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Maladaptive reactive aggression is a core symptom of neuropsychiatric disorders such as schizophrenia. While uncontrolled aggression dampens societal safety, there is a limited understanding of the neural regulation involved in reactive aggression and its treatment. High levels of aggression have been linked to low serotonin (5-HT) levels. Additionally, post-weaning socially isolated (SI) mice exhibit outbursts of aggression following encountering acute stress, and hyperactivated ventral hippocampus (vHip) involves this stress-provoked escalated aggression. Here, we investigated the potential role of the raphe nucleus projecting to the vHip in modulating aggressive behavior. Chemogenetically activating the dorsal raphe nucleus (DRN) soma projecting the vHip or DRN nerve terminals in the vHip reduced reactive aggression. The reduction of attack behavior was abolished by the pretreatment of 5-HT1B receptor antagonist SB-224289. However, activating the median raphe nucleus (MRN)-to-vHip pathway ameliorated depression-like behavior but did not affect reactive aggression. DRNâvHip activation suppressed the vHip downstream area, the ventromedial hypothalamus (VMH), which is a core aggression area. Intra-vHip infusion of 5-HT1B receptor agonists (anpirtoline, CP-93129) suppressed reactive aggression and decreased c-Fos levels in the vHip neurons projecting to the VMH, suggesting an inhibition mechanism. Our findings indicate that activating the DRN projecting to the vHip is sufficient to inhibit reactive aggression in a 5-HT1B receptor-dependent manner. Thus, targeting 5-HT1B receptor could serve as a promising therapeutic approach to ameliorate symptoms of reactive aggression.
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BACKGROUND: Over the past two decades, with the introduction of the perforator flap concept and advances in flap dissections, lower extremities have emerged as the preferred soft tissue flap donor sites. As a modern and high-volume microsurgical center, and the senior author being one of the pioneers and advocates for the use of lower extremity flap donor sites, we aim to investigate the role of latissimus dorsi free flap in head and neck reconstruction within our current practice. METHODS: All free latissimus dorsi flaps used for head and neck reconstruction performed by a single surgeon between January 2010 to June 2023 were reviewed for their indications, immediate and short-term outcomes. RESULTS: A total of 1,586 head and neck free flap reconstructions was performed, and 33 free latissimus dorsi flaps were identified. The patients' median age was 53 (IQR 48.5-63.5) years. Twenty-nine (87.9%) flaps were used to reconstruct oro-maxillo-facial and four (12.1%) flaps were used to reconstruct scalp defects. Most patients had prior radiation (n=28, 84.8%), neck dissection (n=24, 72.7%), and multiple previous head and neck flap reconstructions with a median of 3.0 (IQR 3.0-3.5) previous flaps. Six (18.2%) latissimus dorsi flaps were used to replace failed flaps from other donor sites. No major complications such as total flap failure or take-backs, and no need for vein grafts, but three (9.1%) had flap marginal necrosis. Other complications included flap one flap dehiscence (3.0%), one orocutaneous fistula (3.0%), two wound infections (6.1%), three plate exposures (9.1%), and 3 patients developed local recurrence (9.1%). The median patient follow-up time was 16 (IQR 5-27) months. CONCLUSION: This retrospective study demonstrates the role of latissimus dorsi free flap in head and neck reconstruction as a reliable and versatile backup soft tissue flap when workhorse flaps from lower extremity donor sites are either unavailable or unsuitable.
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Lipomas are the most prevalent type of benign soft tissue tumors, primarily composed of adipocytes, and typically remain asymptomatic unless they reach a significant size. Although giant lipomas are infrequent, their occurrence on the chest wall, particularly in the interpectoral region, is exceedingly rare. We present a unique case of a 48-year-old man with a massive interpectoral lipoma measuring 19.4â ×â 12.9â ×â 9.4 cm, which resulted in venous thoracic outlet syndrome by compressing the subclavian vein. This case highlights the clinical challenges in diagnosing deep-seated chest wall lipomas and underscores the necessity of considering thoracic outlet syndrome as a potential complication, even in the absence of direct neural or arterial compression. The presentation of thoracic outlet syndrome can vary, and a comprehensive evaluation is imperative for accurate diagnosis and management.
