Immunohistohemical expression of the chemokine fractalkine and its receptor in the human brain cortex after severe traumatic brain injury and brain hemorrhage.

AIM: Recent experimental studies have suggested that chemokines, a subclass of chemoattractant cytokines which play an important role in regulating leukocyte migration and intercellular communication, participate in brain responses of traumatic injury. Fractalkine (CX3CL1) is a peculiar chemokine, the only one with a CX3C motif, existing both as a soluble and a membrane-anchored molecule. In the brain, Fractalkine has been suggested to have a role in neuroprotection under experimental conditions of brain injury. METHODS: Eighteen human brain samples were obtained during surgery of decompressive craniotomy for severe traumatic brain injury (TBI) or after spontaneous intracranial haemorrhage (ICH). Five normal brain samples were obtained during surgery for unruptured intracranial aneurysms (standard gyrectomy). Immunohistochemistry of formalin fixed and paraffin embedded tissues was performed in order to verify the expression of fractalkine and its receptor (CX3CR1). The values of chemokine and receptor expression were correlated with the clinical parameters of the patients. RESULTS: The chemokine fractalkine was significantly upregulated in the neural compartment after brain injury, compared to normal brain samples. Intensity scores were significantly higher when the interval between injury and surgery was >5 h, (P=0.015). In the glial compartment, Fractalkine expression was significantly associated with less severe clinical conditions and lower intracranial pressure at surgery (P=0.014). Expression of the receptor CX3CR1 was detected, at low intensity, on both glial and neurons. Higher expression in neurons was associated with better clinical conditions (Glasgow score) of patients at admission (P=0.037). CONCLUSION: The results of this study highlights for the first time that fractalkine and its receptor CX3CR1 are expressed in the human brain after TBI and ICH and may be involved in the limitation of tissue damage.

Las células madre, piedra angular de rejuvenecimiento. Aclarando conceptos / Stem cells, corners stone of rejuvenescence. Clarifying concepts

Las células madre tienen tres características comunes: la autorrenovación, la indiferenciación y la derivación a cualquier célula madura, éstas son el patrimonio (en el caso de las célula madre adultas) con el que cuenta un individuo para regenerar las células senescentes a lo largo de la vida. Las células madre pueden regenerar tejidos en individuos compatibles de la misma especie. El termino célula madre en tecnología cosmética hace referencia principalmente a sustancias extraídas de células madre de origen vegetal, ricas en polifenoles tales como el resveratrol, y luteolina o péptidos capaces de activar los genes de las sirtuinas NAD dependientes, que producen de acetilación del ADN que permiten la compactación de la cromatina (AU)

Stem cells has three common characteristics: self-renewal, differentiation and derivation of any mature cell, these are the assets (in the case of adult stem cell) with which an individual has to regenerate senescent cells along life. Stem cells can regenerate tissue compatible individuals of the same species. In Cosmetic technology the term stem cell refers mainly to stem cells extracted from substances of vegetable origin, rich in polyphenols such as resveratrol, and luteolin or peptides able to activate the genes of the NAD-dependent sirtuins, which produce deacetylation that allow the compaction of chromatin (AU)

Expression of the transcription factor HEY1 in glioblastoma: a preliminary clinical study.

AIMS AND BACKGROUND: The hairy/enhancer of split (E(spl))-related family of transcription factors (HES and HEY) are established targets of the notch signaling pathway, which has been implicated in different developmental processes, tumor formation and the self-renewal of neural stem cells. We determined the expression of HEY1 in human malignant gliomas to investigate whether its expression might be related to prognosis. METHODS: The expression of HEY1 was studied by in situ hybridization on 62 cases of glioblastoma. Patients were treated with surgery followed by chemotherapy and radiotherapy. We considered as end points of the study the overall survival time and progression-free interval. Correlations between HEY1 expression and tumor grade/patient overall survival and free interval before recurrence were analyzed using univariate analysis. RESULTS: Based on the in situ hybridization results, HEY1 expression rate was reported as negative staining in 13 cases (20.6%), as weak staining in 11 cases (17.3%), as moderate staining in 21 cases (33.3%), and as strong staining in 17 cases. We considered in the analysis the cumulative expression of HEY1 at in situ hybridization (Hey Index) as negative in 13 cases and positive in 49 cases (77.78%). The overall survival (P = 0.002) and the free-interval (P = 0.012) were significantly longer in patients who were negative for HEY1 expression. CONCLUSIONS: Our data suggest that expression of HEY1 might be used as a marker to distinguish glioblastoma patients with a relatively good prognosis from those at high-risk, and that, in the future, HEY1 might represent a therapeutic target.

