RESUMEN
Stroke is a major cause of death and disability across the world, and its detrimental impact should not be underestimated. Therapies are available and effective for ischemic stroke (e.g., thrombolytic recanalization and mechanical thrombectomy); however, there are limitations to therapeutic interventions. Recanalization therapy has developed dramatically, while the use of adjunct neuroprotective agents as complementary therapies remains deficient. Pathological TAR DNA-binding protein (TDP-43) has been identified as a major component of insoluble aggregates in numerous neurodegenerative pathologies, including ALS, FTLD and Alzheimer's disease. Here, we show that increased pathological TDP-43 fractions accompanied by impaired mitochondrial function and increased gliosis were observed in an ischemic stroke rat model, suggesting a pathological role of TDP-43 in ischemic stroke. In ischemic rats administered rapamycin, the insoluble TDP-43 fraction was significantly decreased in the ischemic cortex region, accompanied by a recovery of mitochondrial function, the attenuation of cellular apoptosis, a reduction in infarct areas and improvements in motor defects. Accordingly, our results suggest that rapamycin provides neuroprotective benefits not only by ameliorating pathological TDP-43 levels, but also by reversing mitochondrial function and attenuating cell apoptosis in ischemic stroke.
Asunto(s)
Esclerosis Amiotrófica Lateral , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Animales , Ratas , Sirolimus/farmacología , Sirolimus/uso terapéutico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Accidente Cerebrovascular/tratamiento farmacológico , Apoptosis , Esclerosis Amiotrófica Lateral/patologíaRESUMEN
BACKGROUND: Stroke is one of the leading causes of death and disability worldwide and places a heavy burden on the economy in our society. Current treatments, such as the use of thrombolytic agents, are often limited by a narrow therapeutic time window. However, the regeneration of the brain after damage is still active days, even weeks, after stroke occurs, which might provide a second window for treatment. Emodin, a traditional Chinese medicinal herb widely used to treat acute hepatitis, has been reported to possess antioxidative capabilities and protective effects against myocardial ischemia/reperfusion injury. However, the underlying mechanisms and neuroprotective functions of Emodin in a rat middle cerebral artery occlusion (MCAO) model of ischemic stroke remain unknown. This study investigates neuroprotective effects of Emodin in ischemia both in vitro and in vivo. METHODS: PC12 cells were exposed to oxygen-glucose deprivation to simulate hypoxic injury, and the involved signaling pathways and results of Emodin treatment were evaluated. The therapeutic effects of Emodin in ischemia animals were further investigated. RESULTS: Emodin reduced infarct volume and cell death following focal cerebral ischemia injury. Emodin treatment restored PC12 cell viability and reduced reactive oxygen species (ROS) production and glutamate release under conditions of ischemia/hypoxia. Emodin increased Bcl-2 and glutamate transporter-1 (GLT-l) expression but suppressed activated-caspase 3 levels through activating the extracellular signal-regulated kinase (ERK)-1/2 signaling pathway. CONCLUSION: Emodin induced Bcl-2 and GLT-1 expression to inhibit neuronal apoptosis and ROS generation while reducing glutamate toxicity via the ERK-1/2 signaling pathway. Furthermore, Emodin alleviated nerve cell injury following ischemia/reperfusion in a rat MCAO model. Emodin has neuroprotective effects against ischemia/reperfusion injury both in vitro and in vivo, which may be through activating the ERK-1/2 signaling pathway.