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BACKGROUND: This retrospective study aimed to evaluate the precision and safety outcomes of image-guided lung percutaneous thermal ablation (LPTA) methods, focusing on radiofrequency ablation (RFA) and microwave ablation (MWA). The study utilized an innovative angle reference guide to facilitate these techniques in the treatment of lung tumors. METHODS: This study included individuals undergoing LPTA with the assistance of laser angle guide assembly (LAGA) at our hospital between April 2011 and March 2021. We analyzed patient demographics, tumor characteristics, procedure details, and complications. Logistic regressions were employed to assess risk factors associated with complications. RESULTS: A total of 202 patients underwent ablation for 375 lung tumors across 275 sessions involving 495 ablations. Most procedures used RFA, especially in the right upper lobe, and the majority of ablations were performed in the prone position (49.7%). Target lesions were at a median depth of 39.3 mm from the pleura surface, and remarkably, 91.9% required only a single puncture. Complications occurred in 31.0% of ablations, with pneumothorax being the most prevalent (18.3%), followed by pain (12.5%), sweating (6.5%), fever (5.0%), cough (4.8%), hemothorax (1.6%), hemoptysis (1.2%), pleural effusion (2.0%), skin burn (0.6%), and air emboli (0.2%). The median procedure time was 21 min. Notably, smoking/chronic obstructive pulmonary disease emerged as a significant risk factor for complications. CONCLUSION: The LAGA-assisted LPTA enhanced safety by improving accuracy and reducing risks. Overall, this investigation contributes to the ongoing efforts to refine and improve the clinical application of these thermal ablation techniques in the treatment of lung tumors.
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Ablação por Cateter , Hipertermia Induzida , Neoplasias Pulmonares , Humanos , Estudos Retrospectivos , Neoplasias Pulmonares/patologia , Pulmão/patologia , Tomografia Computadorizada por Raios X/métodos , Ablação por Cateter/métodos , Resultado do TratamentoRESUMO
OBJECTIVES: This study assessed the incidence of postfracture radiological temporomandibular joint (TMJ) degeneration in patients with different types of mandibular fractures, focusing on the impact of condylar fractures. METHODS: This retrospective review included patients diagnosed as having mandibular fractures from 2016 to 2020 who had undergone initial computed tomography (CT) and a follow-up CT scan at least 1-month postfracture. Patient demographics, fracture details, treatment methods, and radiological signs of TMJ degeneration on CT were analyzed to identify risk factors for postfracture TMJ degeneration, with a focus on condylar head fracture and non-head (condylar neck or base) fractures. RESULTS: The study included 85 patients (mean age: 38.95 ± 17.64 years). The per-patient analysis indicated that the incidence of new radiologic TMJ degeneration on CT was significantly the highest (p < 0.001) in patients with condylar head fractures (90.91%), followed by those with non-head condylar fractures (57.14%), and those without condylar involvement (24.49%). The per-joint analysis indicated nearly inevitable degeneration (93.94%) in 33 TMJs with ipsilateral condylar head fractures. For the remaining 137 TMJs, multivariate logistic regression revealed that other patterns (ipsilateral non-head, contralateral, or both) of condylar fractures (odds ratio (OR) = 3.811, p = 0.007) and the need for open reduction and internal fixation (OR = 5.804, p = 0.005) significantly increased the risk of TMJ degeneration. CONCLUSIONS: Ipsilateral non-head condylar fractures and contralateral condylar fractures are associated with a high risk of postfracture TMJ degeneration. Indirect trauma plays a vital role in postfracture TMJ degeneration.
