Publications by authors named "Marijan Klarica"

35 Publications

Is there a better future of healthy aging?

Croat Med J 2020 04;61(2):75-78

Mirjana Kujundžić Tiljak, Andrija Štampar School of Public Health, University of Zagreb School of Medicine, Zagreb, Croatia,

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230424PMC
April 2020

The Movement of Cerebrospinal Fluid and Its Relationship with Substances Behavior in Cerebrospinal and Interstitial Fluid.

Neuroscience 2019 08 3;414:28-48. Epub 2019 Jul 3.

Ruđer Bošković Institute, Department of Molecular Biology, Zagreb, Croatia. Electronic address:

The cerebrospinal fluid (CSF) movement and its influence on substance distribution and elimination from the CSF system have been thoroughly analyzed and discussed in the light of the new hypothesis of CSF physiology. As a result, CSF movement is not presented as a circulation, but a permanent rhythmic systolic-diastolic pulsation in all directions. Such movement also represents the main force of substance distribution inside the CSF system. This distribution occurs in all directions, i.e., in the direction of the imagined circulation, as well as in the opposite direction, and depends on the application site and the resident time of tested substance, where longer resident time means longer distribution distance. Transport mechanisms situated on the microvessels inside the central nervous system (CNS) parenchyma play the key role in substance elimination from the CSF and interstitial fluid (ISF) compartments, which freely communicate. If a certain transport mechanism is not available at one site, the substance will be distributed by CSF movement along the CSF system and into the CNS region where that transport mechanism is available. Pharmacological manipulation suggests that the residence time and the substance travel distance along the CSF system depend on the capacity of transport mechanisms situated on CNS blood capillaries. Physiological absorption of the CSF into the venous sinuses and/or lymphatics, due to their small surface area, should be of minor importance in comparison with the huge absorptive surface area of the microvessel network.
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http://dx.doi.org/10.1016/j.neuroscience.2019.06.032DOI Listing
August 2019

The role of the University of Zagreb School of Medicine in the development of education, health care, and science in Croatia.

Authors:
Marijan Klarica

Croat Med J 2018 Oct;59(5):185-188

Marijan Klarica, Dean of the University of Zagreb School of Medicine, Zagreb, Croatia,

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240824PMC
October 2018

New Insight into the Mechanism of Mannitol Effects on Cerebrospinal Fluid Pressure Decrease and Craniospinal Fluid Redistribution.

Neuroscience 2018 11 29;392:164-171. Epub 2018 Sep 29.

Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia. Electronic address:

Intracranial hypertension, which often follows a severe brain injury, is usually treated with intravenous (i.v.) application of hyperosmolar solutions. The mechanism of intracranial cerebrospinal fluid (CSF) pressure decrease after such a treatment is still unclear. The aim of this article was to try to explain the mechanism of CSF pressure reduction after i.v. hyperosmolar mannitol bolus in regard to the changes in CSF volume. Two types of experiments were done on anesthetized cats before and after hyperosmolar mannitol application: ventriculo-cisternal perfusion at different perfusion rates, simultaneously measuring the perfusate outflow volume, and CSF pressure recording in the lateral ventricle before and during artificial CSF infusion. Mannitol application in the first group of cats significantly reduced collected prefusate volume during ventriculo-cisternal perfusion, and in the second group it prevented CSF pressure increase caused by artificial CSF infusion. Our results strongly suggest that the mechanism of hyperosmolar mannitol action after its i.v. application is based on osmotic fluid retrieval from interstitial and cerebrospinal compartments into the microvessels. This shift, without significant volume change inside the cranium, causes a predominant decrease of CSF volume in the spinal part of the system, which in turn leads to lowering of the CSF pressure. Spinal CSF volume decrease is enabled by the extensibility of the spinal dura, this way providing the possibility for CSF volume redistribution inside the CSF system, together with CSF pressure decrease. This mechanism of mannitol action is in accordance with the new hypothesis of CSF physiology.
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http://dx.doi.org/10.1016/j.neuroscience.2018.09.029DOI Listing
November 2018

Reply to Comment on "Role of Choroid Plexus in Cerebrospinal Fluid Hydrodynamics".

