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To analyze the correlation of KI-67-Proliferation Index (KI-67-PI) with preoperative patients and MRI characteristics, WHO grading, histological subtype and long-term-course of patients with newly diagnosed intracranial meningiomas (IM). In this single-center retrospective study, all consecutive patients with IM were analyzed from January 2007 to August 2019. Patient´s demographics (age, sex), imaging parameters (location, volume, edema, necrosis), and tumor features (WHO grade, histology) were assessed and correlated with KI-67-PI. Long-term data were retrieved from patient's last follow-up visits. This study included 463 IM in 457 surgically treated patients. Males exhibited a higher KI-67-PI than females (7.31 ± 0.22 vs. 5.37 ± 0.53; p < 0.01, Mann-Whitney U Test). Age positively correlated with KI-67-PI in both sexes (p < 0.01, Spearman), with older patients having a higher KI-67-PI. KI-67-PI was significantly higher in convexity IM compared to frontobasal IM (7.15 ± 5.56 vs. 4.66 ± 2.94; p < 0.05, ANOVA, Tukey´s HSD), while no difference in KI-67-PI expression was found when other locations were compared to each other (Tukey´s HSD). Higher KI-67-PI was significantly correlated with larger tumor volume (p < 0.01, Spearman), larger tumor necrosis and larger peritumoral edema (p < 0.01, Kruskal-Wallis). Patients with recurrent IM had a significantly higher KI-67-PI than patients without recurrence (8.24 ± 5.88 vs. 5.14 ± 3.53; p < 0.01, ANOVA, Tukey´s HSD) during a mean follow-up period of 80.92 ± 38.1 months. Atypical and anaplastic IM exhibited significantly higher KI-67-PI compared to all other WHO grade 1 histological subtypes (12.09 ± 0.73 vs. 4.51 ± 0.13; p < 0.01, Kruskal-Wallis test) and KI-67-PI was significantly higher in anaplastic IM compared to atypical meningioma (19.67 ± 1.41 vs. 11.01 ± 0.38; p < 0.01, ANOVA). Higher KI-67-PI is not only associated with atypical and anaplastic subtypes of IM, but is also significantly higher in males, positively correlates with patients age, larger tumor volume, lager peritumoral edema and necrosis on preoperative MRI and predicts tumor recurrence. Therefore, KI-67-PI may serve as a decision indicator for adjuvant treatment in patients with IM.
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Antígeno Ki-67 , Imagen por Resonancia Magnética , Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/patología , Meningioma/diagnóstico por imagen , Meningioma/cirugía , Masculino , Femenino , Antígeno Ki-67/metabolismo , Persona de Mediana Edad , Adulto , Anciano , Neoplasias Meníngeas/patología , Neoplasias Meníngeas/cirugía , Neoplasias Meníngeas/diagnóstico por imagen , Estudios Retrospectivos , Adulto Joven , Anciano de 80 o más Años , Proliferación Celular , AdolescenteRESUMEN
BACKGROUND: Sepsis-associated encephalopathy (SAE) is an early and frequent event of infection-induced systemic inflammatory response syndrome. Phosphoinositide 3-kinase γ (PI3Kγ) is linked to neuroinflammation and inflammation-related microglial activity. In homeotherms, variations in ambient temperature (Ta) outside the thermoneutral zone lead to thermoregulatory responses, mainly driven by a gradually increasing sympathetic activity, and may affect disease severity. We hypothesized that thermoregulatory response to hypothermia (reduced Ta) aggravates SAE in PI3Kγ-dependent manner. METHODS: Experiments were performed in wild-type, PI3Kγ knockout, and PI3Kγ kinase-dead mice, which were kept at neutral (30 ± 0.5 °C) or moderately lowered (26 ± 0.5 °C) Ta. Mice were exposed to lipopolysaccharide (LPS, 10 µg/g, from Escherichia coli serotype 055:B5, single intraperitoneal injection)-evoked systemic inflammatory response (SIR) and monitored 24 h for thermoregulatory response and blood-brain barrier integrity. Primary microglial cells and brain tissue derived from treated mice were analyzed for inflammatory responses and related cell functions. Comparisons between groups were made with one-way or two-way analysis of variance, as appropriate. Post hoc comparisons were made with the Holm-Sidak test or t tests with Bonferroni's correction for adjustments of multiple comparisons. Data not following normal distribution was tested with Kruskal-Wallis test followed by Dunn's multiple comparisons test. RESULTS: We show that a moderate reduction of ambient temperature triggers enhanced hypothermia of mice undergoing LPS-induced systemic inflammation by aggravated SAE. PI3Kγ deficiency enhances blood-brain barrier injury and upregulation of matrix metalloproteinases (MMPs) as well as an impaired microglial phagocytic activity. CONCLUSIONS: Thermoregulatory adaptation in response to ambient temperatures below the thermoneutral range exacerbates LPS-induced blood-brain barrier injury and neuroinflammation. PI3Kγ serves a protective role in suppressing release of MMPs, maintaining microglial motility and reinforcing phagocytosis leading to improved brain tissue integrity. Thus, preclinical research targeting severe brain inflammation responses is seriously biased when basic physiological prerequisites of mammal species such as preferred ambient temperature are ignored.