Asunto(s)
Emodina/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Daño por Reperfusión/etiología , Daño por Reperfusión/metabolismo , Animales , Biomarcadores , Supervivencia Celular , Susceptibilidad a Enfermedades , Hipoxia/metabolismo , Inmunohistoquímica , Células PC12 , Ratas , Daño por Reperfusión/tratamiento farmacológicoRESUMEN
Frameshifting is an essential process that regulates protein synthesis in many viruses. The ribosome may slip backward when encountering a frameshift motif on the messenger RNA, which usually contains a pseudoknot structure involving tertiary base pair interactions. Due to the lack of detailed molecular explanations, previous studies investigating which features of the pseudoknot are important to stimulate frameshifting have presented diverse conclusions. Here we constructed a bimolecular pseudoknot to dissect the interior tertiary base pairs and used single-molecule approaches to assess the structure targeted by ribosomes. We found that the first ribosome target stem was resistant to unwinding when the neighboring loop was confined along the stem; such constrained conformation was dependent on the presence of consecutive adenosines in this loop. Mutations that disrupted the distal base triples abolished all remaining tertiary base pairs. Changes in frameshifting efficiency correlated with the stem unwinding resistance. Our results demonstrate that various tertiary base pairs are coordinated inside a highly efficient frameshift-stimulating RNA pseudoknot and suggest a mechanism by which mechanical resistance of the pseudoknot may persistently act on translocating ribosomes.
Asunto(s)
Emparejamiento Base , Sistema de Lectura Ribosómico/fisiología , Conformación de Ácido Nucleico , ARN Mensajero/química , Ribosomas/metabolismo , Transferencia Resonante de Energía de Fluorescencia , Modelos Moleculares , Resonancia Magnética Nuclear Biomolecular , Oligorribonucleótidos/síntesis química , Oligorribonucleótidos/química , Pinzas Ópticas , ARN Mensajero/genética , Sistemas de Lectura , Especificidad por SustratoRESUMEN
Due to its high oxygen demand and abundance of peroxidation-susceptible lipid cells, the brain is particularly vulnerable to oxidative stress. Induced by a redox state imbalance involving either excessive generation of reactive oxygen species (ROS) or dysfunction of the antioxidant system, oxidative stress plays a central role in a common pathophysiology that underpins neuronal cell death in acute neurological disorders epitomized by stroke and chronic ones such as Alzheimer's disease. After cerebral ischemia, for example, inflammation bears a key responsibility in the development of permanent neurological damage. ROS are involved in the mechanism of post-ischemic inflammation. The activation of several inflammatory enzymes produces ROS, which subsequently suppress mitochondrial activity, leading to further tissue damage. Pomalidomide (POM) is a clinically available immunomodulatory and anti-inflammatory agent. Using H2O2-treated rat primary cortical neuronal cultures, we found POM displayed neuroprotective effects against oxidative stress and cell death that associated with changes in the nuclear factor erythroid derived 2/superoxide dismutase 2/catalase signaling pathway. POM also suppressed nuclear factor kappa-light-chain-enhancer (NF-κB) levels and significantly mitigated cortical neuronal apoptosis by regulating Bax, Cytochrome c and Poly (ADP-ribose) polymerase. In summary, POM exerted neuroprotective effects via its anti-oxidative and anti-inflammatory actions against H2O2-induced injury. POM consequently represents a potential therapeutic agent against brain damage and related disorders and warrants further evaluation.
Asunto(s)
Antioxidantes/farmacología , Apoptosis , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Talidomida/análogos & derivados , Animales , Células Cultivadas , Corteza Cerebral/citología , Peróxido de Hidrógeno/toxicidad , Neuronas/metabolismo , Estrés Oxidativo , Ratas , Ratas Sprague-Dawley , Talidomida/farmacologíaRESUMEN
PURPOSE: Mild traumatic brain injury (mTBI) is a major public health concern. The apolipoprotein E (APOE) gene contains three polymorphisms, and the APOE4 polymorphism may affect several physiological states, such as the recovery from mTBI as well as sleep. This study aims to investigate the association between APOE4 with the recovery of sleep disturbance after mTBI. METHODS: From May 2012 to Aug 2015, 189 mTBI patients completed baseline (1st week post-mTBI) and follow-up (6th week post-mTBI) sleep assessments that involved using the Pittsburgh Sleep Quality Index (PSQI). APOE genotypes were determined by sequencing the products of polymerase chain reaction from genomic DNA. Statistical analyses were performed using the Wilcox signed-rank or chi-square test. RESULTS: Thirty-five (18.5%) participants were APOE4 carriers. At baseline, the demographic data and the severity of sleep disturbance were similar in both groups. APOE4 carriers demonstrated significant improvement in the overall PSQI score (8.34±3.9 at baseline and 7.43±3.99 at follow-up, p = 0.05) and scores of several PSQI subscales, including sleep disturbance, sleep latency, daytime dysfunction caused by sleepiness, and overall sleep quality, which was similar to APOE4 noncarriers. CONCLUSION: APOE4 is not associated with the recovery of sleep disturbance after mTBI.