Neuroscience 2018 06 7;380:165. Epub 2018 Mar 7.

Ruđer Bošković Institute, Department of Molecular Biology, Zagreb, Croatia; Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.

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http://dx.doi.org/10.1016/j.neuroscience.2018.02.040DOI Listing
June 2018

The recent state of a hundred years old classic hypothesis of the cerebrospinal fluid physiology.

Croat Med J 2017 Dec;58(6):381-383

Darko Orešković, Ruđer Bošković Institute, Department of Molecular Biology, Zagreb, Croatia,

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778680PMC
http://dx.doi.org/10.3325/cmj.2017.58.381DOI Listing
December 2017

Role of choroid plexus in cerebrospinal fluid hydrodynamics.

Neuroscience 2017 06 27;354:69-87. Epub 2017 Apr 27.

Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine University of Zagreb, Zagreb, Croatia. Electronic address:

The classic hypothesis presents the cerebrospinal fluid (CSF) as the "third circulation," which flows from the brain ventricles through the entire CSF system to the cortical subarachnoid space to eventually be passively absorbed into the superior sagittal sinus through arachnoid granulations. The choroid plexus (CP) represents a key organ in the classic CSF physiology and a powerful biological pump, which exclusively secretes CSF. Thereby, the CP is considered to be responsible for CSF pressure regulation and hydrocephalus development. This article thoroughly analyzes the role of the CP in the CSF dynamics, presenting arguments in favor of the thesis that the CPs are neither biological pumps nor the main site of CSF secretion; that they do not participate in regulation of ICP/CSF pressure; are not the reason for the existence of hydrostatic pressure gradient in the CSF system and that this gradient is not permanent (disappeared in the horizontal position); and that they do not generate imagined unidirectional CSF circulation, hydrocephalus development and increased ICP/CSF pressure. The classic hypothesis cannot provide an explanation for these controversies but the recently formulated Bulat-Klarica-Orešković hypothesis can. According to this hypothesis, CSF production and absorption (CSF exchange) are constant and present everywhere in the CSF system, and although the CSF is partially produced by the CP, it is mainly formed as a consequence of water filtration between the capillaries and interstitial fluid.
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http://dx.doi.org/10.1016/j.neuroscience.2017.04.025DOI Listing
June 2017

New Concepts of Cerebrospinal Fluid Physiology and Development of Hydrocephalus.

Pediatr Neurosurg 2017 21;52(6):417-425. Epub 2016 Dec 21.

Department of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia.

The goal of this review is the presentation of the new (Bulat-Klarica-Orešković) hypothesis of cerebrospinal fluid (CSF) physiology and the ensuing new concept of hydrocephalus development in light of this hypothesis. The widely accepted classic hypothesis of CSF physiology and the traditional concept of hydrocephalus are contradicted by numerous experimental and clinical data, which consequently results in unsatisfying clinical treatment and patient recovery. Therefore, the newly presented concept of hydrocephalus development and possible future treatments are discussed. A new definition suggests that hydrocephalus is a pathological state in which CSF is excessively accumulated inside the cranial part of the CSF system, predominantly in one or more brain ventricles as a consequence of impaired hydrodynamics of intracranial fluids between CSF, brain, and blood compartments.
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http://dx.doi.org/10.1159/000452169DOI Listing
August 2018

Cerebrospinal fluid secretion by the choroid plexus?

Physiol Rev 2016 10;96(4):1661-2

Ruđer Bošković Institute, Department of Molecular Biology, Zagreb, Croatia; and Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine University of Zagreb, Zagreb, Croatia.

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http://dx.doi.org/10.1152/physrev.00021.2016DOI Listing
October 2016

The effects of lumboperitoneal and ventriculoperitoneal shunts on the cranial and spinal cerebrospinal fluid volume in a patient with idiopathic intracranial hypertension.

