ABSTRACT
OBJECTIVE Our previous studies demonstrated that various ingredients from the traditional Chinese medicine (TCM) for promoting blood circulation and removing blood stasis, as exemplified by cryptotanshinone and salvi?anolic acid B, exerted striking effects on modulating angiogenesis and vascular permeability, which suggests that they may be effective in treating vascular leak-driven diseases (e.g. tumor, cerebral cavernous malformation and diabetic reti?nopathy). However, the lack of reliable and advanced technologies and models sets up difficult hurdles for better under?standing the role of TCM for promoting blood circulation and removing blood stasis. To this end, this study is to outline numerous cutting-edge platforms that can be utilized for exploring the function of TCM for promoting blood circulation and removing blood stasis in vascular leak-driven diseases. METHODS Two-photon laser scanning fluorescence micros?copy was used to observe the interactions between neutrophils and blood vessels in a real-time manner. Dynamic flow system was employed to mimic the in vivo behaviors of neutrophils. RIP1-Tag5 spontaneous pancreatic cancer model was used to study the function of tumor blood vessels. CCM2ECKO (deletion of CCM2 in endothelial cells) mice were employed to establish the cerebral cavernous malformation (CCM) animal model. Micro-computed tomography (micro-CT) was utilized to assess the CCM lesion. Müller cell-knockout mouse model was used to study the progression of dia?betic retinopathy. Vascular permeability in this model was assessed by fluorescein angiography. RESULTS The interac?tions between neutrophils and endothelial cells involve a series of complicated processes, including rolling, adhesion, intraluminal crawling and transmigration, which were all monitored in vivo by two-photon laser scanning fluorescence microscopy in a real-time manner. Dynamic flow system was capable of recapitulating the biological behaviors of neutro?phils in vitro. Tumor vascular function in particular vascular perfusion could be assessed in the RIP1-Tag5 spontaneous pancreatic cancer model. In terms of CCM studies, specific deletion of CCM2 in endothelial cells resulted in the initiation of CCM lesion. The size and number of CCM lesions could be visualized and quantified by micro-CT. Furthermore, the Müller cell-knockout mouse model was able to precisely reflect the clinical symptoms of diabetic retinopathy. Vascular leak could be monitored at different time points using fluorescein angiography. CONCLUSION An array of high technol?ogies and animal models can be used in investigating the occurrence and progression of multiple vascular leak-driven diseases. The pre-clinical and clinical studies of TCM for promoting blood circulation and removing blood stasis provide fundamental support for the application of the above-mentioned platforms, with the purpose of uncovering the scientific basis of TCM for promoting blood circulation and removing blood stasis.
ABSTRACT
Objetivo: Presentar los resultados de tratamiento quirúrgico obtenidos en una serie de 14 casos de malformación cavernosa, situadas en diferentes localizaciones encefálicas, además de realizar una revisión bibliográfica sobre el tema. Material y métodos: En el periodo de los años 2014-2019, se diagnosticaron y protocolizaron 14 pacientes por medio de la consulta externa de neurocirugía del Hospital Juárez de México. Todos menos 2, fueron intervenidos quirúrgicamente. Resultados: En 12 de los 14 casos que recibieron tratamiento quirúrgico, se documentó mejoría neurológica posterior a la resección total en 10 pacientes, 1 paciente de cavernoma gigante temporal se hizo resección subtotal, en 1 paciente con lesión de localización protuberancial se le realizó únicamente drenaje de hematoma. El déficit preoperatorio tendió a mejorar progresivamente en las lesiones de mayor tamaño y en ningún caso se documentaron complicaciones, las crisis convulsivas se controlaron disminuyendo progresivamente la dosis de fármacos anticonvulsivantes en el periodo postquirúrgico de este grupo de pacientes. Y dos pacientes, uno con lesión mesencefálica y el otro con cavernomatosis solo se sometieron a observación. Conclusiones: La cirugía es el método de elección hoy en día para el tratamiento de las malformaciones cavernosas, siendo los mejores resultados a menor tamaño de la lesión y con localizaciones más superficiales. Los resultados quirúrgicos de nuestros pacientes son similares a lo reportado en la literatura mundial.