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Côndilo Mandibular , Fraturas Mandibulares , Transtornos da Articulação Temporomandibular , Tomografia Computadorizada por Raios X , Humanos , Fraturas Mandibulares/diagnóstico por imagem , Masculino , Feminino , Estudos Retrospectivos , Adulto , Côndilo Mandibular/diagnóstico por imagem , Côndilo Mandibular/lesões , Transtornos da Articulação Temporomandibular/diagnóstico por imagem , Fatores de Risco , Pessoa de Meia-Idade , Incidência , Articulação Temporomandibular/diagnóstico por imagem , Articulação Temporomandibular/lesões , Idoso , AdolescenteRESUMO
Self-improving dystrophic epidermolysis bullosa (DEB) is a genodermatosis that is inherited autosomal dominantly or recessively, and its clinical symptoms may improve or subside spontaneously. Herein, we report a case of self-improving DEB with COL7A1 p.Gly2025Asp variant. The diagnosis was made through histopathological, electron microscopic examination, and genetic testing. The same variant is also noted on his father, who presents with dystrophic toenails without any blisters. This study highlights that idiopathic nail dystrophy could be linked to congenital or hereditary disease. Furthermore, we conducted a review of the literature on the characteristics of reported cases of self-improving DEB with a personal or family history of nail dystrophy. The results supported our findings that nail dystrophy may be the sole manifestation in some family members. We suggest that individuals suffering from idiopathic nail dystrophy may seek genetic counselling when planning pregnancy to early evaluate the potential risk of hereditary diseases.
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Colágeno Tipo VII , Epidermólise Bolhosa Distrófica , Mutação de Sentido Incorreto , Humanos , Epidermólise Bolhosa Distrófica/genética , Colágeno Tipo VII/genética , Masculino , Taiwan , Heterozigoto , Linhagem , Feminino , Adulto , Doenças da Unha/genéticaRESUMO
BACKGROUND: The beneficial effect of pretreatment with statins on traumatic brain injury (TBI)-induced depression and anxiety and its mechanism of action remain unclear. In this study, we combined epidemiological and experimental animal data to clarify this issue. METHODS: We used the Taiwan National Health Insurance database to identify patients who were diagnosed with TBI from 2000 to 2013 and compared patients with and without statin treatment matched by age, sex, and underlying comorbidities in a 1:1 ratio. The risk of developing depression and/or anxiety was compared between patients with and without a statin using Cox proportional hazards regression. We also used a rat model to assess the effect of lovastatin pretreatment on neurobehavioral and neuropathological changes following TBI. RESULTS: The risk of developing depression was lower in the 41,803 patients in the statin cohort than nonstatin cohort (adjusted hazard ratio, 0.91 [95% confidence interval, 0.83-0.99]). In animal models, the lovastatin group had significantly reduced infarct volume, decreased immobility time and latency to eat, a reduced number of Fluoro- Jade-positive cells and levels of glial fibrillary acidic protein and tumor necrosis factor-alpha, and increased adenosine monophosphate -activated protein kinase (AMPK) and its upstream kinase liver kinase B1 in the hippocampal dentate gyrus. These effects were blocked in AMPK inhibitor-pretreated TBI rats. CONCLUSIONS: Our epidemiological data showed that a decreased risk of depression was associated with statin pretreatment, which was supported by an animal study. The underlying mechanism for this appears to involve AMPK activation in the statin pretreatment-induced alleviation of TBI.