Croat Med J 2016 Jun;57(3):293-7

Marijan Klarica, School of Medicine University of Zagreb, Department of Pharmacology and Croatian Institute for Brain Research, Šalata 11, 10 000 Zagreb, Croatia,

Lumboperitoneal (LP) and ventriculoperitoneal (VP) shunts are a frequent treatment modality for idiopathic intracranial hypertension (IIH). Although these shunts have been used for a long time, it is still not clear how they change the total craniospinal CSF volume and what portions of cranial and spinal CSF are affected. This report for the first time presents the results of a volumetric analysis of the total cranial and spinal CSF space in a patient with IIH. We performed an automated segmentation of the cranial and a manual segmentation of the spinal CSF space first with an LP shunt installed and again after the LP shunt was replaced by a VP shunt. When the LP shunt was in place, the total CSF volume was smaller than when the VP shunt was in place (222.4 cm(3) vs 279.2 cm(3)). The difference was almost completely the result of the spinal CSF volume reduction (49.3 cm(3) and 104.9 cm(3) for LP and VP, respectively), while the cranial CSF volume was not considerably altered (173.2 cm(3) and 174.2 cm(3) for LP and VP, respectively). This report indicates that LP and VP shunts in IIH do not considerably change the cranial CSF volume, while the reduction of CSF volume after LP shunt placement affects almost exclusively the spinal part of the CSF system. Our results suggest that an analysis of both the cranial and the spinal part of the CSF space is necessary for therapeutic procedures planning and for an early recognition of numerous side effects that often arise after shunts placement in IIH patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937228PMC
http://dx.doi.org/10.3325/cmj.2016.57.293DOI Listing
June 2016

Monoamine Neurotransmitter Metabolite Concentration as a Marker of Cerebrospinal Fluid Volume Changes.

Acta Neurochir Suppl 2016 ;122:283-6

Department of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia.

Objective: In our previous papers we demonstrated that changes in blood and cerebrospinal fluid (CSF) osmolarity have a strong influence on CSF pressure and volume, which is in accordance with a new proposed hypothesis of CSF physiology. Thus, acute changes in CSF volume should be reflected in the CSF concentration of different central nervous system (CNS) metabolites.

Methods: In anesthetized cats (n = 4) we measured the outflow volume of CSF by cisternal free drainage at a negative CSF pressure (-10 cmH2O) before and after the intraperitoneal (i.p.) application of a hypo-osmolar substance (distilled water). In samples of CSF collected at different time intervals (30 min) we measured the concentration of homovanillic acid (HVA).

Results: In spite of fact that constant CSF outflow volume was obtained after a 30-min period in our model, the concentration of HVA gradually increased over time and became stable after 90 min. After the i.p. application of distilled water the outflow CSF volume increased significantly, whereas the concentration of HVA significantly decreased over 30 min.

Conclusions: The results observed suggest that alterations in serum osmolarity change the CSF volume and concentrations of neurotransmitter metabolites because of the osmotic arrival of water from CNS blood capillaries in all CSF compartments.
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http://dx.doi.org/10.1007/978-3-319-22533-3_56DOI Listing
July 2017

The Effect of Body Position on Intraocular and Intracranial Pressure in Rabbits.

Acta Neurochir Suppl 2016 ;122:279-82

Department of Molecular Biology, Rudjer Boskovic Institute, Zagreb, Croatia.

Background: The correlation between cerebrospinal fluid (CSF) and intraocular pressure (IOP) is still unclear. We compared CSF and IOP measured by the same invasive technique using a new experimental model in rabbits during changes of body position.

Methods: Pressure changes were recorded in the lateral ventricle (LV), the cortical subarachnoid space (CSS), and the anterior ocular chamber of anesthetized rabbits (n = 12). Animals and measuring instruments were both fixed on a board at an adequate hydrostatic level.

Results: In a horizontal position, control IOP (15.1 ± 1.6 cmH2O) and CSF pressure in the LV (12.4 ± 0.6 cmH2O) and CSS (12.2 ± 0.9 cmH2O) were similar during the 60-min period. When changing the body position from horizontal to vertical (upright), CSF pressures decreased drastically (LV = -5.5 ± 2.6 cmH2O and CSS = -7.7 ± 2.3 cmH2O), while the IOP decreased moderately (IOP = 13.3 ± 0.5 cmH2O).

