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PubMed1975

[Migration of glial cells in the brains of intact mice and mice with brain injuries during the first hours after DNA synthesis and cell division].

The behaviour of labelled (3H-thymidine) glial cells was studied in the brain of intact mice and mice with mechanical trauma of brain. Formation of pairs of labelled cells and their subsequent disjunction in the brain regions under study occurs at different rates. The rates of these processes in white matter and subependymal zone exceed those in parietal cortex, thalamus and hypothalamus. The brain traumatization does not influence the rate of disjunction of separated glial cells. Angles between axes of separated cells are different in the brain regions under study. In cortex and white matter, separated cells with axial angles equal to 180 degrees predominate whereas in thalamus, hypothalamus and subependymal zone many separated cells have axial angles below 180 degrees (120-160 degrees). The possible relationship between the form of the brain regions under study and the value of axial angles of separated cells is discussed.

Animals↗
PubMed2003

Blood-brain barrier genomics and the use of endogenous transporters to cause drug penetration into the brain.

Blood-brain barrier (BBB) genomics enables the rapid discovery of novel transporters that are expressed at the brain capillary endothelium. The BBB transporters are potential conduits to the brain that therapeutic drugs may use to gain passage across the BBB. Due to the small volume of brain occupied by the endothelium (10(-3) parts of the brain), it is necessary to build a BBB genomics program that is separate from a whole-brain genomics analysis. It is estimated that approximately 15% of all genes selectively expressed at the BBB encode for transporter proteins, and that only approximately 50% of BBB transporters are currently known. The development of a BBB genomics program and the discovery of novel BBB transporters could lead to the invention of new approaches to solving the BBB drug delivery problem.

Animals↗
PubMed1992

The 5 alpha-reductase in the brain: molecular aspects and relation to brain function.

All the classes of hormonal steroids physiologically produced in the body (androgens, estrogens, progestagens, and corticosteroids) are able to exert important effects on the brain, but the mechanisms of their actions are not always well understood. Steroids may interact with intracellular receptors to activate the genome, but some of their effects are probably extragenomic and involve interactions with cellular membranes. Moreover, not all the steroids act always in their native molecular form; a large group of them must actually be transformed into "active" metabolites. This may occur at the level of their respective target structures. For example, androgens are metabolized in the brain into estrogens and into 5 alpha-reduced androgens, like 5 alpha-androstan-17 beta-ol-3-one (dihydrotestosterone; DHT) and 5 alpha-androstan-3 alpha, 17 beta-diol (3 alpha-diol). Progesterone, and possibly corticosteroids, may also be transformed into their corresponding 5 alpha-reduced metabolites. Also the cellular target (neurons and/or glial cells) of the hormonal steroids in the brain is not always clear. This review analyzes in detail one of the two major enzymatic systems that transform steroids in the brain, namely the 5 alpha-reductase-3 alpha-(3 beta)-hydroxysteroid dehydrogenase pathway. An active 5 alpha-reductase-3 alpha-hydroxysteroid dehydrogenase system is widely distributed in practically all CNS structures in all phases of development. In the brain, this enzymatic system is not regulated by castration or sex steroid administration; furthermore, neural inputs seem to be ineffective at the hypothalamic level. A recent interesting finding is the presence of high concentrations of the 5 alpha-reductase in the white matter. This probably is due to the fact that the white matter is particularly rich in myelin membranes, with which the enzymatic activity appears to be associated. An active 5 alpha-reductase activity has also been shown to be present in peripheral myelinated nerves. The localization in myelin membranes may suggest a possible involvement of 5 alpha-reduced metabolites of the different steroids in the process of myelination. The presence of the 5 alpha-reductase was analyzed in neurons, astrocytes, and oligodendrocytes isolated from the brains of male rats, as well as in neurons and glial cells grown in culture. Neurons appear to be more active than glial cells in converting testosterone into DHT. Only neurons possess aromatase activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2005

Reevaluation of surgery for the treatment of brain metastases: review of 208 patients with single or multiple brain metastases treated at one institution with modern neurosurgical techniques.