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Lesões Encefálicas Traumáticas , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Ratos , Animais , Lovastatina/farmacologia , Lovastatina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Depressão/tratamento farmacológico , Depressão/etiologia , Proteínas Quinases Ativadas por AMP/metabolismo , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismoRESUMO
BACKGROUND: Orthognathic surgery (OGS) is a common intervention used to correct midfacial hypoplasia in patients with cleft. Previous studies have reported that LeFort I maxillary advancement may impact velopharyngeal function, but similar investigations focusing on two-jaw OGS have not been conducted. METHODS: A total of 162 consecutive patients with cleft lip and palate who underwent two-jaw OGS between 2015 and 2020 were enrolled. Clinical data were collected, and preoperative and postoperative skeletal measurements were obtained from cephalometric images. Velopharyngeal function was evaluated using perceptual analysis and nasopharyngoscopy. A logistic regression model was employed for the risk factors associated with changes in velopharyngeal function. RESULTS: After two-jaw OGS, 82.1% of patients showed no change in velopharyngeal function, while 3.7% experienced improvement and 14.2% exhibited worsening of function. In addition, the changes in velopharyngeal function were statistically significant comparing to the pre-OGS velopharyngeal status. A multivariable logistic regression revealed that the amount of maxillary advancement independently predicted the deterioration of post-OGS velopharyngeal function (odds ratio = 1.74, 95% confidence interval (CI) = 1.20-2.52, p = 0.004). The receiver operating characteristic curve based on maxillary advancement demonstrated good discrimination, with an area under the curve of 0.727 (95% CI = 0.62-0.83, p = 0.001). The Youden index was 4.27 mm. CONCLUSION: Despite the risk of velopharyngeal function deterioration in patients with cleft palate undergoing OGS, some individuals have experienced improved function following two-jaw OGS. The extent of maxillary advancement has a negative impact on the velopharyngeal function.
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BACKGROUND: Timely diagnosis and management of concomitant vascular injuries is usually needed for the management of lower extremity open fractures. In the current study, a prediction model and simplified scoring system of vascular injuries were developed for the primary evaluation of patients with lower extremity open fractures. METHODS: Patients with lower extremity open fractures were retrospectively reviewed from 2017 to 2020. Multivariate logistic regression analysis was used to evaluate independent risk factors for concomitant vascular injuries in these patients using data collected from 2017 through 2019 and a prediction scoring model was created accordingly. Model performance was validated with data from 2020. RESULTS: In total, 949 patients with lower extremity open fractures (development cohort, 705 patients, 2017 through 2019; validation cohort, 244 patients, 2020) were enrolled. Concomitant vascular injuries occurred in 44 patients in the development cohort (6.2%). Three clinical variables were identified for a prediction scoring model with weighted points, including hard or soft vascular signs (3 points), segmental fractures (2 points), and degloving soft-tissue injury (1 point). The model showed good discrimination (area under the receiver operating characteristic curve, 0.928), calibration (Hosmer-Lemeshow test, P = 0.661), and precision (Brier score, 0.041). Subsequent management regarding different aspects (observation only, further imaging study, or direct surgical exploration) can thus be decided. The model also demonstrated good discrimination (area under the receiver operating characteristic curve, 0.949), good calibration (Hosmer-Lemeshow test, P = 0.174), and good precision (Brier score, 0.042) in the validation cohort. CONCLUSION: This model may guide the subsequent management of vascular injuries associated with lower extremity open fractures. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.
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Fraturas Expostas , Traumatismos da Perna , Lesões do Sistema Vascular , Humanos , Fraturas Expostas/complicações , Fraturas Expostas/diagnóstico , Fraturas Expostas/cirurgia , Estudos Retrospectivos , Lesões do Sistema Vascular/diagnóstico , Lesões do Sistema Vascular/epidemiologia , Lesões do Sistema Vascular/etiologia , Fatores de Risco , Extremidade InferiorRESUMO
Drug-associated conditioned cues promote subjects to recall drug reward memory, resulting in drug-seeking and reinstatement. A consolidated memory becomes unstable after recall, such that the amnestic agent can disrupt the memory during the reconsolidation stage, which implicates a potential therapeutic strategy for weakening maladaptive memories. The basolateral amygdala (BLA) involves the association of conditioned cues with reward and aversive valences and projects the information to the nucleus accumbens (NAc) that mediates reward-seeking. However, whether the BLA-NAc projection plays a role in drug-associated memory reactivation and reconsolidation is unknown. We used methamphetamine (MeAM) conditioned place preference (CPP) to investigate the role of BLA-NAc neural projection in the memory reconsolidation. Two weeks before CPP training, we infused adeno-associated virus (AAV) carrying the designer receptor exclusively activated by designer drugs (DREADD) or control constructs. We infused clozapine-N-oxide (CNO) after the recall test to manipulate the neural activity of BLA-NAc projections in mice. We found that after recall, DREADD-mediated inhibition of BLA neurons projecting to the NAc core blunted consolidated MeAM-associated memory. Inhibition of BLA glutamatergic nerve terminals in the NAc core 1 h after recall disrupted consolidated MeAM-associated memory. However, inhibiting this pathway after the time window of reconsolidation failed to affect memory. Furthermore, under the condition without memory retrieval, DREADD-mediated activation of BLA-NAc core projection was required for amnesic agents to disrupt consolidated MeAM-associated memory. Our findings provide evidence that the BLA-NAc pathway activity is involved in the post-retrieval processing of MeAM-associated memory in CPP.