Asunto(s)
Apolipoproteína E4 , Conmoción Encefálica , Trastornos del Sueño-Vigilia , Alelos , Apolipoproteína E4/genética , Conmoción Encefálica/complicaciones , Conmoción Encefálica/genética , Humanos , Polimorfismo Genético , Trastornos del Sueño-Vigilia/genéticaRESUMEN
BACKGROUND: In the central nervous system regions of the sporadic and familial FTLD and ALS patients, TDP-43 has been identified as the major component of UBIs inclusions which is abnormally hyperphosphorylated, ubiquitinated, and cleaved into C-terminal fragments to form detergent-insoluble aggregates. So far, the effective drugs for FTLD and ALS neurodegenerative diseases are yet to be developed. Autophagy has been demonstrated as the major metabolism route of the pathological TDP-43 inclusions, hence activation of autophagy is a potential therapeutic strategy for TDP-43 pathogenesis in FTLD and ALS. Berberine, a traditional herbal medicine, is an inhibitor of mTOR signal and an activator for autophagy. Berberine has been implicated in several kinds of diseases, including the neuronal-related pathogenesis, such as Parkinson's, Huntington's and Alzheimer's diseases. However, the therapeutic effect of berberine on FTLD or ALS pathology has never been investigated. RESULTS: Here we studied the molecular mechanism of berberine in cell culture model with TDP-43 proteinopathies, and found that berberine is able to reverse the processing of insoluble TDP-43 aggregates formation through deregulation of mTOR/p70S6K signal and activation of autophagic degradation pathway. And inhibition of autophagy by specific autophagosome inhibitor, 3-MA, reverses the effect of berberine on reducing the accumulation of insoluble TDP-43 and aggregates formation. These results gave us the notion that inhibition of autophagy by 3-MA reverses the effect of berberine on TDP-43 pathogenesis, and activation of mTOR-regulated autophagy plays an important role in berberine-mediated therapeutic effect on TDP-43 proteinopathies. CONCLUSION: We supported an important notion that the traditional herb berberine is a potential alternative therapy for TDP-43-related neuropathology. Here we demonstrated that berberine is able to reverse the processing of insoluble TDP-43 aggregates formation through deregulation of mTOR/p70S6K signal and activation of autophagic degradation pathway. mTOR-autophagy signals plays an important role in berberine-mediated autophagic clearance of TDP-43 aggregates. Exploring the detailed mechanism of berberine on TDP-43 proteinopathy provides a better understanding for the therapeutic development in FTLD and ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/terapia , Berberina/uso terapéutico , Degeneración Lobar Frontotemporal/terapia , Proteinopatías TDP-43/terapia , Esclerosis Amiotrófica Lateral/genética , Animales , Línea Celular Tumoral , Degeneración Lobar Frontotemporal/genética , Ratones , Proteinopatías TDP-43/genéticaRESUMEN
Glutamate sensors based on the immobilization of glutamate oxidase (GlutOx) were prepared by adsorption on electrodeposited chitosan (Method 1) and by crosslinking with glutaraldehyde (Method 2) on micromachined platinum microelectrodes. It was observed that glutamate sensors prepared by Method 1 have faster response time (<2 s) and lower detection limit (2.5±1.1 µM) compared to that prepared by Method 2 (response time: <5 sec and detection limit: 6.5±1.7 µM); glutamate sensors prepared by Method 2 have a larger linear detection range (20-352 µM) and higher sensitivity (86.8±8.8 nA·µM-1·cm-2, N=12) compared to those prepared by Method 1 (linear detection range: 20-217 µM and sensitivity: 34.9±4.8 nA·µM-1·cm-2, N=8). The applicability of the glutamate sensors in vivo was also demonstrated. The glutamate sensors were implanted into the rat brain to monitor the stress-induced extracellular glutamate release in the hypothalamus of the awake, freely moving rat.