OBJECTIVE: Patients with brain metastases were analyzed retrospectively to assess the risks and benefits of surgery with modern neurosurgical techniques, including image guidance coupled as indicated with corticography. METHODS: We retrospectively analyzed charts of patients treated surgically for brain metastases. We identified patients with single or multiple brain metastases who underwent craniotomies to reverse associated neurological symptoms or establish a diagnosis. We assessed patients according to recursive partitioning analysis (RPA) prognostic groups as well as functional grades of tumor location (eloquent versus noneloquent, Grades I-III). Perioperative complications, neurological outcomes after surgery, survival, and prognostic factors were analyzed. Statistical analysis of survival was performed with the Kaplan-Meier method. A P value of <0.05 was considered statistically significant. RESULTS: Two hundred eight patients were treated between March 1995 and December 2002. Patient age ranged from 31 to 82 years (median, 59 yr). One lesion was resected in 191 patients, and of 76 patients with multiple lesions, two or more metastases were resected in 17 patients. Tumors were located in eloquent cortex in 27 patients and near eloquent cortex in 124 patients. Four patients died within 30 days after surgery for a mortality rate of 1.9%. Neurological deterioration was noted in 13 patients (6%) after surgery for Grade I and II tumors and in 5 patients (19%) of 27 patients with Grade III tumors. Karnofsky Performance Scale scores were improved (68 patients) or unchanged (124 patients) in 192 patients and worse in 16 patients after surgery. The median survival time (MST) from the date of surgery was 8 months for all patients and 9 months for 163 patients who did not undergo prior whole-brain radiation therapy. There was no difference in survival between patients operated for single metastasis (MST, 8 mo) versus patients with two or three metastases (MST, 9 mo; P = 0.9364). By both univariate and multivariate analysis, variables significantly affecting outcome included a high Karnofsky Performance Scale score and RPA Class I assignment. By univariate analysis, significant treatment variables included postoperative radiotherapy and postoperative chemotherapy. The MSTs of RPA Class I, II, and III patients were 16.1 months, 7.2 months, and 1.4 months, respectively (P < 0.001, log-rank test). These survival data compare favorably with the stereotactic radiosurgery boost arm of the recently published Radiation Therapy Oncology Group 9508 trial. CONCLUSION: In most patients with single or multiple brain metastases, surgical resection reversed or stabilized neurological symptoms with therapeutic benefit, conveying a notable survival advantage without apparent increased risk, particularly in RPA Class I patients. In patients with Grade III single metastasis or RPA Class II multiple metastasis, surgical judgment should be exercised, and stereotactic radiosurgery boost treatment may be preferable. An algorithm for treatment of brain metastases is proposed.

Adult↗
PubMed2004

Is brain SPECT a suitable modality for evaluation of postradiotherapy posterior fossa brain tumours? A comparative evaluation with contrast enhanced computed tomography.

Single photon emission computed tomography (SPECT) of the brain is exquisitely sensitive in detecting viable tumour tissue in the supratentorial region, but its efficacy has not been properly evaluated till date in case of infratentorial posterior fossa tumours. Twenty-four patients with primary posterior fossa brain tumour were included in this study. In each case brain SPECT with 99mTc-glucoheptonate (GHA) was performed for the evaluation of disease status. Contrast enhanced computerised tomography of brain was also performed in all the patients. Brain SPECT was positive in four patients with recurrence of tumour as compared to fifteen cases with computed tomography with a mean GHA retention index 5.26 +/- 1.64. Patients with postradiation gliosis (n=9) showed lower GHA retention index of 1.24 +/- 0.27. This study demonstrates that brain SPECT is not sensitive in detecting recurrence of tumour tissue in infratentorial region, as it is in the supratentorial region, with a sensitivity of 20%, accuracy of 45.83% and negative predictive value of 40% and the chance of any single study coming as false negative is about 80%.

Adolescent↗
PubMed1991

Memoirs of an amnesiac--two years with brain cancer, or the outer space of living with brain tumors.