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Regulación de la Temperatura Corporal/fisiología , Fosfatidilinositol 3-Quinasa Clase Ib/deficiencia , Lipopolisacáridos/toxicidad , Encefalopatía Asociada a la Sepsis/enzimología , Encefalopatía Asociada a la Sepsis/fisiopatología , Animales , Animales Recién Nacidos , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/enzimología , Barrera Hematoencefálica/fisiopatología , Temperatura Corporal/efectos de los fármacos , Temperatura Corporal/fisiología , Regulación de la Temperatura Corporal/efectos de los fármacos , Células Cultivadas , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Encefalopatía Asociada a la Sepsis/inducido químicamenteRESUMEN
A 72-year-old woman presented to our emergency centre with acute horizontal diplopia. Neurological examination revealed an isolated abducens nerve paresis on the left. Hilar enlargement seen on the chest x-ray and an elevated serum ACE level led us to suspect sarcoidosis, but the patient declined further evaluation. In the following days, her visual acuity decreased steadily, and she developed cervicothoracic pain, left sided ptosis, weakness of the right arm, and general asthenia. When she was readmitted as an emergency case, neurological examination revealed decreased visual acuity, external ophthalmoplegia and ptosis on the left and a C8 radicular lesion on the right. Imaging studies showed multilocular lesions, e.âg. in the left orbital space, spinal epidural manifestations and lymphoma nodular involvement, including retroperitoneally. Laboratory chemistry showed elevated serum levels of ACE, sIL2 receptor and an elevated CD4â/âCD8 ratio while bronchoalveolar lavage indicated lymphocytic alveolitis. The biopsy performed under the left M. masseter with a presumptive diagnosis of sarcoidosis, showed a diffuse large-cell B-cell lymphoma. We initiated immuno-chemotherapy following the R-CHOP schema with a curative approach. The case shows the lack of specificity of clinical, imaging and laboratory findings and thus underlines the need for histology in the differential diagnosis of sarcoidosis.
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Diplopía/etiología , Diplopía/fisiopatología , Sarcoidosis/complicaciones , Sarcoidosis/diagnóstico , Anciano , Diagnóstico Diferencial , Diplopía/diagnóstico , Femenino , Humanos , Sarcoidosis/fisiopatologíaRESUMEN
Comorbidity of neurofibromatosis type 2 (NF2) and multiple sclerosis (MS) has rarely been reported. Since immunological mechanisms have been implicated in Nf2, coexistence of the two entities may offer insights into schwannoma pathogenesis with respect to the impact of the immune system. We present the case of a woman with a de novo mutation in the NF2 gene who later developed MS. In addition, we found a significantly higher count of T cells in a laryngeal schwannoma of this patient as compared to a schwannoma removed from a NF2 patient without MS. This finding correlated with a higher growth rate in the case of NF+MS.
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PURPOSE: To analyse whether the WHO grade of intracranial meningiomas differs itself depending on patients and meningioma characteristics at diagnosis. METHODS: Single center retrospective study of a series of consecutive patients with primary intracranial meningiomas who underwent surgery between January 2007 and March 2014. Patients (age, sex, outcome) and meningioma characteristics (histological diagnosis, tumor location, WHO grading, size, extend of peritumoral edema and tumor recurrence rate) were analysed. RESULTS: Of 240 included patients, 184 (76.7%) were female and 56 (23.3%) were male. 17 patients (7.1%) were in age group 20-40 years, 112 (46.7%) in group 41-60 years and 111 (46.3%) were in age group > 60 years. 189 patients (78.8%) were diagnosed with WHO grade I, 49 (20.4%) WHO grade II and 2 (0.8%) had a WHO grade III meningioma. WHO grade II meningiomas were significantly more frequent in the age group 20-40 years compared to age group 41-60 years (chi-square p < 0.05). Convexity meningiomas were significantly more frequent classified as WHO grade II meningiomas compared to all other locations (chi-square, p < 0.01). Mean calculated tumor volume and the tumor volume determined by volumetric measurement was significantly larger in grade II meningioma patients compared to grade I (46.3 ± 40.5 cc grade II versus 21.8 ± 27.8 cc grade I and 45.3 ± 38.2 cc versus 23.1 ± 30.0 cc respectively; t test < 0.01). Extend of the peritumoral edema was significantly larger in patients with grade II meningiomas (Wilcoxon test, p < 0.05). Short term outcome did not differ between different age groups nor was it associated with tumor size. During a mean follow up of 49 months (min 3, max 144 months) recurrence rate was significantly higher in WHO grade II (4 out of 49 [8.2]%) compared to WHO grade I patients (3 out if 186, [1.6%]; Chi-square, p < 0.05). CONCLUSION: In this series atypical meningioma was associated with younger age, location on the convexity, larger tumor size and more peritumoral edema.