Objectives: To present the surgical outcomes obtained in a series of 14 cases of cavernous malformation, located in different brain locations, in addition to conducting a literature review on the subject. Method: Between the years, 2014 and 2019, 14 cases were diagnosed and protocolized in neurosurgery department of Hospital Juárez of México. All patients except two, were surgically treated. Results: In 12 of the 14 cases received surgical treatment, neurological improvement was documented after the total resection in ten patients, one patient with giant temporal cavernoma performed a subtotal resection, other case with a lesion in the pontine location a hematoma drainage was performed. All surgical patients the preoperative clinical deficit tended to improve progressively in larger lesions and no complications were documented. Seizures were controlled by gradually decreasing the dose of anticonvulsant drugs in the post-surgical period of this group of patients. And two patients, one with mesencephalic lesion and another with cavernomatosis, were only observe. Conclusion: Surgery is the method of choice today for the treatment of cavernous malformations, with the best outcome being the smallest size of the lesion and with more superficial locations. The surgical outcomes in our patients are similar to those reported in the world literature
Subject(s)
Humans , Hemangioma, Cavernous , Congenital Abnormalities , Central Nervous System , NeurosurgeryABSTRACT
OBJECTIVE: To investigate the effects of knockout cerebral cavernous malformation(CCM) virulence gene CCM3 on the migration induced by lead acetate in immortalized human umbilical vein endothelial cells(HUVECs) and to explore the possible mechanism of endoplasmic reticulum stress(ERS). METHODS: CCM3 wildtype(CCM3-WT) and CCM3 knockout(CCM3-KO) HUVECs were used as experimental cells. a) CCM3-WT and CCM3-KO HUVECs were treated with lead acetate at 0,10,50 and 200 μmol/L for 24 hours. The migration of these cells was observed by woundhealing assay. b) CCM3-WT and CCM3-KO HUVECs were treated with lead acetate at 0,10,50 and 200 μmol/L for 24 hours,and at 50 μmol/L for 0,6,12,24 and 48 hours,and the mRNA expression of genes of unfolded protein response pathway were detected by quantitative real-time polymerase chain reaction; the protein expression of glucose-regulated protein 78(GRP78) was detected by Western blotting. c) CCM3-WT and CCM3-KO HUVECs were divided into lead exposure group and tauroursodeoxycholic acid(TUDCA) group. The former was treated with 50 μmol/L lead acetate for 24 hours,and the latter was pre-treated with ERS inhibitor TUDCA,followed by 50 μmol/L lead acetate. The migration of these cells was observed by wound-healing assay. RESULTS: a) The migration of CCM3-WT and CCM3-KO cells decreased and showed a dose-effect relationship with the increase of lead acetate concentration(P < 0. 05). b) The mRNA relative expression of the GRP78,protein kinase-like endoplasmic reticulum kinase(PERK),transcription activator 4(ATF4) and CCAAT enhancer binding homologous protein(CHOP) in CCM3-KO cells treated with 10,50 and 200 μmol/L lead acetate were higher than that in CCM3-WT cells at the same doses,except for the GRP78 in CCM3-KO cells treated with10 μmol/L lead acetate(P < 0. 05). The mRNA expression of PERK and CHOP in CCM3-KO cells increased in a timeeffect relationship with the increase of lead-exposure time(P < 0. 05). The mRNA relative expression of the four genes in CCM3-KO cells were higher than those in CCM3-WT cells at 48 hours(P < 0. 05). When cells were treated with 50μmol/L lead acetate,the protein expression of GRP78 in CCM3-KO cells was higher than that in CCM3-WT cells(P <0. 05),and the protein expression of GRP78 in CCM3-KO cells increased in a time-effect relationship with the increase of lead-exposure time(P < 0. 05). c) The cell migration of TUDCA group was lower than that of lead-exposure group(P <0. 05). CONCLUSION: Lead acetate may activate ERS by activating the PERK-ATF4-CHOP signaling pathway,thereby reducing the migration of HUVECs. CCM3 gene has a protective effect on cell migration.
ABSTRACT
OBJECTIVE: Surgical resection of thalamic and brainstem cerebral cavernous malformations (CCMs) is associated with significant operative morbidity, but it may be outweighed, in some cases, by the neurological damage from recurrent hemorrhage in these eloquent areas. The goals of this retrospective cohort study are to describe the technical nuances of surgical approaches and determine the postoperative outcomes for CCMs of the thalamus and brainstem. MATERIALS AND METHODS: We reviewed an institutional database of patients harboring thalamic or brainstem CCMs, who underwent surgical resection from 2010 to 2014. The baseline and follow-up neuroimaging and clinical findings of each patient and the operative details of each case were evaluated. RESULTS: A total of eight patients, including two with thalamic and six with brainstem CCMs, were included in the study cohort. All patients had progressive neurological deterioration from recurrent CCM hemorrhage, and the median modified Rankin Scale (mRS) at presentation was 3. The median CCM maximum diameter and volume were 1.7 cm and 1.8 cm³, respectively. The thalamic CCMs were resected using the anterior transcallosal transchoroidal and supracerebellar infratentorial approaches each in one case (13%). The brainstem CCMs were resected using the retrosigmoid and suboccipital trans-cerebellomedullary fissure approaches each in three cases (38%). After a median follow-up of 11.5 months, all patients were neurologically stable or improved, with a median mRS of 2. The rate of functional independence (mRS 0-2) was 63%. CONCLUSION: Microneurosurgical techniques and approaches can be safely and effectively employed for the management of thalamic and brainstem CCMs in appropriately selected patients.