Asunto(s)
Enzimas Inmovilizadas/metabolismo , Aminoácido Oxidorreductasas/metabolismo , Animales , Quitosano/química , Ácido Glutámico/metabolismo , Glutaral/química , Hipotálamo/metabolismo , Masculino , Microelectrodos , Ratas , Ratas Sprague-DawleyRESUMEN
External ventricular drain (EVD) placement is one of the most basic and common neurosurgical procedure which most was performed by young neurosurgical trainees. This study is conducted to determinate the safe and accuracy of EVD placement by freehand method. About 129 EVD placements were evaluated in this study. Eighty-three catheters (64.3%) were located in the ipsilateral frontal horn or third ventricle. The functional accuracy was 86%. Of eighteen misplaced catheters, only 4 (3.1%) catheters were nonfunctional, requiring a replacement or reposition. The higher misplaced rate was significantly observed in patients whose head CT scans revealed the lower hydrocephalus ratio (28.85%) and the smaller ventricular size (5.6 mm). Twenty-one (16.2%) new hemorrhages associated with EVD placements were observed. Using the freehand method, EVD placement is a safe and effective procedure in management of these emergent neurosurgical diseases.
Asunto(s)
Ventrículos Cerebrales/cirugía , Derivaciones del Líquido Cefalorraquídeo/efectos adversos , Drenaje/efectos adversos , Hemorragia/etiología , Hemorragia/cirugía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ventrículos Cerebrales/patología , Falla de Equipo , Femenino , Hemorragia/diagnóstico por imagen , Humanos , Hidrocefalia/diagnóstico por imagen , Hidrocefalia/cirugía , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
Over 2 million people suffer from mild traumatic brain injury (mTBI) each year. Predicting symptoms of mTBI and the characterization of those symptoms has been challenging. Biomarkers that correlate clinical symptoms to disease outcome are desired to improve understanding of the disease and optimize patient care. Bone marrow kinase on chromosome X (BMX), a member of the TEC family of nonreceptor tyrosine kinases, is up-regulated after traumatic neural injury in a rat model of mTBI. The aim of this investigation was to determine whether BMX serum concentrations can effectively be used to predict outcomes after mTBI in a clinical setting. A total of 63 patients with mTBI (Glasgow Coma Score [GCS] between 13 and 15) were included. Blood samples taken at the time of hospital admission were analyzed for BMX. Data collected included demographic and clinical variables. Outcomes were assessed using the Dizziness Handicap Inventory (DHI) questionnaire at baseline and 6 weeks postinjury. The participant was asssigned to the case group if the subject's complaints of dizziness became worse at the sixth week assessment; otherwise, the participant was assigned to the control group. A receiver operating characteristic curve was constructed to explore BMX level. Significant associations were found between serum levels of BMX and dizziness. Areas under the curve for prediction of change in DHI postinjury were 0.76 for total score, 0.69 for physical score, 0.65 for emotional score, and 0.66 for functional score. Specificities were between 0.69 and 0.77 for total score and emotional score, respectively. Therefore, BMX demonstrates potential as a candidate serum biomarker of exacerbating dizziness post-mTBI.
Asunto(s)
Conmoción Encefálica/sangre , Conmoción Encefálica/complicaciones , Mareo/sangre , Mareo/etiología , Proteínas Tirosina Quinasas/sangre , Adulto , Anciano , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Type III odontoid fractures of the axis are the second most common injuries of the cervical spine. Most of these result from motor vehicle accidents and falls. Occult odontoid fractures without preceding trauma are rarely reported in the literature and may be difficult to diagnose. We report the case of a healthy patient who had no history of trauma, but sustained sudden pain in the neck and guarding during head movement after sleep. Initial radiographs of the cervical spine including open-mouth, anterior-posterior, and lateral views did not reveal any obvious fractures. Type III odontoid fracture was uneventfully diagnosed via high-quality three-dimensional reconstruction of computed tomography. The possible mechanism was hyperextension of the neck during the change from the supine to the sitting position. Type III odontoid fractures can occur in the absence of major trauma. The usefulness of computed tomography is emphasized and the literature is also reviewed.
