Knockdown of Porf-2 restores visual function after optic nerve crush injury.

Retinal ganglion cells (RGCs), the sole output neurons in the eyes, are vulnerable to diverse insults in many pathological conditions, which can lead to permanent vision dysfunction. However, the molecular and cellular mechanisms that contribute to protecting RGCs and their axons from injuries are not completely known. Here, we identify that Porf-2, a member of the Rho GTPase activating protein gene group, is upregulated in RGCs after optic nerve crush. Knockdown of Porf-2 protects RGCs from apoptosis and promotes long-distance optic nerve regeneration after crush injury in both young and aged mice in vivo. In vitro, we find that inhibition of Porf-2 induces axon growth and growth cone formation in retinal explants. Inhibition of Porf-2 provides long-term and post-injury protection to RGCs and eventually promotes the recovery of visual function after crush injury in mice. These findings reveal a neuroprotective impact of the inhibition of Porf-2 on RGC survival and axon regeneration after optic nerve injury, providing a potential therapeutic strategy for vision restoration in patients with traumatic optic neuropathy.

A Primary Squamous Cell Carcinoma of the Thyroid Presenting as the Anaplastic Thyroid Carcinoma: A Case Report.

Background: Primary squamous cell carcinoma of the thyroid (PSCCT) is an uncommon malignancy that is difficult to diagnose and differentiate. There is no consensus for the early clinical, radiological, or ultrasonic identification of PSCCT before pathological changes are observed in patients. There is also no suitable treatment due to the absence of a definite diagnosis. Case Presentation: A 76-year-old female patient complained about a rapidly growing cervical mass, dyspnea, dysphagia, and a change in her voice. Based on the results of thyroid ultrasound, fine-needle aspiration, and plain and enhanced CT, the patient was initially diagnosed with anaplastic thyroid carcinoma (ATC). Thereafter, we removed the mass that was the patient's main complaint. The gross examination of the patient's symptoms also supported our previous diagnosis. However, her disease was finally diagnosed as PSCCT, according to the histopathology and immunohistochemistry findings of the mass. Conclusion: Our case highlights the need for a comprehensive framework in the management of PSCCT. The more auxiliary examinations (e.g., ultrasonographic, radiology, or biopsy examinations) we take, the more likely we are to identify this disease. Immunohistochemistry is currently the preferred examination for the diagnosis of PSCCT, while surgical resection combined with radio-sensitizing therapy and adjuvant chemotherapy is the main treatment method for PSCCT.

Porf-2 Inhibits Tumor Cell Migration Through the MMP-2/9 Signaling Pathway in Neuroblastoma and Glioma.

Tumor migration and invasion are key pathological processes that contribute to cell metastasis as well as treatment failure in patients with malignant tumors. However, the mechanisms governing tumor cell migration remain poorly understood. By analyzing the tumor-related database and tumor cell lines, we found that preoptic regulatory factor-2 (Porf-2) is downexpressed in both neuroblastoma and glioma. Using in vitro assays, our data demonstrated that the expression of Porf-2 inhibits tumor cell migration both in neuroblastoma and glioma cell lines. Domain-mutated Porf-2 plasmids were then constructed, and it was found that the GAP domain, which plays a role in the inactivation of Rac1, is the functional domain for inhibiting tumor cell migration. Furthermore, by screening potential downstream effectors, we found that Porf-2 can reduce MMP-2 and MMP-9 expression. Overexpression of MMP-2 blocked the inhibitory effect of Porf-2 in tumor cell migration both in vitro and in vivo. Taken together, we show for the first time that Porf-2 is capable of suppressing tumor cell migration via its GAP domain and the downregulation of MMP-2/9, suggesting that targeting Porf-2 could be a promising therapeutic strategy for nervous system tumors.

Identification and Management of Paroxysmal Sympathetic Hyperactivity After Traumatic Brain Injury.