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Edema Encefálico/epidemiología , Neoplasias Meníngeas/epidemiología , Meningioma/epidemiología , Adulto , Factores de Edad , Edema Encefálico/complicaciones , Edema Encefálico/patología , Femenino , Humanos , Masculino , Neoplasias Meníngeas/complicaciones , Neoplasias Meníngeas/patología , Meningioma/complicaciones , Meningioma/patología , Persona de Mediana Edad , Clasificación del Tumor , Estudios Retrospectivos , Organización Mundial de la Salud , Adulto JovenRESUMEN
Sepsis-induced myocardial depression (SIMD) is an early and frequent consequence of the infection-induced systemic inflammatory response syndrome. In homiotherms, variations in ambient temperature (Ta) outside the thermoneutral zone induce thermoregulatory responses mainly driven by a gradually increased sympathetic activity, which may affect disease severity. We hypothesized that thermoregulatory responses upon reduced Ta exposition aggravate SIMD in mice. Mice were kept at neutral Ta (30 ± 0.5 °C), moderately lowered Ta (26 ± 0.5 °C) or markedly lowered Ta (22 ± 0.5 °C), exposed to lipopolysaccharide- (LPS, 10 µg/g, from Escherichia coli serotype 055:B5, single intraperitoneal injection) evoked shock and monitored for survival, cardiac autonomic nervous system function and left ventricular performance. Primary adult cardiomyocytes and heart tissue derived from treated mice were analyzed for inflammatory responses and signaling pathways of myocardial contractility. We show that a moderate reduction of Ta to 26 °C led to a 40% increased mortality of LPS-treated mice when compared to control mice and that a marked reduction of Ta to 22 °C resulted in an early mortality of all mice. Mice kept at 26 °C exhibited increased heart rate and altered indices of heart rate variability (HRV), indicating sympathovagal imbalance along with aggravated LPS-induced SIMD. This SIMD was associated with reduced myocardial ß-adrenergic receptor expression and suppressed adrenergic signaling, as well as with increased myocardial iNOS expression, nitrotyrosine formation and leukocyte invasion as well as enhanced apoptosis and appearance of contraction band necrosis in heart tissue. While ineffective separately, combined treatment with the ß2-adrenergic receptor (AR) antagonist ICI 118551 (10 ng/gbw) and the inducible nitric oxide synthase (iNOS) inhibitor 1400 W (5 µg/gbw) reversed the increase in LPS-induced mortality and aggravation of SIMD at reduced Ta. Thus, consequences of thermoregulatory adaptation in response to ambient temperatures below the thermoneutral range increase the mortality from LPS-evoked shock and markedly prolong impaired myocardial function. These changes are mitigated by combined ß2-AR and iNOS inhibition.
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Sistema Nervioso Autónomo/fisiopatología , Regulación de la Temperatura Corporal , Cardiopatías/inducido químicamente , Corazón/inervación , Vivienda para Animales , Contracción Miocárdica , Síndrome de Respuesta Inflamatoria Sistémica/inducido químicamente , Temperatura , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Cardiopatías/metabolismo , Cardiopatías/fisiopatología , Hemodinámica , Mediadores de Inflamación/metabolismo , Lipopolisacáridos , Masculino , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo II/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Transducción de Señal , Síndrome de Respuesta Inflamatoria Sistémica/metabolismo , Síndrome de Respuesta Inflamatoria Sistémica/fisiopatologíaRESUMEN
Phosphoinositide 3-kinase γ (PI3Kγ) is linked to neuroinflammation and phagocytosis. This study was conducted to elucidate conjectural differences of lipid kinase-dependent and kinase-independent functions of PI3Kγ in the evolvement of brain damage induced by focal cerebral ischemia/reperfusion. Therefore, PI3Kγ wild-type, knockout, and kinase-dead mice were subjected to middle cerebral artery occlusion followed by reperfusion. Tissue damage and cellular composition were assessed by immunohistochemical stainings. In addition, microglial cells derived from respective mouse genotypes were used for analysis of PI3Kγ effects on phagocytic activity, matrix metalloproteinase-9 release, and cAMP content under conditions of oxygen/glucose deprivation and recovery. Brain infarction was more pronounced in PI3Kγ-knockout mice compared to wild-type and kinase-dead mice 48 h after reperfusion. Immunohistochemical analyses revealed a reduced amount of galectin-3/MAC-2-positive microglial cells indicating that activated phagocytosis was reduced in ischemic brains of knockout mice. Cell culture studies disclosed enhanced metalloproteinase-9 secretion in supernatants derived from microglia of PI3Kγ-deficient mice after 2-h oxygen/glucose deprivation and 48-h recovery. Furthermore, PI3Kγ-deficient microglial cells showed a failed phagocytic activation throughout the observed recovery period. Lastly, PI3Kγ-deficient microglia exhibited strongly increased cAMP levels in comparison with wild-type microglia or cells expressing kinase-dead PI3Kγ after oxygen/glucose deprivation and recovery. Our data suggest PI3Kγ kinase activity-independent control of cAMP phosphodiesterase as a crucial mediator of microglial cAMP regulation, MMP-9 expression, and phagocytic activity following focal brain ischemia/recirculation. The suppressive effect of PI3Kγ on cAMP levels appears critical for the restriction of ischemia-induced immune cell functions and in turn tissue damage.
