Chronic hyperglycemia and intracranial meningiomas.

Meningiomas are among the most common primary tumors of the central nervous system. Previous research into the meningioma histological appearance, genetic markers, transcriptome and epigenetic landscape has revealed that benign meningiomas significantly differ in their glucose metabolism compared to aggressive lesions. However, a correlation between the systemic glucose metabolism and the metabolism of the tumor hasn't yet been found. We hypothesized that chronic levels of glycaemia (approximated with glycated hemoglobin (HbA1c)) are different in patients with aggressive and benign meningiomas. The study encompassed 71 patients with de novo intracranial meningiomas, operated on in three European hospitals, two in Croatia and one in Spain. Our results show that patients with WHO grade 2 meningiomas had significantly higher HbA1c values compared to patients with grade 1 lesions (P = 0.0290). We also found a significant number of patients (19/71; 26.7%) being hyperglycemic, harboring all the risks that such a condition entails. Finally, we found a significant correlation between our patients' age and their preoperative HbA1c levels (P = 0.0008, ρ(rho) = 0.388), suggesting that older meningioma patients are at a higher risk of having their glycaemia severely dysregulated. These findings are especially important considering the current routine and wide-spread use of corticosteroids as anti-edematous treatment. Further research in this area could lead to better understanding of meningiomas and have immediate clinical impact.

"Compensated hyperosmolarity" of cerebrospinal fluid and the development of hydrocephalus.

Acute osmolar loading of cerebrospinal fluid within one lateral ventricle of dogs was examined as a cause of water extraction from the bloodstream and an increase in intracranial pressure. We have shown that a certain amount of (3)H2O from the bloodstream enters osmotically loaded cerebrospinal fluid significantly faster, hence causing a significant increase in intracranial pressure. The noted phenomenon in which intracranial pressure still significantly increases, but in which the hyperosmolarity of the cerebrospinal fluid is no longer present, was named "compensated hyperosmolarity". In the case of the sub-chronic application of hyperosmolar solutions into cat ventricles, we observed an increase in cerebrospinal fluid volume and a more pronounced development of hydrocephalus in the area of application, but without significant increase in intracranial pressure and without blockage of cerebrospinal fluid pathways. These results support the newly proposed hypothesis of cerebrospinal fluid hydrodynamics and the ability to develop new strategies for the treatment of cerebrospinal fluid-related diseases.

Development of hydrocephalus and classical hypothesis of cerebrospinal fluid hydrodynamics: facts and illusions.

According to the classical hypothesis of the cerebrospinal fluid (CSF) hydrodynamics, CSF is produced inside the brain ventricles, than it circulates like a slow river toward the cortical subarachnoid space, and finally it is absorbed into the venous sinuses. Some pathological conditions, primarily hydrocephalus, have also been interpreted based on this hypothesis. The development of hydrocephalus is explained as an imbalance between CSF formation and absorption, where more CSF is formed than is absorbed, which results in an abnormal increase in the CSF volume inside the cranial CSF spaces. It is believed that the reason for the imbalance is the obstruction of the CSF pathways between the site of CSF formation and the site of its absorption, which diminishes or prevents CSF outflow from the cranium. In spite of the general acceptance of the classical hypothesis, there are a considerable number of experimental results that do not support such a hypothesis and the generally accepted pathophysiology of hydrocephalus. A recently proposed new working hypothesis suggests that osmotic and hydrostatic forces at the central nervous system microvessels are crucial for the regulation of interstial fluid and CSF volume which constitute a functional unit. Based on that hypothesis, the generally accepted mechanisms of hydrocephalus development are not plausible. Therefore, the recent understanding of the correlation between CSF physiology and the development of hydrocephalus has been thoroughly presented, analyzed and evaluated, and new insights into hydrocephalus etiopathology have been proposed, which are in accordance with the experimental data and the new working hypothesis.

The formation of cerebrospinal fluid: nearly a hundred years of interpretations and misinterpretations.