Asunto(s)
Fracturas Óseas/complicaciones , Hipoestesia/etiología , Dolor de Cuello/etiología , Apófisis Odontoides/lesiones , Fracturas Óseas/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Apófisis Odontoides/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
Although traumatic injuries to the rectum are not uncommon, they pose significant challenges to surgeons. Challenges relate to timely diagnosis, control of pelvic hemorrhage, multiplicity of associated injuries, difficulties in operative exposure, and prevention of sepsis. We report an unusual case of combined rectal and vertebral body penetrating injuries by a long rusty steel bar as a result of a falling accident. Successful treatment of this condition entailed removal of the bar, perineal and retroperitoneal drainage, and fecal diversion. The patient was discharged without neurologic, hemorrhagic, or intestinal morbidities 20 days later. Closure of colostomy was performed three months later uneventfully.
Asunto(s)
Accidentes de Trabajo , Cuerpos Extraños/cirugía , Vértebras Lumbares/lesiones , Recto/lesiones , Heridas Penetrantes/cirugía , Adulto , Humanos , Masculino , Recto/cirugía , Heridas Penetrantes/patologíaRESUMEN
Modified orbitozygomatic craniotomy (MOZC) is an anterior lateral skull base approach characterized by simplicity and wide exposure. The approach was first introduced in 2003 and there are few clinical reports. This report details treatment of patients with large (>4 cm) sphenoid wing meningiomas via a MOZC approach, and to the authors' knowledge, the first published in English. Total resection was achieved in all 5 patients in this study. One patient experienced a postoperative epidural hematoma that was successfully treated. All patients returned to daily activity without neurological sequellae. The advantages of MOZC are sparing of the zygomatic arch and removal of the orbital rim; hence, the surgeon can plan a capacious operative field without excessive brain retraction and resect the tumor before opening the dura. The MOZC approach is a clinically feasible, low morbidity, surgical option for paraclinoid lesions, such as large sphenoid wing meningiomas.
Asunto(s)
Craneotomía/métodos , Meningioma/cirugía , Procedimientos Neuroquirúrgicos/métodos , Órbita/cirugía , Seno Esfenoidal/cirugía , Cigoma/cirugía , Adulto , Anciano , Femenino , Escala de Consecuencias de Glasgow , Humanos , Imagen por Resonancia Magnética , Masculino , Meningioma/patología , Persona de Mediana Edad , Complicaciones Posoperatorias/patología , Seno Esfenoidal/patologíaRESUMEN
Introduction. Over 1 million mild traumatic brain injury (mTBI) cases are reported annually worldwide and may result in cognitive, physical, and emotional deterioration; depression; anxiety; and sleep problems. However, studies on long-term mTBI effects are limited. This study included 440 patients, and regular follow-ups of psychological assessments were performed for 2 years. Four questionnaires, including the Pittsburgh sleep quality index (PSQI), Epworth sleepiness scale (ESS), Beck's anxiety inventory (BAI), and Beck's depression inventory (BDI), were used to evaluate sleep problems, daytime sleepiness, anxiety, and depression, respectively. Results show that BAI and BDI scores considerably improved at the 6th-week, 1st-year, and 2nd-year follow-ups compared to baseline, yet these remained significantly different. In addition, anxiety and depression were prominent symptoms in a select subgroup of patients with poor initial evaluations, which improved over the 2 years. However, the ESS and PSQI scores fluctuated only mildly over the same time span. In conclusion, the mTBI patients showed a gradual improvement of anxiety and depression over the 2 years following injury. While anxiety and depression levels for mTBI patients in general did not return to premorbid status, improvements were observed. Sleep disorders persisted and were consistent with initial levels of distress.