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Isquemia Encefálica/enzimología , Isquemia Encefálica/patología , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Microglía/enzimología , Neurotoxinas/toxicidad , Animales , Infarto Encefálico/patología , Isquemia Encefálica/complicaciones , Recuento de Células , Células Cultivadas , Fosfatidilinositol 3-Quinasa Clase Ib/deficiencia , AMP Cíclico/metabolismo , Glucosa/deficiencia , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/patología , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/efectos de los fármacos , Modelos Biológicos , Neutrófilos/metabolismo , Oxígeno , Fagocitosis , Factores de TiempoRESUMEN
AIMS: Sepsis-induced myocardial depression (SIMD), an early and frequent event of infection-induced systemic inflammatory response syndrome (SIRS), is characterized by reduced contractility irrespective of enhanced adrenergic stimulation. Phosphoinositide-3 kinase γ (PI3Kγ) is known to prevent ß-adrenergic overstimulation via its scaffold function by activating major cardiac phosphodiesterases and restricting cAMP levels. However, the role of PI3Kγ in SIRS-induced myocardial depression is unknown. This study is aimed at determining the specific role of lipid kinase-dependent and -independent functions of PI3Kγ in the pathogenesis of SIRS-induced myocardial depression. METHODS AND RESULTS: PI3Kγ knockout mice (PI3Kγ(-/-)), mice expressing catalytically inactive PI3Kγ (PI3Kγ(KD/KD)), and wild-type mice (P3Kγ(+/+)) were exposed to lipopolysaccharide (LPS)-induced systemic inflammation and assessed for survival, cardiac autonomic nervous system function, and left ventricular performance. Additionally, primary adult cardiomyocytes were used to analyse PI3Kγ effects on myocardial contractility and inflammatory response. SIRS-induced adrenergic overstimulation induced a transient hypercontractility state in PI3Kγ(-/-) mice, followed by reduced contractility. In contrast, P3Kγ(+/+) mice and PI3Kγ(KD/KD) mice developed an early and ongoing myocardial depression despite exposure to similarly increased catecholamine levels. Compared with cells from P3Kγ(+/+) and PI3Kγ(KD/KD) mice, cardiomyocytes from PI3Kγ(-/-) mice showed an enhanced and prolonged cAMP-mediated signalling upon norepinephrine and an intensified LPS-induced proinflammatory response characterized by nuclear factor of activated T-cells-mediated inducible nitric oxide synthase up-regulation. CONCLUSIONS: This study reveals the lipid kinase-independent scaffold function of PI3Kγ as a mediator of SIMD during inflammation-induced SIRS. Activation of cardiac phosphodiesterases via PI3Kγ is shown to restrict myocardial hypercontractility early after SIRS induction as well as the subsequent inflammatory responses.
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Cardiomiopatías/enzimología , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , AMP Cíclico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Sepsis/complicaciones , Animales , Sistema Nervioso Autónomo/fisiopatología , Calcio/metabolismo , Cardiomiopatías/etiología , Cardiomiopatías/fisiopatología , Células Cultivadas , Ratones Endogámicos C57BL , Ratones Noqueados , Factores de Transcripción NFATC/metabolismo , Función Ventricular IzquierdaRESUMEN
BACKGROUND: The celiac artery compression syndrome (CACS) is a rarely diagnosed disorder, which is characterized by chronic abdominal pain and vegetative symptoms. The role of surgical treatment in celiac artery decompression has been discussed controversially by numerous authors. After first casuistic descriptions of a laparoscopic treatment in adults we established this novel minimally invasive procedure for treatment in children and adolescents. PATIENTS AND METHODS: Between 2005 and 2014 we operated 58 patients (47 female, 11 male) from 7 to 25 years who had been diagnosed with celiac artery compression. The patients presented with severe chronic abdominal pain, vegetative symptoms and a reduced quality of life. Doppler sonography showed an increased blood flow velocity of the celiac artery with maximum of 190 - 450 cm/s (mean 259 cm/s).MR angiography demonstrated a characteristic hook-shaped appearance of the celiac artery with severe localized compression. RESULTS: All patients underwent laparoscopic decompression of the celiac artery. We observed complications in 3 patients (5,2 %). Postoperatively all patients (100 %) were immediately free of abdominal pain. Doppler sonography showed a marked reduction in celiac blood flow velocity to 70 - 190 cm/s postoperatively (mean 178 cm/s). A return of vessel diameters to normal dimensions was documented by postoperative MR angiography. During a median follow up of 62 months we observed a recurrence of the celiac artery compression in 4 patients (6,9 %). CONCLUSIONS: Laparoscopic treatment of celiac artery compression syndrome offers a novel, safe, reliable and, compared to open surgery, less invasive approach. The surgical treatment is indicated in patients with characteristic symptoms and typical findings at Doppler sonography and MRA after exclusion of other abdominal pathologies. The work-up of chronic abdominal pain in children and adolescents should include a color Doppler sonography to look for celiac artery compression.
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Arteria Celíaca/anomalías , Constricción Patológica/cirugía , Descompresión Quirúrgica/métodos , Laparoscopía/métodos , Adolescente , Adulto , Velocidad del Flujo Sanguíneo , Arteria Celíaca/diagnóstico por imagen , Arteria Celíaca/patología , Arteria Celíaca/fisiopatología , Arteria Celíaca/cirugía , Niño , Constricción Patológica/diagnóstico , Constricción Patológica/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Angiografía por Resonancia Magnética , Masculino , Síndrome del Ligamento Arcuato Medio , Estudios Retrospectivos , Resultado del Tratamiento , Ultrasonografía Doppler en Color , Adulto JovenRESUMEN
The breakdown of the blood-brain barrier (BBB) is a key event in the development of sepsis-induced brain damage. BBB opening allows blood-born immune cells to enter the CNS to provoke a neuroinflammatory response. Abnormal expression and activation of matrix metalloproteinases (MMP) was shown to contribute to BBB opening. Using different mouse genotypes in a model of LPS-induced systemic inflammation, our present report reveals phosphoinositide 3-kinase γ (PI3Kγ) as a mediator of BBB deterioration and concomitant generation of MMP by microglia. Unexpectedly, microglia expressing lipid kinase-deficient mutant PI3Kγ exhibited similar MMP regulation as wild-type cells. Our data suggest kinase-independent control of cAMP phosphodiesterase activity by PI3Kγ as a crucial mediator of microglial cell activation, MMP expression and subsequent BBB deterioration. The results identify the suppressive effect of PI3Kγ on cAMP as a critical mediator of immune cell functions.