Alexandra Dane Dor-Ner ("Ali" to friends) was a photographer, writer, and a producer of programs on child development. In February 1989, at the age of 41, she was diagnosed with malignant brain cancer. During the following months she underwent brain surgery, radiation, and implant radiation. Throughout her treatment, she continued to work on a novel and write stores and literary criticism. A volunteer in hospitals before her illness, she now became very active in a support group of brain tumor patients and often served as a first resource and contact for others diagnosed with brain cancer. All was very accomplished; her award-winning photographs have been exhibited in the Smithsonian Institution in Washington, and her articles and pictures were published in books, periodicals, and newspapers around the world. A native of Boston, Ali lived for 17 years in Israel, where she joined a group of photographers documenting disappearing neighborhoods in Jerusalem. She was awarded first prize in the "Israel Through the Camera's Eye" competition in 1977. She also taught English and photography in Israeli high schools. Ali traveled extensively on photographic assignments. Early in their 22-year marriage, she and her husband circumnavigated the globe on a freighter, producing a documentary film of the voyage. "Memoirs of an Amnesiac" was written while Ali was a student at the Warren Wilson College Writers' Program in North Carolina; she intended to explore the compensatory aspects of her disease. In February 1991, within days of completing the piece, Ali had a third brain operation to remove a regrowth of cancerous tumor cells, as well as necrotic tissue. Two days later, she was again operated on to remove blood clots resulting from the previous surgery. For the next 12 weeks she fought to regain her ability to walk, talk, and write. In May, she underwent a fifth operation to relieve pressure in the brain. She was still in the hospital when she learned, to her great pleasure, that she would be awarded a master of fine arts degree from Warren Wilson College. She died on June 19, 1991.

Brain Neoplasms↗
PubMed1991

Relative effects of brain and non-brain injuries on neuropsychological and psychosocial outcome.

Based on the 242 consecutive surviving head injury cases and 132 general trauma cases, this study examined the contribution of brain and non-brain injuries to cognitive and psychosocial outcome 1 month postinjury. The study also examined the relationships among various head injury severity indices. The head injury severity indices were all correlated but patients with Glasgow Coma Scale scores in the mild range had broadly ranging scores on the other head injury severity indices (Abbreviated Injury Scale and time to follow commands). Neuropsychological outcome was related to brain injury severity, but was not independently influenced by severity of other systems injuries. Psychosocial outcome related to both brain and non-brain injuries independently. When evaluating trauma outcome, it is important to consider the contributions of both brain and other system injuries.

Abbreviated Injury Scale↗
PubMed1990

[Effects of neonatal hypothyroidism on brain development: analysis of brain metabolites using high resolution phosphorus and proton magnetic resonance (NMR) spectroscopy].

The brain metabolites were studied in the neonatal hypothyroid rat brain using 31P and 1H nuclear magnetic resonance (NMR) spectroscopy. In vivo 31P spectroscopy of the brains in hypothyroid rats showed the tendency of decrease in phosphocreatine/Pi and phosphocreatine/ATP ratio, suggesting suppressed brain energy status. On proton analysis using perchloric acid extracts of the brain, 10 metabolites were easily recognized. Quantitative analysis of individual metabolites revealed decreased contents of GABA, NAA (N-acetyl aspartate) and phosphocreatine and increased contents of taurine in hypothyroid rat. It was concluded that NMR is a useful and promising tool to evaluate brain metabolites.

Animals↗
PubMed1980

Analysis of brain weight. I. Adult brain weight in relation to sex, race, and age.

The weights of fresh brains obtained at consecutive autopsies over a period of five years were reviewed. Brains with lesions, such as large tumor, hemorrhage, infarct, or edema, were excluded. Analysis of the brain weight of 1,261 subjects, aged 25 to 80 years, show that the mean brain weight decreases in order from white men to black men to white women to black women. These differences are statistically significant and become apparent at age 6 years. The rate of decrease for the brain weight after age 25 years is highest for white men, followed by black women, white women, and black men, and, except that between white men and white women, the differences are statistically insignificant. Contrary to earlier reports, the mass decreases rapidly after age 80 years. In evaluating an individual brain weight, it is important to compare it with the norm for each subgroup of a given age.

Adult↗
PubMed1995

Perinatal brain injury in premature infants born to mothers using alcohol in pregnancy. Neonatal Brain Hemorrhage Study Team.