The first scientific and experimental approaches to the study of cerebrospinal fluid (CSF) formation began almost a hundred years ago. Despite researchers being interested for so long, some aspects of CSF formation are still insufficiently understood. Today it is generally believed that CSF formation is an active energy consuming metabolic process which occurs mainly in brain ventricles, in choroid plexuses. CSF formation, together with CSF absorption and circulation, represents the so-called classic hypothesis of CSF hydrodynamics. In spite of the general acceptance of this hypothesis, there is a considerable series of experimental results that do not support the idea of the active nature of CSF formation and the idea that choroid plexuses inside the brain ventricles are the main places of formation. The main goal of this review is to summarize the present understanding of CSF formation and compare this understanding to contradictory experimental results that have been obtained so far. And finally, to try to offer a physiological explanation by which these contradictions could be avoided. We therefore analyzed the main methods that study CSF formation, which enabled such an understanding, and presented their shortcomings, which could also be a reason for the erroneous interpretation of the obtained results. A recent method of direct aqueductal determination of CSF formation is shown in more detail. On the one hand, it provides the possibility of direct insight into CSF formation, and on the other, it clearly indicates that there is no net CSF formation inside the brain ventricles. These results are contradictory to the classic hypothesis and, together with other mentioned contradictory results, strongly support a recently proposed new working hypothesis on the hydrodynamics of CSF. According to this new working hypothesis, CSF is permanently produced and absorbed in the whole CSF system as a consequence of filtration and reabsorption of water volume through the capillary walls into the surrounding brain tissue. The CSF exchange between the entire CSF system and the surrounding tissue depends on (patho)physiological conditions that predominate within those compartments.

New experimental model of acute aqueductal blockage in cats: effects on cerebrospinal fluid pressure and the size of brain ventricles.

It is generally assumed that cerebrospinal fluid (CSF) is secreted in the brain ventricles, and so after an acute blockage of the aqueduct of Sylvius an increase in the ventricular CSF pressure and dilation of isolated ventricles may be expected. We have tested this hypothesis in cats. After blocking the aqueduct, we measured the CSF pressure in both isolated ventricles and the cisterna magna, and performed radiographic monitoring of the cross-sectional area of the lateral ventricle. The complete aqueductal blockage was achieved by implanting a plastic cannula into the aqueduct of Sylvius through a small tunnel in the vermis of the cerebellum in the chloralose-anesthetized cats. After the reconstitution of the occipital bone, the CSF pressure was measured in the isolated ventricles via a plastic cannula implanted in the aqueduct of Sylvius and in the cisterna magna via a stainless steel cannula. During the following 2 h, the CSF pressures in the isolated ventricles and cisterna magna were identical to those in control conditions. We also monitored the ventricular cross-sectional area by means of radiography for 2 h after the aqueductal blockage and failed to observe any significant changes. When mock CSF was infused into isolated ventricles to imitate the CSF secretion, the gradient of pressure between the ventricle and cisterna magna developed, and disappeared as soon as the infusion was terminated. However, when mock CSF was infused into the cisterna magna at various rates, the resulting increased subarachnoid CSF pressure was accurately transmitted across the brain parenchyma into the CSF of isolated ventricles. The lack of the increase in the CSF pressure and ventricular dilation during 2 h of aqueductal blockage suggests that aqueductal obstruction by itself does not lead to development of hypertensive acute hydrocephalus in cats.

Spinal contribution to CSF pressure lowering effect of mannitol in cats.