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Barrera Hematoencefálica/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ib/fisiología , AMP Cíclico/metabolismo , Lipopolisacáridos/farmacología , Microglía/metabolismo , Encefalopatía Asociada a la Sepsis/metabolismo , Síndrome de Respuesta Inflamatoria Sistémica/metabolismo , 3',5'-AMP Cíclico Fosfodiesterasas/metabolismo , Animales , Transporte Biológico Activo , Permeabilidad Capilar , Células Cultivadas , Fosfatidilinositol 3-Quinasa Clase Ib/deficiencia , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Colorantes/farmacocinética , Azul de Evans/farmacocinética , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasas de la Matriz/biosíntesis , Metaloproteinasas de la Matriz/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/enzimología , ARN Mensajero/biosíntesis , Sistemas de Mensajero SecundarioRESUMEN
Paediatric traumatic brain injury (TBI) is a leading cause of death and disability. Previous studies showed neuroprotection after TBI by (endo)cannabinoid mechanisms, suggesting involvement of cannabinoid receptors (CBR). We therefore determined CBR densities and expression of the translocator protein 18 kDA (TSPO) in newborn piglets after experimental TBI. Newborn female piglets were subjected to sham operation (n=6) or fluid-percussion (FP) injury (n=7) under controlled physiological conditions. After six hours, brains were frozen, sagittally cut and incubated with radioligands for CBR ([3HCP-55,940, [3H]SR141716A) and TSPO ([3H]PK11195), an indicator of gliosis/brain injury. Early after injury, FP-TBI elicited a significant ICP increase at a temporary reduced cerebral perfusion pressure; however, CBF and CMRO2 remained within physiological range. At 6 hours post injury, we found a statistically significant increase in binding of the non-selective agonist [3H]CP-55,940 in 15 of the 24 investigated brain regions of injured animals. By contrast, no significant changes in binding of the CB1R-selective antagonist [3H]SR141716A were observed. A non-significant trend towards increased binding of [3H]PK11195 was observed, suggesting an incipient microglial activation. We therefore conclude that in this model and time span after injury, the increase in [3H]CP-55,940 binding reflects changes in CB2R density, while CB1R density is not affected. The results may provide explanation for the neuroprotective properties of cannabinoid ligands and future therapeutic strategies of TBI.
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Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Encéfalo/metabolismo , Receptores de Cannabinoides/metabolismo , Análisis de Varianza , Animales , Animales Recién Nacidos , Autorradiografía , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Lesiones Encefálicas/diagnóstico por imagen , Moduladores de Receptores de Cannabinoides/farmacocinética , Ciclohexanoles/farmacocinética , Modelos Animales de Enfermedad , Femenino , Isoquinolinas , Piperidinas/farmacocinética , Unión Proteica/efectos de los fármacos , Pirazoles/farmacocinética , Cintigrafía , Receptores de GABA/metabolismo , Rimonabant , Porcinos , Factores de Tiempo , Tritio/farmacocinéticaRESUMEN
Glioblastomas are neuroepithelial tumors with lost cellular differentiation and tenfold increased growth rates compared to low-grade gliomas. Despite of very aggressive treatment options based on surgery, irradiation, and chemotherapy, the prognosis of affected patients has remained poor and showed only slight improvements during the last 30 years. Research on glioblastoma border zone was hindered by the tumor's intense invasion into the brain parenchyma and the lack of suitable tumor cell markers. Nevertheless, the compact tumor mass and tumor invasion zone are composed of distinct cell types that need to be distinguished from each other to be addressed selectively. As the isoform 140 of the neural cell adhesion molecule (NCAM-140) was recently demonstrated to be lost in human gliomas with rising WHO grade, human multiform glioblastomas were characterized as a NCAM-140 negative entity displaying three main distinct invasion patterns. Evaluation of putative therapy targets within the tumor tissue and tumor invasion zone has been made possible through NCAM-140 negativity. In the present study, brain tissue controls and human glioblastoma samples with compact tumor mass and invasion areas were analyzed for their vascularization at the tumor border and the expression of thrombin receptor protease-activated receptor type 1 (PAR-1) within tumor tissue and vascular vessel walls. Use of NCAM-140 enabled the identification of the tumor invasion zone and its experimental investigation. Tissue vascularization was found to be significantly increased in the compact tumor mass of glioblastomas compared to their invasion zone and tumor-free controls with a significantly high and specific overexpression of PAR-1 within tumor cells and within tumor blood vessels depending upon the tumor area. This suggests thereby a functional role of the thrombin receptor PAR-1 in glioma cell malignancy and glioblastoma neoangiogenesis.