Paroxysmal sympathetic hyperactivity (PSH) has predominantly been described after traumatic brain injury (TBI), which is associated with hyperthermia, hypertension, tachycardia, tachypnea, diaphoresis, dystonia (hypertonia or spasticity), and even motor features such as extensor/flexion posturing. Despite the pathophysiology of PSH not being completely understood, most researchers gradually agree that PSH is driven by the loss of the inhibition of excitation in the sympathetic nervous system without parasympathetic involvement. Recently, advances in the clinical and diagnostic features of PSH in TBI patients have reached a broad clinical consensus in many neurology departments. These advances should provide a more unanimous foundation for the systematic research on this clinical syndrome and its clear management. Clinically, a great deal of attention has been paid to the definition and diagnostic criteria, epidemiology and pathophysiology, symptomatic treatment, and prevention and control of secondary brain injury of PSH in TBI patients. Potential benefits of treatment for PSH may result from the three main goals: eliminating predisposing causes, mitigating excessive sympathetic outflow, and supportive therapy. However, individual pathophysiological differences, therapeutic responses and outcomes, and precision medicine approaches to PSH management are varied and inconsistent between studies. Further, many potential therapeutic drugs might suppress manifestations of PSH in the process of TBI treatment. The purpose of this review is to present current and comprehensive studies of the identification of PSH after TBI in the early stage and provide a framework for symptomatic management of TBI patients with PSH.

Take it seriously or not: postoperative pneumocephalus in CSDH patients?

Background: Pneumocephalus is a common finding after burr-hole drainage of chronic subdural hematoma (CSDH). Its effects have not been specifically studied.Methods: A retrospective analysis was performed in 140 patients with CSDH with single burr-hole drainage. The pre- and postoperative volumes of intracranial hematoma and the postoperative volume of pneumocephalus were calculated and analyzed with their relationships with Glasgow Coma Scale (GCS) and Glasgow Outcome Scale (GOS) scores.Results: The preoperative hematoma volume and the patient ages are positively correlated with the 1-day postoperative pneumocephalus volume (p < 0.001, p < 0.01). There is no correlation between postoperative pneumocephalus volume and GCS/GOS scores (p > 0.05) and there is no difference of GCS/GOS scores or CSDH recurrence rate between patients with and without pneumocephalus (p > 0.05). The age and the volume of 1-day postoperative pneumocephalus are positively correlated with the absorbing rate of pneumocephalus (p < 0.01, p < 0.001).Conclusions: The pneumocephalus at a certain range has no effect on the prognosis of patients with CSDH and requires no specific intervention due to its self-absorbing capacity in the normal progress after surgery.HighlightsNo correlation between postoperative pneumocephalus volume and GCS/GOS scores.No difference of GCS/GOS or recurrence between patients with pneumocephalus or not.Pneumocephalus at certain range has no effect on the prognosis of patients.

Gene expression profile of the hippocampus of rats subjected to traumatic brain injury.

Traumatic brain injury (TBI) is a serious public health problem as well as a leading cause of severe posttraumatic disability. Numerous studies indicate that the differentially expressed genes (DEGs) of neural signaling pathways are strongly correlated with brain injury. To further analyze the roles of the DGEs in the central nervous system, here we systematically investigated TBI on the hippocampus and its injury mechanism at the whole genome level. On the basis of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes Analyses, we revealed that the DEGs were involved in many signaling pathways related to the nervous system, especially neuronal survival-related pathways. Finally, we verified the microarray results and detected the gene expression of neuronal survival-related genes in the hippocampus by using real-time quantitative polymerase chain reaction. With Western blot and axon growth assay, the expression of P2rx3 was upregulated in rats subjected to TBI, and overexpression of P2rx3 promoted neurite growth of NG108 cells. Our results suggested that the DEGs (especially P2rx3) and several signaling pathways might play a pivotal role in TBI. We also provided several targeted genes related to TBI for future investigation.

4-Phenylbutyrate Ameliorates Anxiety Disorder by Inhibiting Endoplasmic Reticulum Stress after Diffuse Axonal Injury.