Asunto(s)
Conmoción Encefálica/complicaciones , Conmoción Encefálica/psicología , Adulto , Ansiedad/psicología , Depresión/psicología , Trastorno Depresivo , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Psicometría/métodos , Sueño , Trastornos del Sueño-Vigilia/psicología , Encuestas y CuestionariosRESUMEN
Stroke is a leading cause of death and severe disability worldwide. After cerebral ischemia, inflammation plays a central role in the development of permanent neurological damage. Reactive oxygen species (ROS) are involved in the mechanism of post-ischemic inflammation. The activation of several inflammatory enzymes produces ROS, which subsequently suppress mitochondrial activity, leading to further tissue damage. Pomalidomide (POM) is a clinically available immunomodulatory and anti-inflammatory agent. Prior cellular studies demonstrate that POM can mitigate oxidative stress and lower levels of pro-inflammatory cytokines, particularly TNF-α, which plays a prominent role in ischemic stroke-induced brain damage and functional deficits. To evaluate the potential value of POM in cerebral ischemia, POM was initially administered to transgenic mice chronically over-expressing TNF-α surfactant protein (SP)-C promoter (SP-C/TNF-α mice) to assess whether systemically administered drug could lower systemic TNF-α level. POM significantly lowered serum levels of TNF-α and IL-5. Pharmacokinetic studies were then undertaken in mice to evaluate brain POM levels following systemic drug administration. POM possessed a brain/plasma concentration ratio of 0.71. Finally, rats were subjected to transient middle cerebral artery occlusion (MCAo) for 60 min, and subsequently treated with POM 30 min thereafter to evaluate action on cerebral ischemia. POM reduced the cerebral infarct volume in MCAo-challenged rats and improved motor activity, as evaluated by the elevated body swing test. POM's neuroprotective actions on ischemic injury represent a potential therapeutic approach for ischemic brain damage and related disorders, and warrant further evaluation.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Isquemia Encefálica/tratamiento farmacológico , Talidomida/análogos & derivados , Inhibidores de la Angiogénesis/farmacología , Animales , Masculino , Ratones , Ratas , Talidomida/farmacología , Talidomida/uso terapéuticoRESUMEN
BACKGROUND: Instead of surgical intervention, endovascular treatment with GDC has become an important tool to treat intracranial aneurysm in recent years. However, intraoperative aneurysm rupture remains a devastating complication for physicians. Rapid and precise packing with coils and external ventricular drainage are advised. Stereotactic aspiration of an enlarged intracerebral hematoma caused by intraprocedural perforation of aneurysm has been rarely discussed as a method of dealing with this consequence. CASE DESCRIPTION: The authors describe a case of a 45-year-old man who presented with sudden onset of headache. A ruptured aneurysm of approximately 5.5 mm, arising from the proximal segment of superior sylvian M2 branch on the right middle cerebral artery, was diagnosed via intracranial angiography. During transarterial embolization, perforation of the aneurysm dome by coil and microcatheter was noted. Although the aneurysm was secured by rapid coiling, progressive weakness of left extremities related to enlarged intracranial hematoma was noted. The neurologic deficits improved successfully after stereotactic aspiration of hematoma. CONCLUSION: The role of stereotactic aspiration in the management of an enlarged hematoma due to intraprocedural perforation of aneurysm during coil embolization may have further implications, and it may be considered as an alternative treatment to open clot evacuation for intracranial hemorrhages with aneurysms.