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Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Moléculas de Adhesión Celular Neuronal/metabolismo , Glioblastoma/metabolismo , Receptor PAR-1/metabolismo , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patología , Neoplasias Encefálicas/irrigación sanguínea , Neoplasias Encefálicas/patología , Glioblastoma/irrigación sanguínea , Glioblastoma/patología , Humanos , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
UNLABELLED: Actinomycosis of the spine with spinal cord compression is rare. Only 22 cases are reported in the literature. The authors describe a remarkable case of a large lesion leading to bony destruction and spinal cord compression in the cervicothoracic junction with a large intrathoracic extension, which was considered to be a metastatic pulmonary disease but turned out to be actinomycosis. CLINICAL PRESENTATION: A 55-year-old man presented with acute tetraparesis. Magnetic resonance imaging (MRI) and computed tomography (CT) imaging showed vertebral body collapse of T1 and partially C7 with spinal cord compression as well as a mass in the right upper lobe with multiple intrapulmonary nodules. Moreover, dorsal elements (laminae and spinous process) were also involved and partially destructed. Differential diagnosis favored metastatic pulmonary disease. INTERVENTION: Decompression surgery was performed by anterior corpectomy of T1, stabilization with an expandable titanium cage and additional anterior plate C7-T2. Histology revealed typical sulfur granules. Microbiology exams were positive for Actinobacillus actinomycetemcomitans. There was no proof of malignancy in thoracic biopsy in the late diagnostic work-up. To prevent instrumentation failure, an external immobilization (halo fixation) was applied until complete fusion was documented in CT during the postoperative course. After an 11-month course of ampicillin/sulbactam, there was complete resolution of the intrapulmonary and spinal pathology. CONCLUSION: Thoracic actinomycosis with spinal involvement is a rare disease. Therefore, diagnosis may be difficult. Surgical intervention, correct diagnosis, and specific long-term antibiotic treatment resulted in favorable outcome.
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Actinomicosis/diagnóstico , Enfermedades Pulmonares/diagnóstico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/secundario , Enfermedades de la Columna Vertebral/diagnóstico , Actinomicosis/microbiología , Actinomicosis/patología , Aggregatibacter actinomycetemcomitans , Antibacterianos/uso terapéutico , Diagnóstico Diferencial , Servicios Médicos de Urgencia , Humanos , Enfermedades Pulmonares/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Cuadriplejía/etiología , Enfermedades de la Columna Vertebral/microbiología , Enfermedades de la Columna Vertebral/patología , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
PURPOSE: There is compelling evidence that interference of various anesthetics with synaptic functions and stress-provoking procedures during critical periods of brain maturation results in increased neuroapoptotic cell death. The hypothesis is that adverse intrauterine environmental conditions leading to intrauterine growth restriction (IUGR) with altered brain development may result in enhanced susceptibility to developmental anesthetic neurotoxicity. METHODS: This was a prospective, randomized, blinded animal study performed in a university laboratory involving 20 normal-weight (NW) and 19 IUGR newborn piglets. General inhalation anesthesia with isoflurane and nitrous oxide at clinically comparable dosages were administered for about 10 h. Surgical and monitoring procedures were accompanied by appropriate stage of general anesthesia. Resulting effects on developmental anesthetic and stress-induced neurotoxicity were assessed by estimation of apoptotic rates in untreated piglets and piglets after 10-h general anesthesia with MAC 1.0 isoflurane in 70 % nitrous oxide and 30 % oxygen. RESULTS: IUGR piglets exposed to different levels of isoflurane inhalation exhibited a significant increased apoptosis rate (TUNEL-positive neuronal cells) compared to NW animals of similar condition (P < 0.05). Cardiovascular and metabolic monitorings revealed similar effects of general anesthesia together with similar effects on brain electrical activity and broadly a similar dose-dependent gradual restriction in brain oxidative metabolism in NW and IUGR piglets. CONCLUSIONS: There is no indication that the increased rate in neuroapoptosis in IUGR piglets is confounded by additional adverse systemic or organ-specific impairments resulting from administered mixed inhalation anesthesia. Developmental anesthetic and stress-induced neuroapoptosis presumably originated in response to fetal adaptations to adverse conditions during prenatal life and should be considered in clinical interventions on infants having suffered from fetal growth restriction.
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Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Retardo del Crecimiento Fetal/fisiopatología , Isoflurano/toxicidad , Óxido Nitroso/toxicidad , Análisis de Varianza , Anestésicos por Inhalación/toxicidad , Animales , Animales Recién Nacidos/fisiología , Encéfalo/crecimiento & desarrollo , Modelos Animales de Enfermedad , Isoflurano/administración & dosificación , Neuronas/efectos de los fármacos , Óxido Nitroso/administración & dosificación , Estudios Prospectivos , Estrés Fisiológico/efectos de los fármacos , Porcinos , Transmisión Sináptica/efectos de los fármacosRESUMEN
BACKGROUND: Patients with malignancies often suffer from thrombembolic events that complicate the course of cancer disease and reduce the patients' quality of life or shorten the survival time in severe cases. This phenomenon is also known for patients with primary or secondary brain tumors; but the reasons are not identified. METHODS: We performed a prospective case-controlled study of patients with brain metastases but without any active peripheral tumor site. Blood of patients was collected perioperatively and investigated for coagulation factor activities. Moreover, we analyzed the expression of coagulation factors and their receptors within the tumor material of brain metastases from clear-cell renal cell carcinomas and small-cell carcinomas of the lung. RESULTS: Here, we show that even patients without an active peripheral tumor disease that means without any tumor masses outside the central nervous system after anticancer treatment by surgery, radiation therapy, or chemotherapy but with symptomatic brain metastasis develop an increased systemic activation of multiple coagulation factors. The pro-coagulatory state is expressed preoperatively, but also can be observed in the early postoperative period. Additionally to that, intracerebral metastases of clear-cell renal cell carcinomas and of small-cell carcinomas of the lung express prothrombin, thrombin, factor X, and the protease-activated receptors type 1, 2, 3, and 4. CONCLUSIONS: These observations support the hypothesis of a link between the hemostatic system in the periphery and the malignant tumor disease even when the tumor is an intracerebral metastasis and the affected patient currently is free of a systemically active tumor. The results of this study support the hypothesis that the concerted action of coagulation factors and their receptors within the metastasis tissue itself and the systemic coagulation system could control the malignant behavior of tumor disease and make larger prospective trials mandatory.