OBJECTIVE: Alcohol has been shown to have teratogenic effects on the fetal central nervous system. However, little research has been done to assess the impact of prenatal alcohol exposure on premature infants, a group particularly vulnerable to perinatal brain injury. METHODS: We examined the relation between maternal alcohol use and the most common forms of brain injury in premature infants--germinal matrix/intraventricular hemorrhage (GM/IVH) and white-matter damage--in a large population-based cohort of infants weighing 2000 g or less. The analyses included 349 infants younger than 31 weeks' gestation who received at least one cranial ultrasound scan and whose mothers were queried about prenatal alcohol use in a postpartum interview. RESULTS: Infants of mothers who reported "moderate" alcohol use (fewer than seven drinks per week and fewer than three drinks per occasion) to "high" use (seven or more drinks per week and/or three or more drinks per occasion) before recognized pregnancy, and moderate alcohol use during pregnancy, were not at increased risk for brain injury. However, after controlling for potentially confounding factors, infants of women reporting high alcohol use during pregnancy were at increased risk of developing isolated brain hemorrhage (odds ratio [OR] = 5.5, 95% confidence interval [CI] = 1.2, 24.7), any brain hemorrhage (OR = 6.7, 95% CI = 1.8, 26.4), and white-matter damage (OR = 9.5, 95% CI = 1.9, 46.4). CONCLUSION: Premature infants of women who report consuming seven or more drinks per week and/or three or more drinks per occasion during pregnancy have substantially elevated risks of both of the most common forms of brain injury in premature infants.

Alcohol Drinking↗
PubMed1993

Determination of creatine kinase kinetic parameters in rat brain by NMR magnetization transfer. Correlation with brain function.

The pseudo first-order rate constant kf of the creatine kinase (CK) forward reaction as well as the CK forward flux FCK,f have been shown to correlate better with cardiac performance than the steady-state levels of ATP and PCr (Bittl, J. A., and Ingwall, J. S. (1985) J. Biol. Chem. 260, 3512-3517). In order to elucidate the relationship between the CK kinetic parameters and brain activity, we have determined, using the non-invasive NMR technique of magnetization transfer, kf and FCK,f in rats, in which brain activity was experimentally varied by administration of either thiopental sodium or bicuculline to decrease or increase electro-encephalogram (EEG) intensity, respectively. The steady-state levels of ATP and PCr, as well as the accumulation of deoxyglucose 6-phosphate (DG-6P) in brain following intraperitoneal administration of deoxyglucose, were determined simultaneously by the NMR technique, whereas the cortical EEG was recorded in a separate experiment. The EEG intensity (range, 1-20 Hz), taken as a measure for brain performance, as well as the amount of DG-6P formed in brain, reflecting the synthesis rate of high energy phosphates (ATP and PCr), linearly correlated with kf. Despite large changes in both EEG intensity (50-250%) and kf (0.12-0.69 s-1) between thiopental sodium- and bicuculline-treated rats, the ATP levels remained constant, whereas the PCr levels decreased with high EEG activity. In contrast to the expectation based on model calculations of CK kinetics, the PCr levels did not increase above control values at reduced EEG intensity (50% of controls). At EEG intensities exceeding control values (bicuculline-treated rats) FCK,f increased as predicted by CK equilibrium. In conclusion, we have shown that in the rat brain, like in the heart, the CK forward rate constant kf, in contrast to ATP and PCr levels, is a sensitive reliable indicator of both increased and reduced function.

Adenosine Triphosphate↗
PubMed2000

Growth hormone in the brain: characteristics of specific brain targets for the hormone and their functional significance.

