A decade-long epidemiology population-based study.

Introduction: Stroke remains a leading cause of death worldwide. Stroke in young adults is an important issue, gaining extra attention in recent years. This study aims to investigate the mortality after stroke in young adults in Taiwan. Patients and methods: This is a registry- and population-based study in Taiwan of patients aged 20-50 years with first-ever stroke between 1999 and 2012, with follow-up until January 1, 2022. Patients and mortalities were identified through Taiwan National Health Insurance database. Results: The study population included 65,097 patients with stroke (mean age, 42.6 ± 6.6 years; 30.5% woman). There were 23,481 (36.1%) intracranial hemorrhage, 37,522 (57.6%) ischemic stroke, and 4094 (6.3%) stroke not otherwise specified. At the end of follow-up, a total of 18,248 deaths (28.0%) occurred during a median follow-up of 9.8 years (interquartile range, 6.4-13.7 years). Conclusion: Taiwan young adults who were 30-day survivors of first-ever stroke have significantly higher long-term mortality rates when compared to other population-based studies.

Rapid antidepressant-like effects of muscarinic receptor antagonists require BDNF-dependent signaling in the ventrolateral periaqueductal gray.

RATIONALE: Clinical reports reveal that scopolamine, an acetylcholine muscarinic receptor antagonist, exerts rapid antidepressant effects in depressed patients, but the mechanisms underlying the therapeutic effects have not been fully identified. OBJECTIVES: The present study examines the cellular mechanisms by which scopolamine produces antidepressant-like effects through its action in the ventrolateral midbrain periaqueductal gray (vlPAG). METHODS: We used a well-established mouse model of depression induced by chronic restraint stress (CRS) exposure for 14 days. Behaviors were tested using the forced swim test (FST), tail suspension test (TST), female urine sniffing test (FUST), novelty-suppressed feeding test (NSFT), and locomotor activity (LMA). Synaptic transmission in the vlPAG was measured by whole-cell patch-clamp recordings. IntravlPAG microinjection was used to pharmacologically verify the signaling cascades of scopolamine in the vlPAG. RESULTS: The results demonstrated that intraperitoneal injection of scopolamine produced antidepressant-like effects in a dose-dependent manner without affecting locomotor activity. CRS elicited depression-like behaviors, whereas intraperitoneal injection of scopolamine alleviated CRS-induced depression-like behaviors. CRS diminished glutamatergic transmission in the vlPAG, while scopolamine reversed the above effects. Moreover, intravlPAG microinjection of the L-type voltage-dependent calcium channel (VDCC) blocker verapamil, tropomyosin-related kinase B (TrkB) receptor antagonist ANA-12, mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) antagonist CNQX prevented scopolamine-induced antidepressant-like effects. CONCLUSIONS: Scopolamine ameliorated CRS-elicited depression-like behavior required activation of VDCC, resulting in activity-dependent release of brain-derived neurotrophic factor (BDNF), engaging the TrkB receptor and downstream mTORC1 signaling in the vlPAG.

Approaching patients with panfacial fractures by using an anatomical reference: A novel concept and preliminary study.

Panfacial fractures are challenging for craniofacial surgeons. Aside from involving multiple subunits, they also lack the reliability of a useful landmark of the facial skeleton. Properly, reducing and fixing palatal fracture to re-establish the premorbid maxillary dental arch is important. This was a retrospective study conducted from 2015 to 2020. All patients underwent computed tomography (CT) scan for surgical planning of orthognathic surgery due to either esthetic or occlusion concerns. The classification of occlusion was recorded as class I, II, and III. The parameters measured on CT were the distance between the midpoint of the supra-orbital foramen/notch (IS), mesio-buccal cusp tips (IB), central fossa (IC), palatal cusp tips (IP), and the midpoint of the palatal marginal gingiva (IM) of the bilateral maxillary first molars. The IS was compared with the IB, IC, IP, and IM. The results were analyzed by using one-way repeated measurement analysis of variance. Eighty-seven patients (36 men and 51 women) were included in the study. There were 13 patients of class I malocclusion, 8 of class II malocclusion, and 66 of class III malocclusion. The IS was comparable to the IC in all three groups. The IS can predict the IC, regardless of the patient's occlusion, and can be subsequently used to decide the width of maxillary dental arch in panfacial fracture management. Further studies are necessary to obtain more definite results.