Conclusion: Change in body position from horizontal to vertical causes drastic changes in CSF pressure and moderate changes in IOP. Thus, IOP is not reflected by the CSF pressure. In an upright position, the values of CSF pressure were equal to the hydrostatic distance between measuring points and the foramen magnum, which suggests that CSF pressure inside the cranium depends on its anatomical and biophysical features, and not on CSF secretion and absorption.
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http://dx.doi.org/10.1007/978-3-319-22533-3_55DOI Listing
July 2017

Experimental Spinal Stenosis in Cats: New Insight in Mechanisms of Hydrocephalus Development.

Brain Pathol 2016 11 14;26(6):701-712. Epub 2015 Dec 14.

Department of Molecular Biology, Ruđer Bošković Institute.

In our new experimental model of cervical stenosis without inflammation we have tested hypothesis that cranio-spinal communication impairment could lead to hydrocephalus development. Spinal and cranial cerebrospinal fluid (CSF) space separation was obtained with positioning of plastic semiring in epidural space at C2 level in cats. Brain ventricles planimetry, and CSF pressure recording in lateral ventricle (LV) and lumbar subarachnoid space (LSS) were performed in acute and subchronic experiments. In all experiments opening CSF pressures were normal. However, in acute experiments, an infusion of artificial CSF into the LV led to increase of CSF pressure and significant gradient pressure development between LV and LSS due to limited pressure transmission. After 3 or 6 weeks spinal cord atrophy was observed at the site of cervical stenosis, and pressure transmission from LV to LSS was improved as a consequence of spinal tissue atrophy. Planimetry of both the coronal brain slices and the ventricles' surface showed that control ventricular surface was 0.6 ± 0.1% (n = 5), and 1.6 ± 0.2% (n = 4) in animals with subchronic cervical stenosis (P < 0.002). These results support the mentioned hypothesis claiming that CSF volume cranio-spinal displacement impairment could start pathophysiological processes leading to development of hydrocephalus.
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http://dx.doi.org/10.1111/bpa.12337DOI Listing
November 2016

Fluid filtration and reabsorption across microvascular walls: control by oncotic or osmotic pressure? (secondary publication).

Croat Med J 2014 Aug;55(4):291-8

Aim: Relationships between hydrostatic and oncotic (colloid osmotic) pressures in both capillaries and interstitium are used to explain fluid filtration and reabsorption across microvascular walls. These pressures are incorporated in the Starling oncotic hypothesis of capillaries which fails, however, to explain fluid homeostasis when hydrostatic capillary pressure is high (in feet during orthostasis) and low (in lungs), or when oncotic plasma pressure is significantly decreased in experiments and some clinical states such as genetic analbuminaemia.

Methods: To explain fluid homeostasis we propose osmotic counterpressure hypothesis of capillaries which claims: 1) during water filtration across microvascular wall in arterial capillary, the plasma osmolytes are sieved (retained) so that plasma osmotic counterpressure is generated, 2) this osmotic counterpressure rises along the length of capillary and when it reaches capillary hydrostatic pressure the water filtration is halted, and 3) in venous capillaries and postcapillary venules where hydrostatic pressure is low, the osmotic counterpressure is instrumental in water reabsorption from interstitium what leads to dissipation of osmotic counterpressure. According to modified van’t Hoff’s equation the generation of osmotic counterpressure depends on plasma concentration of osmolytes and their restricted passage (reflection coefficient) across microvascular wall in comparison to water.

Results: Plasma NaCl makes 83% of plasma osmolarity and shows restricted passage across the walls of cerebral and peripheral continuous capillaries, so that Na and Cl are the most important osmolytes for generation of osmotic counterpressure. Our calculation indicates that at various rates of water filtration the osmotic counterpressure of NaCl acts as negative feedback control: higher hydrostatic pressure and water filtration rate create higher osmotic counterpressure which opposes filtration and leads to higher water reabsorption rate. Furthermore, our analysis indicates that fluid volume changes in arterial capillaries are proportionally 100 times larger than in interstial fluid.

Conclusion: The osmotic counterpressure hypothesis explains fluid homeostasis at high, mean and low capillary hydrostatic pressures. Plasma proteins and inorganic electrolytes contribute 0.4% and 94% to plasma osmolarity, respectively, so that plasma proteins have low osmotic (oncotic) pressure and despite high restriction of their passage across microvascular wall they contribute little to build up of osmotic counterpressure in comparison to electrolytes. However, absence or very low concentration of plasma proteins increases microvascular wall permeability to water and osmolytes compromising build up of osmotic counterpressure leading to development of interstial oedema.
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August 2014

Long lasting near-obstruction stenosis of mesencephalic aqueduct without development of hydrocephalus--case report.