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Complexo Nuclear Basolateral da Amígdala , Metanfetamina , Camundongos , Animais , Metanfetamina/farmacologia , Metanfetamina/metabolismo , Tonsila do Cerebelo/metabolismo , Núcleo Accumbens/metabolismo , Memória/fisiologiaRESUMO
BACKGROUND: Epidermolysis bullosa (EB) is a heterogeneous group of hereditary skin diseases characterized by skin fragility. Primary data on Taiwanese population remain scarce. METHODS: We gathered clinical information from EB patients at National Cheng Kung University Hospital from January, 2012, to June, 2021. Diagnostic tests including transmission electron microscopy, immunofluorescence studies, and whole-exome sequencing (WES) were performed. The pathogenicity of novel splice-site mutations was determined through reverse transcriptase-PCR of skin mRNA followed by Sanger and/or RNA sequencing. RESULTS: Seventy-seven EB patients from 45 families were included: 19 EB simplex, six junctional EB, and 52 dystrophic EB. Pathogenic variants were identified in 37 of 38 families (97.4%), in which WES was used as a first-line tool for mutational analysis; RNA sequencing determined pathogenic variants in the remaining one family. A total of 60 mutations in EB-related genes were identified, including 22 novel mutations. The mutations involved KRT5, KRT14, PLEC, COL17A1, LAMB3, LAMA3, ITGB4, and COL7A1. Over one-quarter of DEB patients had EB pruriginosa. CONCLUSIONS: The distinct clinical presentation and molecular pathology of EB in Taiwan expand our understanding of this disorder. WES was an effective first-line diagnostic tool for identifying EB-associated variants. RNA sequencing complemented WES when multiple potentially pathogenic splice-site mutations were found.
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Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa , Humanos , Sequenciamento do Exoma , Taiwan , Epidermólise Bolhosa/diagnóstico , Mutação/genética , Pele/patologia , Epidermólise Bolhosa Distrófica/patologia , Colágeno Tipo VII/genéticaRESUMO
BACKGROUND: Direct-to-implant (DTI) breast reconstruction after nipple-sparing mastectomy (NSM) with the use of acellular dermal matrix (ADM) provides reliable outcomes; however, the use of ADM is associated with a higher risk of complications. We analyzed our experiences of post-NSM DTI without ADM and identified the predictive factors of adverse surgical outcomes. METHODS: Patients who underwent NSM and immediate DTI or two-stage tissue expander (TE) breast reconstruction from 2009 to 2020 were enrolled. Predictors of adverse endpoints were analyzed. RESULTS: There were 100 DTI and 29 TE reconstructions. The TE group had a higher rate of postmastectomy radiotherapy (31% vs. 11%; P=0.009), larger specimens (317.37±176.42 g vs. 272.08±126.33 g; P=0.047), larger implants (360.84±85.19 g vs. 298.83±81.13 g; P=0.004) and a higher implant/TE exposure ratio (10.3% vs. 1%; P=0.035). In DTI reconstruction, age over 50 years (odds ratio [OR], 5.43; 95% confidence interval [CI], 1.50-19.74; P=0.010) and a larger mastectomy weight (OR, 1.65; 95% CI, 1.08-2.51; P=0.021) were associated with a higher risk of acute complications. Intraoperative radiotherapy for the nipple-areolar complex increased the risk of acute complications (OR, 4.05; 95% CI, 1.07-15.27; P=0.039) and the likelihood of revision surgery (OR, 5.57; 95% CI, 1.25-24.93; P=0.025). CONCLUSIONS: Immediate DTI breast reconstruction following NSM is feasible in Asian patients with smaller breasts.