Purse-string suture combined with subcision and dermal graft for the treatment of wide depressed scars and boxcars.

BACKGROUND: Dermal layer injuries can result in depressed or indented scars even when there is no subcutaneous injury. These scars can result from acne, chickenpox, trauma, or skin infection. Several procedures, including primary closure, subcision, microneedling, and dermal grafting, have been reported to be used to treat depressed scars, boxcars, or acne cosmetics. These procedures have not, however, been shown to be very effective when applied to the treatment of deep depressed scars, boxcars, or acne cosmetics. In this retrospective study, we assessed scar improvement in patients with deep depressed facial scars and boxcars treated with our novel combination of techniques. METHODS: This study included all patients treated for deep depressed scars and boxcars at our clinic from 2018 to 2021. To be included, patients had to present in our clinic for the treatment of deep depressed scars or boxcars, have no prominent subcutaneous layer injury, and have full set of clear pre-and post-procedure photographs. All patients initially received technique combination including scar subcision, inner purse-string suturing, and dermal grafting for the first stage surgery treatment. In cases of residual uneven superficial scars, laser dermabrasion resurfacing was used as second-staged treatment. Preoperative and six-month postoperative scar appearance photographs were assessed for improvement by our three nonmedical staff members and divided into four improvement groups, as minimal, moderate, good, and excellent. RESULTS: This study included a total of 24 patients (20 females and four males) with facial scarring. Two patients (8.3%) had moderate, 13 (54.2%) good and nine (37.5%) excellent improvement post-treatment. There were no instances of minimal improvement. Four patients received second stage laser dermabrasion resurfacing for residual uneven superficial scars. CONCLUSION: We concluded deep depressed scars and boxcars can be easily, safely, and effectively treated using our novel combined scar subcision, inner purse-string suturing, and dermal grafting treatment with possible second-staged laser dermabrasion, and without major complications.

The Predictability of the Surgical Outcomes of Class III Patients in the Transverse Dimension-A Study of Three-Dimensional Assessment.

This study aimed to assess the outcomes of planned maxillary surgical movements in the transverse direction in patients possessing a Class III skeletal pattern. The available consecutive patients' records were retrospectively reviewed. Only those possessing a Class III skeletal pattern, and for whom the same virtual planning system was used, were enrolled. The waferless technique was used to guide the jawbone repositioning. A representative triangle in the virtual maxilla of each stage was used to validate the planned surgical movements (PSMs) and the outcome discrepancy (OD). The linear and angular measurements were retrieved for the assessments of the correlation between PSM and OD. In total, 44 adult patients who met the inclusion criteria were studied. The average linear OD of the A-point in the transverse direction was 0.66 ± 0.54 mm, and the yaw correction showed 1.02 ± 0.84 degrees in difference. There was no specific correlation between the linear PSMs and ODs; however, the angular ones were positively correlated. With the help of the waferless technique to transfer the virtual planning results, the practitioners could confidently predict the postsurgical maxillary position in the transverse direction in the orthognathic surgery of Class III patients. However, the yaw correction should be carefully planned to avoid postsurgical instabilities.

Neurobiology of Depression: Chronic Stress Alters the Glutamatergic System in the Brain-Focusing on AMPA Receptor.

Major depressive disorder (MDD) is a common neuropsychiatric disorder affecting the mood and mental well-being. Its pathophysiology remains elusive due to the complexity and heterogeneity of this disorder that affects millions of individuals worldwide. Chronic stress is frequently cited as the one of the risk factors for MDD. To date, the conventional monoaminergic theory (serotonin, norepinephrine, and/or dopamine dysregulation) has received the most attention in the treatment of MDD, and all available classes of antidepressants target these monoaminergic systems. However, the contributions of other neurotransmitter systems in MDD have been widely reported. Emerging preclinical and clinical findings reveal that maladaptive glutamatergic neurotransmission might underlie the pathophysiology of MDD, thus revealing its critical role in the neurobiology of MDD and as the therapeutic target. Aiming beyond the monoaminergic hypothesis, studies of the neurobiological mechanisms underlying the stress-induced impairment of AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-glutamatergic neurotransmission in the brain could provide novel insights for the development of a new generation of antidepressants without the detrimental side effects. Here, the authors reviewed the recent literature focusing on the role of AMPA-glutamatergic neurotransmission in stress-induced maladaptive responses in emotional and mood-associated brain regions, including the hippocampus, amygdala, prefrontal cortex, nucleus accumbens and periaqueductal gray.