Croat Med J 2014 Aug;55(4):394-8

Darko Orešković, Rudjer Bošković Institute, Department of Molecular Biology, Bijenička 54, 10 000 Zagreb, Croatia,

The aim of this study is to present the five-year longitudinal magnetic resonance imaging (MRI) follow up of a patient with incidental finding of near-obstruction stenosis of the aqueduct of Sylvius due to a large pineal cyst. The patient was scanned 3 times on a 3T MR device using a set of standard structural sequences supplemented with high-resolution constructive interference of steady state (CISS) T2 sequence for precise delineation of the aqueduct of Sylvius and cardiac-gated phase-contrast sequences for the analysis of cerebrospinal fluid (CSF) movement. On all MR scans, the size of the pineal cyst and severity of near-obstruction aqueductal stenosis did not show any morphological changes. There was no significant ventricular enlargement although structural CISS sequence showed a near-obstruction stenosis and cardiac-gated phase-contrast sequences did not detect CSF movement through the aqueduct of Sylvius. Our findings are contradictory to the classic hypothesis of CSF physiology based on secretion, circulation, and absorption of CSF, which states that the impairment of CSF circulation through the aqueduct of Sylvius inevitably leads to a hypertensive hydrocephalus development involving the third and the lateral ventricle. Our research group previously proposed a new hypothesis of CSF physiology, which offers more suitable explanation for such clinical cases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157388PMC
http://dx.doi.org/10.3325/cmj.2014.55.394DOI Listing
August 2014

Volumetric analysis of cerebrospinal fluid and brain parenchyma in a patient with hydranencephaly and macrocephaly--case report.

Croat Med J 2014 Aug;55(4):388-93

Marijan Klarica, University of Zagreb, School of Medicine, Department of Pharmacology and Croatian Institute for Brain Research, Šalata 11, 10 000 Zagreb, Croatia,

The aim of this study was to perform for the first time the intracranial volumetric analysis of cerebrospinal fluid (CSF) and brain parenchyma in the supratentorial and infratentorial space in a 30-year-old female patient with hydranencephaly and macrocephaly. A head scan performed using a 3T magnetic resonance was followed by manual segmentation of the brain parenchyma and CSF on T2 coronal brain sections. The volume of CSF and brain parenchyma was measured separately for the supratentorial and infratentorial space. The total volume of the intracranial space was 3645.5 cm3. In the supratentorial space, the volume of CSF was 3375.2 cm3 and the volume of brain parenchyma was 80.3 cm3. In the infratentorial space, the volume of CSF was 101.3 cm3 and the volume of the brain parenchyma was 88.7 cm3. In the supratentorial space, there was severe malacia of almost all brain parenchyma with no visible remnants of the choroid plexuses. Infratentorial structures of the brainstem and cerebellum were hypoplastic but completely developed. Since our patient had no choroid plexuses in the supratentorial space and no obstruction between dural sinuses and CSF, development of hydrocephalus and macrocephaly cannot be explained by the classic hypothesis of CSF physiology with secretion, unidirectional circulation, and absorption as its basic postulates. However, the origin and turnover of the enormous amount of intracranial CSF volume, at least 10-fold larger than normal, and the mechanisms of macroencephaly development could be elucidated by the new hypothesis of CSF physiology recently published by our research team.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157378PMC
http://dx.doi.org/10.3325/cmj.2014.55.388DOI Listing
August 2014

Measurement of cerebrospinal fluid formation and absorption by ventriculo-cisternal perfusion: what is really measured?