OBJECTIVES: After application of hyperosmolar mannitol the cerebrospinal (CSF) pressure is usually lowered within 30 min but this effect cannot be explained either by changes in intracranial blood volume and flow or by changes in brain volume. We assume that this effect of mannitol my be consequence of CSF volume decrease primarily in the spinal CSF due to high compliance of the spinal dura. METHODS: To explore such a possibility we planned to separate spinal and cerebral CSF. In chloralose anaesthetized cats dorsal laminectomy of C2 vertebrae was performed and a plastic semi ring was positioned extradurally separating cranial and spinal CSF. CSF pressures were recorded via cannulas positioned in lateral ventricle and lumbar subarachnoid space at L3 vertebrae, respectively. RESULTS: After intravenous bolus of 20% mannitol (0.5 or 1.0 g/kg/ 3 min) in control animals without cervical stenosis, the fall of both ventricular and lumbar CSF pressures was equal over time. At 15 min after mannitol application in cats with cervical stenosis an slight increase of ventricular and a fall of lumbar CSF pressures were observed, while at 30 min a gradient of these pressures of 5.5 and 7 cm H2O at lower and higher dose of mannitol, respectively, were registered. However, after removal of cervical stenosis these gradients disappeared. CONCLUSION: The observed changes of CSF pressures in spinal and intracranial space indicate that spinal subarachnoid space contributes a great deal to overall fall of CSF pressure and volume in the early period after mannitol application probably due to high compliance of the spinal dura.

Does the secretion and circulation of the cerebrospinal fluid really exist?

The secretion and circulation of cerebrospinal fluid have been studied in anaesthetized cats by means of a plastic cannula introduced into the aqueduct of Sylvius and by inspection of free escape of cerebrospinal fluid out of the end of the cannula. The fact that during the 120-minute period of observation not a single drop of CSF escaped out of the cannula, at physiological pressure, indicates that cerebrospinal fluid does neither secrete nor circulate.

Physiological characteristics of platelet/circulatory serotonin: study on a large human population.

The aim of this work was the study of platelet/circulatory serotonin (5-hydroxytryptamine, 5-HT), specifically alternative ways of its measurement and main physiological characteristics. The study was performed on a large human population (N=500) of blood donors of both sexes over the course of a longer time period (17 months). Owing to the heterogeneity in measurement of circulatory serotonin encountered in the literature, three ways of expression were comparatively studied: per unit number of platelets, per unit mass of platelet protein and per unit volume of whole blood. Results demonstrated unimodal distribution of individual frequencies of platelet/circulatory serotonin in the human population with the mean values of 579+/-169 ng 5-HT/10(9) platelets; 332+/-89.9 ng 5-HT/mg protein and 130+/-42.3 ng 5-HT/ml blood (mean+/-S.D.). A progressive decrease of serotonin level with age (18-65 years) was demonstrated, reaching statistical significance between the extreme age groups. No significant differences in the serotonin level between the sexes were observed. No seasonal oscillations in platelet/circulatory serotonin were found. Platelet serotonin demonstrated intra-individual stability over time. Finally, regarding the methodology of measurement, our results demonstrated a good correlation among the above-mentioned ways of expression of platelet/circulatory serotonin. This indicates the possibility of intercomparison of the literature reports expressing this physiological parameter either as 5-HT concentration in platelets or as 5-HT level in the circulation.

Effect of intracranial pressure on cerebrospinal fluid formation in isolated brain ventricles.

The effect of intracranial pressure on cerebrospinal fluid formation has been studied in cats by ventricular perfusion with the aqueduct of Sylvius blocked (isolated ventricular perfusion). It has been found that intracranial pressure has a considerable effect on the rate of cerebrospinal fluid formation, while increases in pressure cause a significant and prolonged decrease in cerebrospinal fluid formation. The effect was observed in animals whether they were initially perfused under lower or under higher intracranial pressure. Cerebrospinal fluid absorption has been studied under the above conditions and it has been noted that the ventricles are capable of significant cerebrospinal fluid absorption, since in isolated ventricles cerebrospinal fluid formation and absorption were in balance at physiological intracranial pressure. In addition, cerebrospinal fluid formation rate within the isolated brain ventricles has been compared with the formation rate in the whole cerebrospinal fluid system. Since only about 30% of the total cerebrospinal fluid formation was observed by isolated ventricular perfusion, it seems that the brain ventricles are not the exclusive site of cerebrospinal fluid formation.