Repairing Facial Fractures with Interrupted Maxillary-mandibular Arches by Computer-assisted Reverse Planning Model Surgery.

BACKGROUND: Management of comminuted facial fractures with maxillary-mandibular arch interruption is difficult, resulting in inadequate bone reduction and malocclusion. Traditionally, a good quality dental splint is helpful, but difficult to obtain in acute trauma. We apply a computer-assisted design and three-dimensional printing technology to improve splint fabrication and utilization, thus facilitating restoration of dental occlusion and facial fracture. METHODS: We retrospectively reviewed patients who suffered from facial fractures with interruption of the maxillary-mandibular arches. We developed the "computer-assisted reverse planning and three-dimensional printing model surgery" algorithm and applied it in selected patients. An occlusal splint was created as a surgical guide to enhance the maxilla-mandibular unit repair by taking care of the bone reduction and occlusion. All included patients were followed up to assess the functional outcome and patients suitable for this method. RESULTS: From Jan 2015 to Aug 2020, 10 patients (eight men and two women) with comminuted facial fractures were included. The average time of surgery was 9.2 days. The average follow-up time was 8.6 months. There was no patient who needed major revision to correct malocclusion or facial asymmetry. CONCLUSIONS: A computer-assisted design splint decreases intraoperative inaccuracies and difficulty in comminuted maxillo-mandibular fractures. It is a useful and reliable alternative. Collaboration with an experienced engineer and patient selection are indispensable in delivering successful outcomes. Patients who have more than three bone fragments in a single dental arch or more than four bone fragments in the entire maxillary-mandibular unit appear to be excellent candidates for this method.

Mifepristone Directly Disrupts Mouse Embryonic Development in Terms of Cellular Proliferation and Maturation In Vitro.

Mifepristone (RU-486), a synthetic steroid with potent antiprogestogen and anti-glucocorticoid properties, has been widely used in clinical practice. Its effect on the endometrium, ovary, and fallopian tube has been well reported in many human and animal studies. However, its direct impact on post-implantation embryos remains underexplored. Additionally, some women choose to keep their pregnancy after mifepristone treatment fails. Thus, the potential risk remains controversial. Hence, this study investigated the direct effects of mifepristone on the development of mice blastocysts in vitro in terms of implantation and post-implantation. We detected the level of progesterone (P4) associated with ovulation in vivo. The presence of progesterone receptors (PRs) in blastocysts and post-implantation embryos was also evaluated. Cultured embryos were treated directly with mifepristone. We further examined embryonic implantation and post-implantation of blastocysts in vitro to evaluate the direct effects of mifepristone on embryos by the assessment of embryonic outgrowth and differential cell staining. In the oviduct lumen, the P4 level dramatically increased at 48 h and slightly decreased at 72 and 96 h following ovulation. PR was expressed in blastocysts not only in the preimplantation stage but also in the early post-implantation period. In the evaluation of developmental stages, mifepristone significantly reduced the successful ratio of developing into the late egg cylinder and the early somite stage. In addition, it further decreased the cell number of the embryos' inner cell mass and trophectoderm. We herein provide evidence that mifepristone affects blastocyst viability directly and inhibits post-implantation embryo development in vitro. Furthermore, our data reveal a potential risk of fetus fatality and developmental problems when pregnancies are continued after mifepristone treatment fails.

Restoration of HDAC1 Enzymatic Activity after Stroke Protects Neurons from Ischemia/Reperfusion Damage and Attenuates Behavioral Deficits in Rats.

A therapeutic approach for promoting neuroprotection and brain functional regeneration after strokes is still lacking. Histone deacetylase 1 (HDAC1), which belongs to the histone deacetylase family, is involved in the transcriptional repression of cell-cycle-modulated genes and DNA damage repair during neurodegeneration. Our previous data showed that the protein level and enzymatic activity of HDAC1 are deregulated in stroke pathogenesis. A novel compound named 5104434 exhibits efficacy to selectively activate HDAC1 enzymatic function in neurodegeneration, but its potential in stroke therapy is still unknown. In this study, we adopted an induced rat model with cerebral ischemia using the vessel dilator endothelin-1 to evaluate the potential of compound 5104434. Our results indicated compound 5104434 selectively restored HDAC1 enzymatic activity after oxygen and glucose deprivation, preserved neurite morphology, and protected neurons from ischemic damage in vitro. In addition, compound 5104434 attenuated the infarct volume, neuronal loss, apoptosis, DNA damage, and DNA breaks in cerebral ischemia rats. It further ameliorated the behavioral outcomes of neuromuscular response, balance, forepaw strength, and functional recovery. Collectively, our data support the efficacy of compound 5104434 in stroke therapy and contend that it can be considered for clinical trial evaluation.