Croat Med J 2014 Aug;55(4):317-27

Darko Orešković, Rudjer Bošković Institute, Department of Molecular Biology, Bijenička 54, 10 000 Zagreb, Croatia,

The generally accepted hypothesis on cerebrospinal fluid (CSF) hydrodynamics suggests that CSF is actively formed mainly by the choroid plexuses, circulates unidirectionally along the brain ventricles and subarachnoid space, and is passively absorbed mainly into the dural venous sinuses. CSF formation rate (Vf) has been extensively studied using the ventriculo-cisternal perfusion technique and the results have been used as the key evidence confirming the mentioned hypothesis. This technique and the equation for Vf calculation are based on the assumption that the dilution of the indicator substance is a consequence of the newly formed CSF, ie, that a higher CSF formation rate will result in a higher degree of dilution. However, it has been experimentally shown that the indicator substance dilution inside the CSF system does not occur because of a "newly formed" CSF, but as consequence of a number of other factors (departure of substances into the surrounding tissue, flowing around the collecting cannula into the cortical and spinal subarachnoid space, departure into the contralateral ventricle, etc). This technique allows "calculation" of the CSF formation even in dead animals, in an in vitro model, and in any other part of the CSF system outside the ventricles that is being perfused. Therefore, this method is indirect and any dilution of the indicator substance in the perfusate caused by other reasons would result in questionable and often contradictory conclusions regarding CSF formation rates.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157383PMC
http://dx.doi.org/10.3325/cmj.2014.55.317DOI Listing
August 2014

Enigma of cerebrospinal fluid dynamics.

Croat Med J 2014 Aug;55(4):287-90

Marijan Klarica, Department of Pharmacology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia,

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157379PMC
http://dx.doi.org/10.3325/cmj.2014.55.287DOI Listing
August 2014

A new look at cerebrospinal fluid movement.

Fluids Barriers CNS 2014 27;11:16. Epub 2014 Jul 27.

Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine University of Zagreb, Zagreb, Croatia ; Ruđer Bošković Institute, Department of Molecular Biology, Bijenička 54, 10 000 Zagreb, Croatia.

Brinker et al. extensively reviewed recent findings about CSF circulation in a recent article: "A new look at cerebrospinal circulation", but did not analyze some important available data in sufficient detail. For example, our findings as well as some clinical data and experimental results obtained from different animal species, do not support unidirectional CSF circulation but strongly suggest that there are cardiac cycle-dependent systolic-diastolic to-and-fro cranio-spinal CSF movements. These are based on: a) physiological oscillations of arterial and venous blood during cranio-spinal blood circulation; b) respiratory activity, and c) body activity and posture. That kind of complex CSF movement could explain the observed distribution of many different substances in all directions along the CSF system and within central nervous system tissue. It seems that efflux transport systems at capillary endothelium may be more important for brain homeostasis than the removal of metabolites by CSF flow. Thus, when discussing the CSF dynamics we suggest that a more appropriate term would be CSF movement rather than CSF circulation.
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http://dx.doi.org/10.1186/2045-8118-11-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118619PMC
August 2014

The influence of body position on cerebrospinal fluid pressure gradient and movement in cats with normal and impaired craniospinal communication.

PLoS One 2014 18;9(4):e95229. Epub 2014 Apr 18.

Department of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia.

Intracranial hypertension is a severe therapeutic problem, as there is insufficient knowledge about the physiology of cerebrospinal fluid (CSF) pressure. In this paper a new CSF pressure regulation hypothesis is proposed. According to this hypothesis, the CSF pressure depends on the laws of fluid mechanics and on the anatomical characteristics inside the cranial and spinal space, and not, as is today generally believed, on CSF secretion, circulation and absorption. The volume and pressure changes in the newly developed CSF model, which by its anatomical dimensions and basic biophysical features imitates the craniospinal system in cats, are compared to those obtained on cats with and without the blockade of craniospinal communication in different body positions. During verticalization, a long-lasting occurrence of negative CSF pressure inside the cranium in animals with normal cranio-spinal communication was observed. CSF pressure gradients change depending on the body position, but those gradients do not enable unidirectional CSF circulation from the hypothetical site of secretion to the site of absorption in any of them. Thus, our results indicate the existence of new physiological/pathophysiological correlations between intracranial fluids, which opens up the possibility of new therapeutic approaches to intracranial hypertension.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095229PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991613PMC
January 2015

The effect of body position on intraocular and CSF pressures in the lateral ventricle, and in cortical and lumbar subarachnoid spaces in cats.