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Reactive impulsive aggression is characterized by outbursts of rage and violence when subjects encounter threatening stressful events. Although impulsive aggression and violence create a high-cost burden on health and society, relatively little is known about treatment. Early adolescent social isolation (SI) alters brain development and functions. It induces hyper-excitatory in the ventral hippocampus (vHip) to promote acute stress-provoked outbursts of aggression, referred to as impulsive aggression, in mouse models. Cannabinoid type 1 receptors (CB1Rs) act on presynaptic sites and suppress neurotransmitter release into synapses. Given that CB1R activation inhibits neurotransmitter releases and modulates excitatory network activity, we tested the hypothesis that CB1R activation reduces impulsive aggression in SI mice through decreasing excitatory activity in the vHip. Here, we report that CB1R agonists, WIN-552122 (WIN) or arachidonylcyclopropylamide (ACPA), ameliorated acute stress-provoked attack behavior in the resident-intruder test without affecting general locomotion activity. Increasing endocannabinoids (eCBs) by inhibiting degradation enzymes in the vHip reduced impulsive aggression, and the effect was blunted by administration of AM251, a CB1R antagonist. Acute stress in SI mice induced c-Fos expression, a marker of neuronal activation, on vHip neurons projecting to the ventromedial hypothalamus (VMH), a well-known brain area that controls attack behavior. eCB augmentation inhibited c-Fos expression in VMH-projecting vHip neurons surrounded by CB1Rs. These results suggest that enhancing eCB signaling in order to activate CB1Rs suppresses impulsive aggression via suppressing vHipâVMH neural activity and point to a role of CB1R activation in ameliorating impulsive aggression in adults who have had adverse experiences during early adolescence.
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BACKGROUND: Major burn-induced acute kidney injury (AKI) causes extremely high mortality, even though renal replacement therapy (RRT) was thought of as the most efficient treatment. There was scanty research for investigating the characteristic of burn-AKI-RRT patients during intensive care. This study aims to investigate the factors impacting the survival outcomes in those burn-AKI-RRT cases. METHODS: Using the Taiwan National Health Insurance Research Database and its affiliated database, the Registry for Catastrophic Illness Patients, we defined a cohort composed of 171 patients encountering major burn-induced AKI and receiving RRT during burn care for a 15-year observation period. Demographic characteristic, comorbidities, total body surface area (TBSA), major procedures, and complications were analyzed to explore the factors affecting the survival outcomes during acute burn care and 1 year after discharge. RESULTS: Patients who underwent tracheostomy and skin grafting had higher survival rates during acute burn care (tracheostomy: mortality vs survival, 15.7% vs 30.2%; P = 0.0257; skin grafting: mortality vs survival, 57.4% vs 76.2%; P = 0.0134). Multivariate regression analysis showed that tracheostomy group significantly presented with lower mortality risk by 65% (odds ratio [OR], 0.35; P = 0.0372), and subgroup analysis of delaminating follow-up duration showed that patients with tracheostomy had higher overall survival by 22% (90-day postburn mortality: nontracheostomy vs tracheostomy, 58.3% vs 36.3%; adjusted hazards ratio, 0.39; 95% confidence interval, 0.22-0.69; P = 0.0011), especially during postburn first 30 days (adjusted hazards ratio, 0.15; 95% confidence interval, 0.05-0.49; P = 0.0016). Total body surface area did not significantly affect survival; however, mortality risk was significantly higher in those with a larger TBSA (TBSA, ≥80%; OR, 6.48; P = 0.0022; TBSA, 60-79%; OR, 3.12; P = 0.0518; TBSA, 40-59%; OR, 1.88; P = 0.2402; TBSA, 30-39% as reference). CONCLUSIONS: For patients with major burn-induced AKI receiving RRT, tracheostomy and skin grafting may improve survival in the cases living through acute burn stage.