Diffuse axonal injury (DAI) is accompanied frequently by adverse sequelae and psychiatric disorders, such as anxiety, leading to a decreased quality of life, social isolation, and poor outcomes in patients. The mechanisms regulating psychiatric disorders post-DAI are not well elucidated, however. Previous studies showed that endoplasmic reticulum (ER) stress functions as a pivotal factor in neurodegeneration disease. In this study, we showed that DAI can trigger ER stress and unfolded protein response (UPR) activation in both the acute and chronic periods, leading to cell death and anxiety disorder. Treatment with 4-phenylbutyrate (4-PBA) is able to inhibit the UPR and cell apoptosis and relieve the anxiety disorder in our DAI model. Later (14 days post-DAI) 4-PBA treatment, however, can restore only the related gene expression of ER stress and UPR but not the psychiatric disorder. Therefore, the early (5 min after DAI) administration of 4-PBA might be a therapeutic approach for blocking the ER stress/UPR-induced cell death and anxiety disorder after DAI.

Neuronal GAP-Porf-2 transduces EphB1 signaling to brake axon growth.

Axonal outgrowth and guidance require numerous extracellular cues and intracellular mediators that transduce signals in the growth cone to regulate cytoskeletal dynamics. However, the way in which cytoskeletal effectors respond to these signals remains elusive. Here, we demonstrate that Porf-2, a neuron-expressed RhoGTPase-activating protein, plays an essential role in the inhibition of initial axon growth by restricting the expansion of the growth cone in a cell-autonomous manner. Furthermore, the EphB1 receptor is identified as an upstream controller that binds and regulates Porf-2 specifically upon extracellular ephrin-B stimulation. The activated EphB forward signal deactivates Rac1 through the GAP domain of Porf-2, which inhibits growth cone formation and brakes axon growth. Our results therefore provide a novel GAP that regulates axon growth and braking sequentially through Eph receptor-independent and Eph receptor-dependent pathways.

Rac1 Guides Porf-2 to Wnt Pathway to Mediate Neural Stem Cell Proliferation.

The molecular and cellular mechanisms underlying the anti-proliferative effects of preoptic regulator factor 2 (Porf-2) on neural stem cells (NSCs) remain largely unknown. Here, we found that Porf-2 inhibits the activity of ras-related C3 botulinum toxin substrate 1 (Rac1) protein in hippocampus-derived rat NSCs. Reduced Rac1 activity impaired the nuclear translocation of ß-catenin, ultimately causing a repression of NSCs proliferation. Porf-2 knockdown enhanced NSCs proliferation but not in the presence of small molecule inhibitors of Rac1 or Wnt. At the same time, the repression of NSCs proliferation caused by Porf-2 overexpression was counteracted by small molecule activators of Rac1 or Wnt. By using a rat optic nerve crush model, we observed that Porf-2 knockdown enhanced the recovery of visual function. In particular, optic nerve injury in rats led to increased Wnt family member 3a (Wnt3a) protein expression, which we found responsible for enhancing Porf-2 knockdown-induced NSCs proliferation. These findings suggest that Porf-2 exerts its inhibitory effect on NSCs proliferation via Rac1-Wnt/ß-catenin pathway. Porf-2 may therefore represent and interesting target for optic nerve injury recovery and therapy.

Rho GTPase-activating proteins: Regulators of Rho GTPase activity in neuronal development and CNS diseases.

The Rho family of small GTPases was considered as molecular switches in regulating multiple cellular events, including cytoskeleton reorganization. The Rho GTPase-activating proteins (RhoGAPs) are one of the major families of Rho GTPase regulators. RhoGAPs were initially considered negative mediators of Rho signaling pathways via their GAP domain. Recent studies have demonstrated that RhoGAPs also regulate numerous aspects of neuronal development and are related to various neurodegenerative diseases in GAP-dependent and GAP-independent manners. Moreover, RhoGAPs are regulated through various mechanisms, such as phosphorylation. To date, approximately 70 RhoGAPs have been identified; however, only a small portion has been thoroughly investigated. Thus, the characterization of important RhoGAPs in the central nervous system is crucial to understand their spatiotemporal role during different stages of neuronal development. In this review, we summarize the current knowledge of RhoGAPs in the brain with an emphasis on their molecular function, regulation mechanism and disease implications in the central nervous system.