Asunto(s)
Aneurisma Roto/cirugía , Embolización Terapéutica/efectos adversos , Hematoma/cirugía , Aneurisma Intracraneal/terapia , Técnicas Estereotáxicas , Hemorragia Subaracnoidea/cirugía , Aneurisma Roto/diagnóstico por imagen , Aneurisma Roto/etiología , Embolización Terapéutica/instrumentación , Hematoma/diagnóstico por imagen , Hematoma/etiología , Humanos , Masculino , Persona de Mediana Edad , Radiografía , Hemorragia Subaracnoidea/diagnóstico por imagen , Hemorragia Subaracnoidea/etiología , SucciónRESUMEN
BACKGROUND: Diffusion tensor imaging is a newly developed technique used to visualize the white matter fibers in the human brain. In previous reports, DTI has been applied in patients with neoplasms, lacunar infarction, ischemic stroke, degenerative motor disease, and diffuse axonal injury, and has become a powerful tool in predicting clinical outcome. However, the implementation of DTI in patients with spontaneous ICH treated by stereotactic evaluation of hematoma has never been reported. CASE DESCRIPTION: The authors describe a case of a well-predicted outcome of DTI in a 37-year-old right-handed man who presented with sudden onset of vomiting and weakness of right extremities 2 hours before admission. Computed tomographic head scan revealed 1 hyperdense hematoma measuring about 3.9 x 2.2 x 2.6 cm (about 15 mL in volume) located in the left putamen, compressing the posterior limb of left internal capsule. Preoperative DTI revealed that white matter tracts were compressed by the hematomas. After the patient underwent stereotactic evacuation of hematoma, good recovery of muscle power was noted in the right extremities. Postoperative DTI revealed the restoration of white matter tracts. CONCLUSION: Diffuse tensor imaging is a useful tool for the visualization of white matter tracts, especially the corticospinal tract, which regulates motor function in human beings. In patients with ICH treated by stereotactic aspiration of hematomas, clinical outcome could be more precisely predicted by preoperative DTI.
Asunto(s)
Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/cirugía , Imagen de Difusión por Resonancia Magnética , Hematoma/diagnóstico , Hematoma/cirugía , Técnicas Estereotáxicas , Adulto , Humanos , Masculino , Tomografía Computarizada por Rayos XRESUMEN
Stroke commonly leads to adult disability and death worldwide. Its major symptoms are spastic hemiplegia and discordant motion, consequent to neuronal cell death induced by brain vessel occlusion. Acetylcholinesterase (AChE) is upregulated and allied with inflammation and apoptosis after stroke. Recent studies suggest that AChE inhibition ameliorates ischemia-reperfusion injury and has neuroprotective properties. (-)-Phenserine, a reversible AChE inhibitor, has a broad range of actions independent of its AChE properties, including neuroprotective ones. However, its protective effects and detailed mechanism of action in the rat middle cerebral artery occlusion model (MCAO) remain to be elucidated. This study investigated the therapeutic effects of (-)-phenserine for stroke in the rat focal cerebral ischemia model and oxygen-glucose deprivation/reperfusion (OGD/RP) damage model in SH-SY5Y neuronal cultures. (-)-Phenserine mitigated OGD/PR-induced SH-SY5Y cell death, providing an inverted U-shaped dose-response relationship between concentration and survival. In MCAO challenged rats, (-)-phenserine reduced infarction volume, cell death and improved body asymmetry, a behavioral measure of stoke impact. In both cellular and animal studies, (-)-phenserine elevated brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2) levels, and decreased activated-caspase 3, amyloid precursor protein (APP) and glial fibrillary acidic protein (GFAP) expression, potentially mediated through the ERK-1/2 signaling pathway. These actions mitigated neuronal apoptosis in the stroke penumbra, and decreased matrix metallopeptidase-9 (MMP-9) expression. In synopsis, (-)-phenserine significantly reduced neuronal damage induced by ischemia/reperfusion injury in a rat model of MCAO and cellular model of OGD/RP, demonstrating that its anti-apoptotic/neuroprotective/neurotrophic cholinergic and non-cholinergic properties warrant further evaluation in conditions of brain injury.