During the past decade studies have shown that growth hormone (GH) may exert profound effects on the central nervous system (CNS). For instance, GH replacement therapy was found to improve the psychological capabilities in adult GH deficient (GHD) patients. Furthermore, beneficial effects of the hormone on certain functions, including memory, mental alertness, motivation, and working capacity, have been reported. Likewise, GH treatment of GHD children has been observed to produce significant improvement in many behavioral problems seen in these individuals. Studies also indicated that GH therapy affects the cerebrospinal fluid levels of various hormones and neurotransmitters. Further support that the CNS is a target for GH emerges from observations indicating that the hormone may cross the blood-brain barrier (BBB) and from studies confirming the presence of GH receptors in the brain. It was previously shown that specific binding sites for GH are present in discrete areas in the CNS of both humans and rats. Among these regions are the choroid plexus, hippocampus, hypothalamus, and spinal cord. The density of GH binding in the various brain regions was found to decline with increasing age. More recently, we were able to clone and determine the structure of several GH receptors in the rat and human brain. Although the brain receptor proteins for the hormone were shown to differ in molecular size compared to those present in peripheral tissues the corresponding transcripts did not seem to differ from their peripheral congeners. GH receptors in the hypothalamus are likely to be involved in the regulatory mechanism for hormone secretion and those located in the choroid plexus have been suggested to have a role in the receptor-mediated transport of GH across the BBB. The functions mediated by the GH receptors identified in the hippocampus are not yet known but recently it was speculated that they may be involved in the hormone's action on memory and cognitive functions.

Animals↗
PubMed2006

Ex vivo measurement of brain tissue viscoelasticity in postischemic brain edema.

Knowledge of the biomechanical properties of postischemic brain tissue is important for understanding the mechanisms of postischemic secondary brain tissue injury. We describe the method and results of biomechanical property measurement in ex vivo postischemic brain tissue by applying an indentation method. Mongolian gerbils were subjected to a transient unilateral hemispheric ischemia. At day 1 after ischemia, multi-parametric MRI was performed, the brain was removed under anesthesia, sliced, and kept in a container with silicone oil for the measurement. A compression probe attached to a pressure transducer was inserted to a pre-determined depth at the regions of interest and maintained at a constant speed. A pressure relaxation curve was recorded for the calculation of elasticity modulus (E) and viscosity modulus (eta) according to Maxwell-Voigt's 3-element model. One day after ischemia, E and eta decreased to 78.7% and 73.1% of the control level, respectively. This decrease corresponded to a mild decrease in apparent diffusion coefficient (ADC) and magnetization transfer ratio, and an increase in T2 value. Tissue water content increased to 105.1% of control. Microvacuolation with demyelination and axonal disruption was evident in the postischemic brain tissue.

Animals↗
PubMed1997

Changes of MPO activity and brain water accumulation in traumatic brain injury experiments.

Comparison of brain tissue water content (BWC) data with myeloperoxidase activity assay (MPO) allows for analysis of the complex pathophysiological mechanisms of cerebral edema following catastrophic brain injuries. The neuroprotective effect of an experimental anti inflammatory drug (FL1003, butyrolactone) was tested in a traumatic brain injury (TBI) model using BWC and MPO analysis. We conducted these studies on a mini-pig model of severe TBI that is well characterized in our laboratory. The animals were divided into three animal groups: no injury, no treatment (control), injured and treated with FL1003, and injured, untreated with FL1003. They were maintained with fluids for 24 hours under general anesthesia. We employed the MPO assay to identify the degree of inflammatory cellular response (polymorphonuclear leukocytes, PMNLs) 24 hours following TBI and calculated brain density from the data of the gravimetric (Percoll) column method for BWC on brain samples. Our results demonstrated increased infiltration of PMNLs and a shift of water into the extravascular space in the injured animals. These changes were significantly (P < 0.05) attenuated in the animal group treated with FL1003.

4-Butyrolactone↗
PubMed1990

Perifocal brain oedema in experimental brain abscess in rats.

An experimental cerebral abscess model in which staphylococcus aureus was inoculated into the brain parenchyma of rats was evaluated for perifocal brain oedema. Blood-brain barrier permeability was studied using various kinds of tracers; sodium fluorescein as a small molecule and Evans blue and HRP as macromolecular tracers. Brain abscess with clear delineation of fibrous capsule formation were found in all animals. Extravasation of tracers was demonstrated in the capsule (Evans blue), extracellular space (HRP) and white matter (sodium fluorescein). There were two types of oedema formation, so called vasogenic oedema and cytotoxic brain oedema.

Animals↗
PubMed1994

Formation and resolution of brain edema associated with brain tumors. A comprehensive theoretical model and clinical analysis.