Porf-2 Inhibits Neural Stem Cell Proliferation Through Wnt/ß-Catenin Pathway by Its GAP Domain.

Neural stem cell (NSC) proliferation and differentiation play a pivotal role in the development of brain, the plasticity of the brain network, and the repair for brain function in CNS diseases. The mechanisms regulating NSC behavior are not well elucidated. Previous studies showed porf-2 functions as a modulator in central nerve system development. We here show that porf-2, a conserved family of RhoGAPs, is highly and specifically expressed in NSCs. We also demonstrate that porf-2 inhibits the proliferation of NSCs in vivo and in vitro, but has no effect on NSC differentiation. We investigated which domain is required for the role of porf-2 on NSC proliferation. By using neurosphere formation and Edu assay we confirmed the GAP domain is necessary for its function. In addition, we surveyed a few classical pathways on NSC proliferation and found that porf-2 inhibits NSC proliferation by suppressing the ß-catenin nuclear translocation. Taken together, we show for the first time that porf-2 inhibits NSC proliferation through Wnt/ß-catenin pathway by its GAP domain.

Insight into astrocyte activation after optic nerve injury.

In response to optic nerve damage, astrocytes become reactive. This reactivity can be identified by the presence of morphological and molecular changes throughout the retina and optic nerve as well as the formation of a glial scar. The process of astrocyte activation exhibits spatial and temporal characteristics, and it is finely regulated by complex signaling mechanisms. Excessive astrocyte activation plays a crucial role in progressive optic nerve injury. This review focuses on the spatial and temporal characteristics and mechanisms of astrocyte activation and discusses the modulation of astrocyte activation. Further insight into astrocyte activation might provide targets for future therapeutic interventions.

[Early, middle and long-term clinical outcomes of coronary artery bypass grafting for left main coronary stenosis].

OBJECTIVE: To evaluate the early, middle and long-term clinical outcomes of coronary artery bypass grafting (CABG) for a special subset of left main coronary stenosis (LMS). METHODS: A total of 626 LMS patients, recruited at our hospital between January 1998 and March 2008, were classified them into the statin therapy group (Group A, n = 322) or the non-statin therapy group (Group B, n = 304) according to whether or not taking statins pre-operatively. Then their clinical data were retrospectively analyzed. RESULTS: The inhospital mortality was 4.31% (n = 27). And the mortality was 1.90% (n = 6) for Group A and 6.91% for Group B (n = 21) (χ² test, χ² = 9.642, P = 0.002). Preoperative statin therapy could lower the all-cause mortality rate (1.90% vs 6.91%, P = 0.002), the prevalence of new atrial fibrillation or flutter (14.69% vs 19.61%, P = 0.016, χ ²= 5.780) and disabling stroke (2.50% vs 4.58%, P = 0.047, χ(2) = 3.94). Among 599 CABG survivors, 565 cases (94.3%) were actually followed up with a mean duration of 55.5 ± 26.1 months (range: 2 - 98). During the follow-up period, there were 29 (4.63%) cardiac events, including 12 deaths and 17 myocardial infarctions. There were 43 (7.18%) cases with relapsing angina pectoris. The univariate analysis showed that emergency procedure, abnormal C-reactive protein (CRP), abnormal troponin I(TnI), complicated LMS pathology, preoperative IABP (intra-aortic balloon pump) support, preoperative cardiac arrest, preoperative history of myocardium infarction and no preoperative statin therapy were the risk factors for perioperative death while complicated LMS pathology, preoperative IABP support, preoperative cardiac arrest, preoperative myocardium infarction and no preoperative statin therapy were the risk factor for late cardiac events. The multivariate binary logistic regression showed that emergency procedure, preoperative IABP support, no preoperative statin therapy and preoperative IABP support were independent predictors for peri-operative death. And preoperative IABP support, preoperative cardiac arrest, no preoperative statin therapy and complicated LMS pathology were independent predictors for late cardiac events. There was no statistical significance in inhospital mortality between on pump CABG and OPCAB (off pump coronary artery bypass). CONCLUSION: The CABG procedure for LMS carries a relative high mortality. However preoperative statin therapy may offer such protective effects as lowering the all-cause mortality rate and reducing the prevalence of new atrial fibrillation or flutter and disabling stroke.