Asunto(s)
Apoptosis/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Fisostigmina/análogos & derivados , Daño por Reperfusión/tratamiento farmacológico , Animales , Apoptosis/fisiología , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Hipoxia de la Célula/efectos de los fármacos , Hipoxia de la Célula/fisiología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Inhibidores de la Colinesterasa/farmacología , Relación Dosis-Respuesta a Droga , Glucosa/deficiencia , Humanos , Masculino , Neuronas/metabolismo , Neuronas/patología , Fisostigmina/farmacología , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patologíaRESUMEN
Physical clusters of co-regulated, but apparently functionally unrelated, genes are present in many genomes. Despite the important implication that the genomic environment contributes appreciably to the regulation of gene expression, no simple statistical method has been described to identify physical clusters of co-regulated genes. Here we report the development of a model that allows the direct calculation of the significance of such clusters. We have implemented the derived statistical relation in a software program, Pyxis, and have analyzed a selection of Saccharomyces cerevisiae gene expression microarray data sets. We have identified many gene clusters where constituent genes exhibited a regulatory dependence on proteins previously implicated in chromatin structure. Specifically, we found that Tup1p-dependent gene domains were enriched close to telomeres, which suggested a new role for Tup1p in telomere silencing. In addition, we identified Sir2p-, Sir3p- and Sir4p-dependent clusters, which suggested the presence of Sir-mediated heterochromatin in previously unidentified regions of the yeast genome. We also showed the presence of Sir4p-dependent gene clusters bordering the HMRa heterothallic locus, which suggested leaky termination of the heterochromatin by the boundary elements. These results demonstrate the utility of Pyxis in identifying possible higher order genomic features that may contribute to gene regulation in extended domains.
Asunto(s)
Cromatina/fisiología , Regulación de la Expresión Génica , Modelos Estadísticos , Programas Informáticos , Análisis por Conglomerados , Perfilación de la Expresión Génica , Genes Fúngicos , Histona Desacetilasas/metabolismo , Proteínas Nucleares/fisiología , Proteínas Represoras/fisiología , Reproducibilidad de los Resultados , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/fisiología , Proteínas Reguladoras de Información Silente de Saccharomyces cerevisiae/metabolismo , Sirtuina 2 , Sirtuinas/metabolismo , Telómero/genéticaAsunto(s)
Fosa Craneal Posterior/cirugía , Procedimientos Neuroquirúrgicos/efectos adversos , Posicionamiento del Paciente/efectos adversos , Complicaciones Posoperatorias/etiología , Sialadenitis/etiología , Enfermedades de la Glándula Submandibular/etiología , Enfermedad Aguda , Femenino , Humanos , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos/métodos , Complicaciones Posoperatorias/patología , Sialadenitis/patología , Enfermedades de la Glándula Submandibular/patologíaRESUMEN
Mild traumatic brain injury (mTBI) is a major public health issue, representing 75-90% of all cases of TBI. In clinical settings, mTBI, which is defined as a Glascow Coma Scale (GCS) score of 13-15, can lead to various physical, cognitive, emotional, and psychological-related symptoms. To date, there are no pharmaceutical-based therapies to manage the development of the pathological deficits associated with mTBI. In this study, the neurotrophic and neuroprotective properties of glucose-dependent insulinotropic polypeptide (GIP), an incretin similar to glucagon-like peptide-1 (GLP-1), was investigated after its steady-state subcutaneous administration, focusing on behavior after mTBI in an in vivo animal model. The mTBI rat model was generated by a mild controlled cortical impact (mCCI) and used to evaluate the therapeutic potential of GIP. We used the Morris water maze and novel object recognition tests, which are tasks for spatial and recognition memory, respectively, to identify the putative therapeutic effects of GIP on cognitive function. Further, beam walking and the adhesive removal tests were used to evaluate locomotor activity and somatosensory functions in rats with and without GIP administration after mCCI lesion. Lastly, we used immunohistochemical (IHC) staining and Western blot analyses to evaluate the inflammatory markers, glial fibrillary acidic protein (GFAP), amyloid-ß precursor protein (APP), and bone marrow tyrosine kinase gene in chromosome X (BMX) in animals with mTBI. GIP was well tolerated and ameliorated mTBI-induced memory impairments, poor balance, and sensorimotor deficits after initiation in the post-injury period. In addition, GIP mitigated mTBI-induced neuroinflammatory changes on GFAP, APP, and BMX protein levels. These findings suggest GIP has significant benefits in managing mTBI-related symptoms and represents a novel strategy for mTBI treatment.