Plasma level of dipropylacetamide and dipropylacetic acid and effect of these drugs on 5-hydroxytryptamine metabolism in mouse brain.

After intraperitoneal application of the antiepileptics dipropylacetamide (DPM, 200 mg/kg) and dipropylacetic acid (DPA, 200 mg/kg) in mice their concentration in plasma and their effects on 5-hydroxytryptamine (5-HT) metabolism in the brain were followed during 360 minutes. Peak plasma level of DPA and DPM was observed at 30 minutes, but level of DPM was only about 25% that of DPA. Plasma content of both drugs declined to low levels by 360 minutes. Both drugs increased brain content of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA). After DPA application 5-HIAA level increased rapidly and had returned to control value by 360 minutes, while following DPM 5-HIAA increase was much more gradual and was more prolonged. Neither DPM nor DPA significantly altered brain 5-HT content. An apparent relationship between DPA plasma level and brain 5-HIAA content was observed while after DPM no association between plasma drug content and effect on cerebral 5-HT metabolism was seen.

Effect of valproic acid on 5-hydroxytryptamine turnover in mouse brain.

The effect of the antiepileptic drug valproic acid (di-n-propylacetic acid, 200 mg kg-1) on brain 5-hydroxytryptamine (5-HT) synthesis during monoamine oxidase inhibition by pargyline hydrochloride (120 mg kg-1) was studied in mice. Valproic acid increased 5-HT synthesis and elevated 5-hydroxyindoleacetic acid level in brain indicating that turnover of 5-HT is increased. The possible significance of this effect in relation to anticonvulsant action of valproic acid is discussed.

Effect of the antiepileptic di-n-propylacetamide on 5-hydroxytryptamine turnover in the brain and 5-hydroxyindoleacetic acid level in the cerebrospinal fluid.

The effect of antiepileptic drug di-n-propylacetamide (DPM) on 5-hydroxytryptamine (5-HT) turnover in rat brain and 5-hydroxyindoleacetic acid (5-HIAA) in cat cerebrospinal fluid (CSF) was investigated. DPM (200 mg/kg) increased brain 5-HIAA without altering the 5-HT level. DPM augmented the accumulation of 5-HT induced by monoamine oxidase inhibition with pargyline (80 mg/kg) and enhanced the accumulation of 5-HIAA in the brain following blockade of transport of this metabolite by probenecid (200 mg/kg). Prior inhibition of 5-HT synthesis by p-chlorophenylalanine (300 mg/kg) abolished the DPM-induced increase in cerebral 5-HIAA. DPM (100 mg/kg) given daily for 5 days considerably elevated 5-HIAA in the CSF of cat during the treatment period. We conclude that DPM increases the turnover of 5-HT in brain and that this can be observed by monitoring the 5-HIAA content of CSF.

Distribution of vipera ammodytes toxic phospholipase A in the cat and its ability to cross the blood-brain barrier.

Several phospholipases A could be isolated from the venom of the European viper, Vipera ammodytes, having different specific activities toward egg lecithin and different lethalities. The most lethal of these enzymes is fraction "k2" having an intravenous LD50 for white mice of 0.021 mg per kg and a specific activity of 280 microM/min mg at 40 degrees C. The enzyme could be labeled with 131I without loosing its enzymatic activity and lethality. The passage of this enzyme from blood into cerebrospinal fluid (CSF) was followed in anesthetized cats. Approximately 1% of the blood level of the enzyme was found in CSF indicating the ability of this protein to penetrate the blood-brain barrier. Although the lethality of fraction "k2" becomes as low as 0.085 microgram/kg when applied intraventricularly, it is not very likely that the central effects of this fraction are of major importance in envenomation since the distribution pattern of the labeled enzyme shows that most of the protein remains in liver, lungs and kidneys, presumably non-selectively bound to membranes and only 0.2% of the injected fraction can reach the brain. Relatively high amount of enzyme was also found in the diaphragm. The penetration of the blood-brain barrier of the radiolabeled phospholipase is within the limits for the proteins of this size (M.w. 14500).