Asunto(s)
Factores de Coagulación Sanguínea/biosíntesis , Neoplasias Encefálicas/sangre , Neoplasias Encefálicas/secundario , Receptores Proteinasa-Activados/biosíntesis , Adulto , Anciano , Antitrombina III/biosíntesis , Carcinoma de Células Renales/sangre , Carcinoma de Células Renales/secundario , Carcinoma de Células Pequeñas/sangre , Carcinoma de Células Pequeñas/secundario , Estudios de Casos y Controles , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/biosíntesis , Fibrinógeno/biosíntesis , Humanos , Inmunohistoquímica , Neoplasias Renales/sangre , Neoplasias Renales/patología , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Regulación hacia Arriba , Adulto JovenRESUMEN
OBJECTIVE: Inherited ataxias are heterogeneous disorders affecting both children and adults. The primary cause can be identified in about half of the patients and only very few can receive causative therapy. METHODS: The authors performed sequencing of known Coenzyme Q10 (CoQ10) deficiency genes in 22 patients with unexplained recessive or sporadic ataxia. RESULTS: CABC1/ADCK3 mutations were detected in four patients and two siblings presenting with cerebellar ataxia, epilepsy and muscle symptoms. Spasticity, dystonia, tremor and migraine were variably present; cognitive impairment was severe in early childhood cases, but was absent in adults. In contrast to previous reports, two of the patients had a later-onset, very mild phenotype and remained ambulatory in their late forties. Muscle biopsy revealed lipid accumulation, mitochondrial proliferation and cytochrome c oxidase-deficient fibres, but no typical ragged red fibres. Respiratory-chain enzyme activities and CoQ10 were decreased in severely affected patients but remained normal in a mildly affected patient at 46 years of age. CONCLUSIONS: These observations highlight the importance of screening for a potentially treatable cause, CABC1/ADCK3 mutations, not only in severe childhood-onset ataxia, but also in patients with mild cerebellar ataxia in adult life.
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Proteínas Mitocondriales/genética , Degeneraciones Espinocerebelosas/genética , Adolescente , Adulto , Edad de Inicio , Biopsia , Análisis Mutacional de ADN , Femenino , Eliminación de Gen , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias Musculares/enzimología , Mitocondrias Musculares/patología , Músculo Esquelético/patología , Mutación/fisiología , Polimorfismo de Nucleótido Simple , Degeneraciones Espinocerebelosas/patología , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Adulto JovenRESUMEN
PURPOSE: Gliomas are highly invasive neuroepithelial tumors with a propensity of malignant transformation and very restricted treatment options. The neural cell adhesion molecule (NCAM) modulates cellular migration, proliferation, and synaptic plasticity by homophilic and heterophilic interactions. Hereby, we investigated its relevance as a glioma tissue marker for the biological aggressiveness of these tumors and compared these features with the carcinoma brain metastasis invasion zone. MATERIALS AND METHODS: We analyzed 194 human brain samples. Human tumor-free brain specimens served as control for the white and gray matter. In addition to that, we used human glioblastomas from nude rats. All tissues were investigated immunohistochemically for the expression of the NCAM isoform 140. Additionally, the multiplanar MRI-CT fusion neuronavigation-guided serial stereotactic biopsy was performed and completed by histopathological workup. RESULTS: Human gliomas loose NCAM-140 with the rise of their WHO grade. Meningiomas are NCAM-140 negative. As the most striking feature, human brain metastases and the majority of human glioblastomas of our patients and of nude rats were totally NCAM-140 negative. This NCAM negativity led us to the conclusion of three different main glioblastoma invasion patterns. Surprisingly, the majority of brain metastasis samples that contained surrounding brain parenchyma demonstrated invasive tumor cell nests beyond the sharply demarcated metastasis border. We also found invasive metastatic cell nests outside the contrast enhancing tumor zone by means of the MRI-CT fusion neuronavigation-guided serial stereotactic biopsy. CONCLUSION: The expression of NCAM-140 inversely correlates with the WHO grade of human gliomas. The lost expression of NCAM-140 in human glioblastomas and in brain metastases enables the investigation of the brain-tumor interface and the definition of glioblastoma invasion patterns and shows that brain metastases are more invasive than ever thought.