Importancia y fundamentación del sistema de clasificación biofarmacéutico, como base de la exención de estudios de biodisponibilidad y bioequivalencia in vivo / The biopharmaceutic drug classification, the theoretical basis and its importance in the biowaiver studies

El Sistema de Clasificación Biofarmacéutica (SCB), publicado por Gordon Amidon y cols. en 1995, se basa en un sólido fundamento científico para clasificar un fármaco considerando los parámetros de solubilidad y permeabilidad, factores estrechamente relacionados con el proceso de absorción, y plantea como objetivo, la posibilidad de establecer correlaciones in vitro-in vivo que permitan sustituir los ensayos realizados en humanos por ensayos de disolución in vitro, de acuerdo con la clasificación obtenida para el fármaco. Actualmente la aplicación del SCB está enfocada a los estudios de bioequivalencia para demostrar intercambio de medicamentos, presentados en forma sólida de liberación inmediata, de administración peroral y al aseguramiento de que los cambios realizados durante el escalonamiento o en las formulaciones o procesos de éstos, una vez aprobados, no tengan incidencia en su comportamiento in vivo. La proyección de la aplicación del SCB se está dando hacia su implantación como herramienta en el desarrollo de nuevos fármacos, en el diseño y desarrollo de medicamentos y en la posibilidad de bioexenciones para los sistemas de liberación controlada.

The Biopharmaceutics Classification System (BCS), published in 1995 by Gordon Amidon and coworkers, is proposed based on recognizing the underlying process that is controlling the drug absorption rate and extent, namely, drug solubility and intestinal membrane permeability, classifying a drug according to this. Its objective is the possibility to set standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process, avoiding human studies. The BCS can be used to classify drugs and set standards for scale-up and post-approval changes to show that the efficacy has not been altered, as well as standards for in vitro/in vivo correlation for bioequivalence studies, for solid oral immediate release products. About this, exists discusses for further potential applications of the BCS in the development of new drugs and drug products and in the possibility of biowaivers for controlled-release products.

Effect of nimodipine on arachidonic acid metabolites after subarachnoid hemorrhage.

Arachidonic acid metabolites are under investigation as possible vasoactive agents involved in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage. Prostaglandins, as well as other vasoactive compounds, activate contractile proteins through utilization of extracellular bound Ca++ to the intracytoplasmic free fraction. Recently, calcium-antagonists, mainly Nimodipine, have been proposed for the prophylaxis and/or reversal of the ischemic damage caused by vasospasm. Nimodipine failed to reduce vasospasm incidence in a series of 30 patients admitted with diagnosis of subarachnoid hemorrhage from ruptured intracranial aneurysm. Nimodipine failed to reduce level of four arachidonate metabolites measured (prostaglandin D2, prostacyclin, thromboxane B2 and leukotriene C4) in lumbar and cisternal CSF. After subarachnoid hemorrhage there is a significant increase of CSF levels of arachidonate metabolites; in perianeurysmic cisterns level of prostaglandin D2, thromboxane B2 and leukotriene C4 are significantly higher than lumbar CSF levels. Moreover, cisternal CSF level of prostaglandin D2 and leukotriene C4 are significantly higher in patients with symptomatic vasospasm. Nimodipine did not significantly modify CFS level of arachidonate metabolites: this suggests that Nimodipine treatment, which definitely improves long-term results of patients for intracranial aneurysms, could exert its pharmacological action reducing Ca++ intake from the extracellular compartment and preventing a direct toxic effect of calcium, without a direct action against the release of vasoactive compounds.

[Potassium canreonate in neurosurgical brain edema]. / Il canrenoato di potassio nell'edema cerebrale neurochirurgico

The effect on the hydroelectrolytic metabolism and on the evolution of cerebral oedema of a new injectable aldosterone-antagonist, canreonate-potassium (Soldactone) was studied in two groups of subjects. The first group consisted of 14 patients who had undergone neurosurgical operations for expansive endocranial processes. The second group consisted of 18 non-operated cases of post-traumatic coma. The water-salt balance and the neurologic picture were carefully controlled during anf after 6-8 days of treatment with 600 mg/day of canrenoate-potassium by intravenous route. Comparison was also made between the conventional treatment with hyperventilation and that combined with canrenoate-K. The results obtained demonstrate that the aldosterone-antagonist induces a clinically significant retention of sodium. This is accompanied by a more favourable evolution of the cerebral oedema. Canrenoate-potassium was very well tolerated both locally and generally.