The purpose of this study is to quantify the relative contribution of the mechanisms in the absorption of edema fluid. The convection/diffusion and the comprehensive bulk flow model were applied for the finite element analysis of peritumoral brain edema. For clinical analysis, 90 meningiomas studied by MRI were selected. Serial CT scan and MRI were performed at 0, 2, 4, 6 hours after injection of Iopamidol or Gadpenteic acid respectively. Then the tracer distributions in the edematous brain was analyzed. The tracer movement in the brain is well represented by the convection/diffusion equation. The absence of the preferential fluid flow directing toward the ventricle indicates that a limited role of CSF sink action into the ventricle. From capillary surface area (240 cm2/g brain), capillary hydraulic conductivity (1.8 x 10(-8) ml/cmH2O/cm2/min) and the simulated average tissue pressure of 9.8 mmHg, maximum absorption rate into capillaries was estimated to be 0.003 ml/h/cm3 brain tissue. Considering the limited role of edema fluid clearance into the ventricle, the results indicate a possible role of subarachnoid CSF space for the clearance of edema fluid. The clearance of edema fluid into subarachnoid CSF space should be studied quantitatively. Finally, unification of the convection/diffusion and the comprehensive bulk flow model will provide a more quantitative analysis of edema formation and resolution by using MRI and tracer studies.

Blood-Brain Barrier↗
PubMed1987

Blood-brain barrier leakage and brain edema in stroke-prone spontaneously hypertensive rats. Effect of chronic sympathectomy and low protein/high salt diet.

Brain edema associated with severe chronic hypertension was studied in stroke-prone spontaneously hypertensive rats (SHRSP), 5 to 9 months of age. Blood-brain barrier (BBB) leakage sites and intracerebral spreading pathways for plasma proteins were delineated by an intravenously (i.v.) injected exogenous dye tracer (Evans blue), known to form a complex with albumin in blood, and by immunohistochemical visualization of extravasated endogenous plasma proteins. The tissue content of edema fluid was estimated by measuring the specific gravity of selected brain regions, stained or unstained by the tracer dye, on a bromobenzene-kerosene gradient column. Multifocal BBB leakage sites were macroscopically detected within the cerebral cortex and the deep gray matter after i.v. circulation of Evans blue-albumin for 30 min. After 24 h of i.v. circulation the dye tracer had spread not only locally in the gray matter but also into the adjacent white matter, where it was widely distributed. Immunohistochemically visualized plasma proteins showed similar distribution. Unilateral superior cervical ganglionectomy performed at 4 weeks of age neither increased the incidence of major BBB opening to Evans blue-albumin nor altered the specific gravity of the ipsilateral cerebral hemisphere in grown-up SHRSP, furthermore, the blood pressure remained unchanged. The lack of significant effect on BBB function may possibly be attributed to the extensive reinnervation of the cerebral arteries, verified in the grown-up SHRSP using the Falck-Hillarp fluorescence method for visualization of catecholaminergic nerve fibers. In SHRSP raised on a low-protein and high-salt diet the mean arterial blood pressure was 212 mm Hg compared to 195 mm Hg in controls (P less than 0.05) and the incidence of BBB opening was 72% compared to 25% in controls (P less than 0.05). After 24 h of i.v. circulation of Evans blue-albumin, brain regions stained by the dye tracer showed significantly reduced specific gravity (P less than 0.001), while unstained regions had normal values. Thus the brain edema fluid spread, as revealed by specific gravity measurements, corresponded to the intracerebral distribution of extravasated plasma proteins.

Animals↗
PubMed2006

Blood-brain barrier interfaces and brain tumors.

In the developing brain, capillaries are differentiated and matured into the blood-brain barrier (BBB), which is composed of cerebral endothelial cells, astrocyte end-feet, and pericytes. Since the BBB regulates the homeostasis of central nervous system (CNS), the maintenance of the BBB is important for CNS function. The disruption of the BBB may result in many brain disorders including brain tumors. However, the molecular mechanism of BBB formation and maintenance is poorly understood. Here, we summarize recent advances in the role of oxygen tension and growth factors on BBB development and maintenance, and in BBB dysfunction related with brain tumors.

Animals↗