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Biomarcadores de Tumor/biosíntesis , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Moléculas de Adhesión Celular Neuronal/biosíntesis , Glioblastoma/metabolismo , Glioblastoma/patología , Animales , Astrocitoma/metabolismo , Astrocitoma/patología , Astrocitoma/secundario , Biopsia/métodos , Neoplasias Encefálicas/secundario , Glioblastoma/secundario , Humanos , Imagen por Resonancia Magnética/métodos , Meningioma/metabolismo , Meningioma/patología , Meningioma/secundario , Invasividad Neoplásica , Ratas , Ratas DesnudasRESUMEN
PURPOSE: Calcium ions are highly versatile spacial and temporal intracellular signals of non-excitable cells and have an important impact on nearly every aspect of cellular life controlling cell growth, metabolism, fluid secretion, information processing, transcription, apoptosis, and motility. Neurons and glia respond to stimuli, including neurotransmitters, neuromodulators, and hormones, which increase the intracellular calcium concentration. The function of intracellular calcium in gliomas is unknown. Lots of daily used drugs may act via receptors that can be linked to the intracellular calcium system and therefore could influence glioma biology. METHODS: Glioma cells were loaded with the calcium ion sensitive dye Fura 2-AM. Subsequently, cells were stimulated with 25 different medical drugs for 30 s. The increase of free intracellular calcium ions was measured and calculated by a microscope-camera-computer-unit. RESULTS: Except for the buffer solution HEPES that served as negative control and for the cortisol derivative dexamethasone, all other 24 tested drugs induced a rise of intracellular calcium ions. The cellular calcium responses were classified into seven functional groups. The tested substances activated several types of calcium channels and receptors. CONCLUSIONS: Our study impressively demonstrates that medical drugs are potent inducers of intracellular calcium signals. Totally unexpected, the results show a high amount of functional cellular receptors and channels on glioma cells, which could be responsible for certain biological effects like migration and cell growth. This calcium imaging study proves the usability of the calcium imaging as a screening system for functional receptors on human glioma cells.
Asunto(s)
Membrana Celular/metabolismo , Glioblastoma/metabolismo , Medicamentos sin Prescripción/farmacología , Receptores de Superficie Celular/agonistas , Calcio/metabolismo , Señalización del Calcio/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Diagnóstico por Imagen/instrumentación , Diagnóstico por Imagen/métodos , Humanos , Modelos Biológicos , Medicamentos sin Prescripción/clasificación , Receptores de Superficie Celular/metabolismo , Receptores de Superficie Celular/fisiología , Células Tumorales CultivadasRESUMEN
Generally, gliomas do not metastasize. Therefore, larger series are not available to investigate the pathways of tumour spread. Here, we present the case of a young man with a glioblastoma multiforme WHO grade IV and distant metastases in several tissues. The glioblastoma multiforme WHO grade IV of a young male patient recurred within a very short time along the surgical resection pathway within the temporalis muscle. After removal of the tumour bulk, the patient developed a distant intracranial tumour lesion around the contralateral ventricular system and a pulmonary tumour. Later on, the patient underwent an operation on a facial lesion representing a local extracranial glioblastoma recurrence and containing metastases within lymph nodes and lymphatic vessels. Our case report indicated a lymphatic pathway of metastasis, which could be demonstrated by our histopathological analysis. We suggest that altered gene expression stimulated by glioblastoma-environment interaction altered the properties of glioblastoma cells, whether caused by a spontaneous genetic shift or induced by factors provided by the extracranial tissue.
Asunto(s)
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patología , Glioblastoma/patología , Glioblastoma/secundario , Adulto , Neoplasias Encefálicas/complicaciones , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/etiología , Glioblastoma/complicaciones , Glioblastoma/diagnóstico , Humanos , Metástasis Linfática , Imagen por Resonancia Magnética , Masculino , Neoplasias Mandibulares/patología , Neoplasias Mandibulares/secundario , Músculo Masetero/patologíaRESUMEN
OBJECTIVE: Neurofibromatosis type 2 (NF2) is a common neurocutaneous disorder that exhibits an autosomal dominant inheritance, with a mutation at chromosome 22q12.2. Two forms can be distinguished: the Wishart-phenotype with an early and aggressive course and the Feiling-Gardner-phenotype with a less dramatic presentation. In general, patients present bilateral vestibular schwannomas, meningiomas and neurinomas of the central and peripheral nervous system as well as neurofibromas and gliomas. There is no reported case of pulmonary meningiomas and neurinomas associated with NF2 until now. PATIENT AND METHODS: Here, we present a 16-year-old girl with NF-2 associated to CNS and pulmonary tumours and we discuss the case in the backlight of the literature. RESULTS: The reported patient presented a de novo NF2 germline mutation (R341X) and displayed the Wishart-type of NF-2 since she is 11 years old, with a huge anaplastic biparietal falx meningioma and a tentorium meningioma and a tumour-associated parietal mass as well as hypacusis starting at the infant age of 3 years. Multiple cranial and spinal tumours with extra- and intramedullary localization were also found. Moreover, recurrent pulmonary tumours developed and were classified as benign meningiomas and a single neurinoma. No direct evidence concerning a relationship between the pulmonary and cerebral tumours could be drawn. CONCLUSION: This rare case extends our knowledge of NF2 and also raises interesting questions about the pathogenesis of meningiomas outside the CNS.