Smoking Status and Functional Outcomes in Young Stroke.

Objective: Stroke in young adults is uncommon, and the etiologies and risk factors of stroke in young adults differ from those in older populations. Smoker's paradox is an unexpected favorable outcome, and age difference is used to explain the association between smoking and the favorable functional outcome. This study aimed to investigate the existence of this phenomenon in young stroke patients. Methods: We analyzed a total of 9,087 young stroke cases registered in the nationwide stroke registry system of Taiwan between 2006 and 2016. Smoking criteria included having a current history of smoking more than one cigarette per day for more than 6 months. After matching for sex and age, a Cox model was used to compare mortality and function outcomes between smokers and non-smokers. Results: Compared with the non-smoker group, smoking was associated with older age, higher comorbidities, and higher alcohol consumption. Patients who report smoking with National Institutes of Health Stroke Scale scores of 11-15 had a worse functional outcome (adjusted odds ratio, 0.81; 95% confidence interval, 0.76 - 0.87). Conclusion: Smokers had a higher risk of unfavorable functional outcomes at 3 months after stroke, and therefore, we continue to strongly advocate the importance of smoking cessation.

HDAC1 deregulation promotes neuronal loss and deficit of motor function in stroke pathogenesis.

Stroke is a common cause of death worldwide and leads to disability and cognitive dysfunction. Ischemic stroke and hemorrhagic stroke are major categories of stroke, accounting for 68% and 32% of strokes, respectively. Each year, 15 million people experience stroke worldwide, and the stroke incidence is rising. Epigenetic modifications regulate gene transcription and play a major role in stroke. Accordingly, histone deacetylase 1 (HDAC1) participates in DNA damage repair and cell survival. However, the mechanisms underlying the role of HDAC1 in stroke pathogenesis are still controversial. Therefore, we investigated the role of HDAC1 in stroke by using a rat model of endothelin-1-induced brain ischemia. Our results revealed that HDAC1 was deregulated following stroke, and its expressional level and enzymatic activity were decreased. We also used MS-275 to inhibit HDAC1 function in rats exposed to ischemic insult. We found that HDAC1 inhibition promoted the infarct volume, neuronal loss, DNA damage, neuronal apoptosis after stroke, and levels of reactive oxygen species and inflammation cytokines. Additionally, HDAC1 inhibition deteriorated the behavioral outcomes of rats with ischemic insult. Overall, our findings demonstrate that HDAC1 participates in ischemic pathogenesis in the brain and possesses potential for use as a therapeutic target.

Three-Dimensional Outcome Assessments of Surgical Correction in Cleft and Noncleft Patients with Class III Skeletal Relation: A Case-Control Study.

BACKGROUND: The orthognathic strategies to treat patients with a concave profile but different tissue conditions remain controversial. The aim of this case-control study was to investigate the outcome predictability of orthognathic surgery in cleft lip and palate (CLP) patients and matched controls. METHODS: Fifty consecutive CLP and 45 matched non-CLP patients who received whole-piece Le Fort I and bilateral sagittal split osteotomy to correct class III skeletal relations were enrolled. The outcome discrepancies (ODs) from simulations among all groups were evaluated with consideration of the possible influences from planned surgical movements (PSM). Receiver operating characteristic curves were used to determine threshold values of PSMs that yielded clinically relevant OD. RESULTS: Unilateral CLP (UCLP) patients had comparable postsurgical OD to non-CLP patients in both jaws, whereas bilateral CLP (BCLP) patients had greater deviations from predicted results. Vertical movement of the A - point > 1.33 mm and yaw correction > 1.65° in the BCLP patients was associated with clinically relevant maxillary OD. CONCLUSIONS: The OGS outcomes of BCLP patients were less predictable than those of the UCLP and noncleft patients. Vertical movements of the A - point > 1.33 mm and yaw correction > 1.65° in BCLP patients increased OD to a clinically relevant extent.