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Injúria Renal Aguda , Queimaduras , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Queimaduras/complicações , Queimaduras/terapia , Seguimentos , Humanos , Unidades de Terapia Intensiva , Estudos Retrospectivos , Taiwan/epidemiologiaRESUMO
Glioblastoma (GBM) often recurs after radio- and chemotherapies leading to poor prognosis. Glioma stem-like cells (GSCs) contribute to drug resistance and recurrence. Thus, understanding cellular mechanism underlying the growth of GSCs is critical for the treatment of GBM. Here GSCs were isolated from human U87 GBM cells with magnetic-activated cell sorting (MACS) using CD133 as a marker. The CD133+ cells highly expressed sonic hedgehog (Shh) and were capable of forming tumor spheroids in vitro and tumor in vivo. Athymic mice received intracranial injection of luciferase transduced parental and CD133+ GBM cells was utilized as orthotopic GBM model. Inhibited Shh by LDE225 delayed GBM growth in vivo, and downregulated Ptch1 and Gli1. CD133+ cell proliferation was more sensitive to inhibition by LDE225 than that of CD133- cells. Treatment with LDE225 significantly reduced CD133+-derived tumor spheroid formation. Large membranous vacuoles appeared in the LDE225-treated cells concomitant with the conversion of LC3-I to LC3-II. In addition, LDE225-induced cell death was mitigated in the presence of autophagy inhibitor 3-methyladenine (3-MA). Tumor growth was much slower in Shh shRNA-knockdown mice than in control RNA-transfected mice. Conversely, tumor growth was faster in Shh overexpressed mice. Furthermore, combination of LDE225 and rapamycin treatment resulted in additive effect on LC3-I to LC3-II conversion and reduction in cell viability. However, LDE225 did not affect the phosphorylated level of mTOR. Similarly, amiodarone, an mTOR-independent autophagy enhancer, reduced CD133+ cell viability and tumor spheroid formation in vitro and exhibited anti-tumor activity in vivo. These results suggest that Shh inhibitor induces autophagy of CD133+ cells likely through mTOR independent pathway. Targeting Shh signal pathway may overcome chemoresistance and provide a therapeutic strategy for patients with malignant gliomas.
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When facing stressful conditions, some people tend to be impulsively aggressive whereas others are not. However, the causes and underlying mechanisms remain elusive. It has been reported that acute stress induces outbursts of aggression in post-weaning social isolation (SI) mice but not in group housing (GH) mice. Here we report epigenetic regulation of impulsive aggression in SI mice. At post-natal day 21, mice were randomly assigned to GH or SI groups. We found that SI mice exhibited a higher level of microRNA 206 (miR-206) compared with GH mice. Intra-hippocampal injection of AM206, an antagomir of miR-206, decreased stress-induced attack behavior in SI mice and increased BDNF expression. Moreover, BDNF expression was required for AM206 effects on the reduction of aggression. On the other hand, miR-206 overexpression in GH mice induced attack behavior. Intranasal administration of AM206 rather than a scramble control significantly reduced attack behavior and depression-like behavior in SI mice. Our results suggest that miR-206 mediates development of maladaptive impulsive aggression in early life adversity and that its antagomir could potentially be a therapeutic target against stress-exacerbated aggressive behavior.