[Repair of anterior leaflet mitral valve prolapse: the comparison between chordal replacement and chordal shortening].

OBJECTIVE: To compare the relative merits between chordal shortening and artificial chordae to repair the anterior leaflet prolapses (ALP). METHODS: The clinic data of 50 cases underwent repair of ALP from March 1990 to March 2008 were analyzed retrospectively. There were 29 male and 21 female patients with a mean age of (42.6 +/- 11.3) years old. There were 23 patients in chordal shortening group and 27 patients in artificial chordae group. RESULTS: There were 3 operative deaths in chordal shortening group (13.0%), and 1 death in artificial chordae group (3.7%, P = 0.199). With a mean follow-up of (5.8 +/- 4.8) years and a total follow-up of 278 patient-years, there were 3 late deaths respectively in each group. According the Kaplan-Meier survival curve, the actuarial survival rate at 5-8 years was 70.0% +/- 18.2% for chordal shortening group and 86.8% +/- 9.2% for artificial chordae group (chi(2) = 8.17, P = 0.046). There were 5 reoperations, of which 4 in chordal shortening group and 1 in artificial chordae group. According to the Kaplan-Meier freedom from reoperation curve, the freedom from reoperation at 5 years was 83.3% +/- 15.2% for chordal shortening group and 100% for artificial chordae group (chi(2) = 12.06, P = 0.007). The COX proportional hazard regressions revealed that chordal-shortening technique was the independent risk predictor for the late cardiac event after ALP surgical repair. CONCLUSION: Artificial chordae techniques has a relative superiority to chordal shortening for repair of mitral valve ALP.

[Ross procedure in treatment of aortic disease: clinical experience of 15 cases].

OBJECTIVE: To summarize the clinical experience of Ross procedure in treatment of aorta valve diseases. METHODS: The clinical data of 15 patients with aorta valve diseases, 12 men and 3 women, aged 30 +/- 14, including 13 cases of congenital aorta valve disease, 1 case of senile degenerative aortic valve disease, and 1 case of subacte bacterial endocarditis complicated by aortic stenosis (AS), with the heart function (NYHA) of class II in 11 cases and class III in 4 cases, underwent Ross procedure from October 1994 to September 2002 in Anzhen Hospital. Before operation, ultrasound cardiography showed moderate to severe AS and/or aortic insufficiency (AI) with an average aortic valve annulus diameter (AVD) of 2.4 +/- 0.4 cm and normal pulmonary valve. Operation was performed on all patients under cardiopulmonary bypass and moderate hypothermia. The operation procedure was as follows: (1) to take off the auto-pulmonary artery valve; (2) to remove the dysfunctional aortic valve and auto-transplant the pulmonary valve on the aortic root; and (3) to put a pulmonary homograft so as to re-establish on the right ventricular outflow tract. RESULTS: The perieoperative mortality is 0. After the operation, the mean pressure gradient of aortic valve was in the normal limitation (7.23 +/- 0.14 mm Hg), the left ventricular diastolic diameter decreased significantly (P < 0.001), the left ventricular ejection fraction was 0.48 +/- 0.22, and the heart function (NYHA) was at the classes I - II in all the patients. All cases received follow-up of 1 - 9 years, their heart function was all in Class I, and the function of their aortic and pulmonary valves remained well. CONCLUSION: Ross procedure is a kind of effective alterative operation in treating patients with aortic valve disease.