Subject(s)
Humans , Brain Stem , Cohort Studies , Follow-Up Studies , Hemangioma, Cavernous, Central Nervous System , Hemorrhage , Intracranial Hemorrhages , Microsurgery , Neuroimaging , Retrospective Studies , Thalamus , Vascular MalformationsABSTRACT
ABSTRACT Neurocysticercosis (NCC) is an endemic disease and important public health problem in some areas of the World and epilepsy is the most common neurological manifestation. Multiple intracranial lesions, commonly calcified, are seen on cranial computed tomography (CT) in the chronic phase of the disease and considered one of the diagnostic criteria of the diagnosis. Magnetic resonance imaging (MRI) is the test that better depicts the different stages of the intracranial cysts but does not show clearly calcified lesions. Cerebral cavernous malformations (CCM), also known as cerebral cavernomas, are frequent vascular malformations of the brain, better demonstrated by MRI and have also epilepsy as the main form of clinical presentation. When occurring in the familial form, cerebral cavernomas typically present with multiple lesions throughout the brain and, very often, with foci of calcifications in the lesions when submitted to the CT imaging. In the countries, and geographic areas, where NCC is established as an endemic health problem and neuroimaging screening is done by CT scan, it will be important to consider the differential diagnosis between the two diseases due to the differences in adequate management.
RESUMO A neurocisticercose (NCC) é um importante problema endêmico de saúde pública em algumas áreas do mundo, sendo epilepsia sua manifestação clínica mais comum. Múltiplas lesões intracranianas, geralmente com calcificações visualizadas em tomografia computorizada de crânio, são interpretadas como um dos critérios diagnósticos na fase crônica da doença. A ressonância magnética é o melhor teste de imagem para identificar a doença em diferentes estágios de sua forma cística mas apresenta limitações para demonstrar lesões calcificadas. Malformações cavernosas cerebrais, ou cavernomas, são malformações vasculares comuns ao sistema nervoso e epilepsia é também a sua forma mais frequente de apresentação. Na sua forma familiar cavernomas apresentam-se tipicamente com múltiplas lesões encefálicas e, frequentemente, com focos de calcificações na TC. Em alguns países, e determinadas regiões geográficas, onde neurocisticercose é endêmica, a neuroimagem mais usada para diagnóstico é a TC de crânio. Nesse contexto torna-se importante estabelecer bases para o diagnóstico diferencial entre as duas doenças, devido às diferentes formas de acompanhamento e tratamento adequado.
Subject(s)
Humans , Neurocysticercosis/diagnosis , Hemangioma, Cavernous, Central Nervous System/diagnosis , Magnetic Resonance Imaging , Tomography, X-Ray Computed , Neurocysticercosis/pathology , Hemangioma, Cavernous, Central Nervous System/pathology , Diagnosis, DifferentialABSTRACT
Cerebral cavernous malformation (CCM) is a vascular malformation characterized by abnormally enlarged capillary cavities without any intervening neural tissue. We report 2 cases of familial CCMs diagnosed with the CCM1 mutation by using a genetic assay. A 5-year-old boy presented with headache, vomiting, and seizure-like movements. Brain magnetic resonance imaging (MRI) revealed multiple CCM lesions in the cerebral hemispheres. Subsequent mutation analysis of his father and other family members revealed c.940_943 del (p.Val314 Asn315delinsThrfsX3) mutations of the CCM1 gene. A 10-month-old boy who presented with seizure-like movements was reported to have had no perinatal event. His aunt was diagnosed with cerebral angioma. Brain and spine MRI revealed multiple angiomas in the cerebral hemisphere and thoracic spinal cord. Mutation analysis of his father was normal, although that of the patient and his mother revealed c.535C>T (p.Arg179X) mutations of the CCM1 gene. Based on these studies, we suggest that when a child with a familial history of CCMs exhibits neurological symptoms, the physician should suspect familial CCMs and consider brain imaging or a genetic assay.