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When faced with stressful conditions, people with a tendency toward impulsive aggression may suddenly hurt others. We have previously shown that the blockade of NMDA receptors (NMDARs) within the ventral hippocampus (VH) produces anti-aggressive effects. However, little is known about the mechanism for tamping down stress-provoked attack behavior. Here, we report that expression of brain-derived neurotrophic factor (BDNF) after inhibition of NMDARs in the VH is required for blunting stress-provoked attack behavior in post-weaning socially isolated mice. Administration of NMDAR antagonist MK-801 decreased the phosphorylated eukaryotic elongation factor 2 (p-eEF2) and increased BDNF expression in the VH. Infusion of eEF2 kinase inhibitor NH125 to the VH decreased attack behavior and increased BDNF expression. Knockdown of BDNF in the VH blocked the anti-aggressive effect of MK-801 and NH125. Furthermore, MK-801 rapidly increased the activity of protein phosphatase 2A (PP2A). Intra-VH infusion of PP2A inhibitor okadaic acid blocked the anti-aggressive effects of MK-801. These results suggest that blockade of NMDAR reduces attack behavior through increasing PP2A activity leading to dephosphorylation of eEF2 and an increase in BDNF expression. Our findings indicate that the enhancement of BDNF expression is beneficial for preventing impulsive aggression in at-risk beings.
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Agressão/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Psicotrópicos/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Isolamento Social , Agressão/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Quinase do Fator 2 de Elongação/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Comportamento Impulsivo/efeitos dos fármacos , Comportamento Impulsivo/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Proteína Fosfatase 2/antagonistas & inibidores , Proteína Fosfatase 2/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Isolamento Social/psicologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
OBJECTIVE: The aim of this study is to investigate the preexisting predictive factors associated with comorbidities for diabetic foot ulcer (DFU) in King classification III at an outpatient clinic. METHOD: This prospective study included 100 patients with DFU in King classification III treated at outpatient clinics in Chiayi Chang Gung Memorial Hospital from January 2011 to December 2011. The least follow-up time was 1 year. Medical documentations were in respect of patient's baseline characteristics, associated history, presence of comorbidities, follow-up time, and condition of wounds. Patients were divided into success group (healed or healing with wound reduction), stagnate group, and failure group (amputation or infection, need in-hospital medical service) in accordance with the treatment response of wounds. χ Test, Fisher exact test, and 1-way analysis of variance were used for variables in 3-group comparison, whereas Student t test was applied in 2-group comparison. The predictive factors with P value less than 0.1 were further investigated using the model of univariate logistic regression. RESULTS: With 3-group stratification according to treatment response-failure (n = 8), stagnate (n = 22), and success (n = 70)-the occurrence rate of retinopathy was higher in the treatment stagnate group (42.1%) than in the treatment failure (14.3%) and success groups (12.5%; P = 0.019); the rate of previous percutaneous transluminal angioplasty (PTA) history was higher in the treatment failure group (25%) than in the treatment stagnate (4.8%) and success groups (1.5%; P = 0.020). With 2-group stratification-failure (n = 8) versus nonfailure (n = 92), and success (n = 70) versus nonsuccess (n = 30)-PTA history was strongly associated with treatment failure (odds ratio [OR], 14.33; 95% confidence interval [CI], 1.71-120.32; P = 0.014), whereas retinopathy (OR, 0.21; 95% CI, 0.07-0.65; P = 0.006) was the major negative predictor for treatment success. Previous debridement met borderline significance to predict treatment nonsuccess (OR, 0.09; 95% CI, 0.01-1.01; P = 0.051). Sex, age, associated history, dyslipidemia, hypertension, coronary artery disease, cerebrovascular accident, chronic kidney disease, and end-stage renal disease and wound condition had no statistical significance. CONCLUSIONS: Previous PTA and retinopathy, which indicated preexisting severe vasculopathy, are univariate predictive factors for treatment failure and nonsuccess, respectively, in patients with King classification III DFU. With the subdivision of King classification III DFU, medical history taking and fundus examination are acceptable methods for risk screening at an outpatient clinic.