Acta Neurochir Suppl 2012 ;114:357-61

Department of Ophthalmology, University of Zagreb School of Medicine, Zagreb, Croatia.

Background: Correlation between cerebrospinal fluid (CSF) and intraocular pressure (IOP) is still unclear. We compared CSF pressure from different parts of the CSF system and IOP measured by the same invasive technique in a new experimental model in cats during changes of body position.

Methods: Pressure changes were recorded on anesthetized cats (n = 7) in the lateral ventricle (LV), in the cortical (CSS) and lumbar (LSS) subarachnoid spaces, and in the anterior ocular chamber. Animals and measuring instruments were both fixed on a board at an adequate hydrostatic level.

Results: In a horizontal position, IOP (18.5 ± 0.6 cm H(2)O) and CSF pressures (LV = 17.4 ± 0.9; CSS = 17.2 ± 0.7; LSS = 17.8 ± 1.2 cm H(2)O) were similar. In a vertical position, pressure in the LSS increased (33.5 ± 2.3 cm H(2)O), pressures inside the cranial cavity dropped (LV = -4.1 ± 0.9 cm H(2)O; CSS = -4.8 ± 0.5 cm H(2)O), while IOP slightly decreased (14.3 ± 0.1 cm H(2)O).

Conclusion: Change in body position from horizontal to upright causes drastic changes in CSF pressure and relatively small changes in IOP, which indicates that the IOP does not reflect CSF pressure. In an upright position, CSF pressures were equal at the same hydrostatic level in LV and CSS, which suggests that CSF pressure inside the cranium depends on its anatomical and biophysical features, and not on CSF secretion and absorption.
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http://dx.doi.org/10.1007/978-3-7091-0956-4_69DOI Listing
May 2012

Dependence of cerebrospinal fluid pressure and volume on the changes in serum osmolarity in cats.

Acta Neurochir Suppl 2012 ;114:351-5

Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia.

Objectives: To study the effect of blood osmolarity on cerebrospinal fluid (CSF) volume and CSF pressure in cats.

Methods: Three types of methods were used on anesthetized cats. The first, ventriculo-cisternal perfusion (12.96 μL/min) before and after i.v. application of 20% mannitol; the second, measuring the outflow of CSF by cisternal free drainage; and the third, measuring CSF pressure in the ventricles of an intact CSF system, with the second and third method being performed before and after the i.p. application of a hypo-osmolar substance (distilled water).

Results: In the first group, the application of 20% mannitol led to a significantly reduced (p < 0.005) outflow volume (from 12.60 ± 0.29 to 0.94 ± 0.09 μL/min). In the second group, the outflow CSF volume significantly increased (p < 0.001) after the application of distilled water (from 18.8 ± 0.3 to 28.2 ± 0.7 μL/min). In the third group, after the application of distilled water, the CSF pressure also significantly increased (p < 0.05; from 8.3 ± 0.8 to 16.1 ± 0.14 cm H(2)O).

Conclusion: We conclude that changes in serum osmolarity change the CSF volume because of the osmotic gradient between the blood and all of the CSF compartments, and also that the change in CSF pressure is closely associated with changes in CSF volume.
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http://dx.doi.org/10.1007/978-3-7091-0956-4_68DOI Listing
May 2012

Methods for measuring acoustic power of an ultrasonic neurosurgical device.

Coll Antropol 2011 Jan;35 Suppl 1:107-13

University of Zagreb, Faculty of Electrical Engineering and Computing, Zagreb, Croatia.

Measurement of the acoustic power in high-energy ultrasonic devices is complex due to occurrence of the strong cavitation in front of the sonotrode tip. In our research we used three methods for characterization of our new ultrasonic probe for neuroendoscopic procedures. The first method is based on the electromechanical characterization of the device measuring the displacement of the sonotrode tip and input electrical impedance around excitation frequency with different amounts of the applied electrical power The second method is based on measuring the spatial pressure magnitude distribution of an ultrasound surgical device produced in an anechoic tank. The acoustic reciprocity principle is used to determinate the derived acoustic power of equivalent ultrasound sources at frequency components present in the spectrum of radiated ultrasonic waves. The third method is based on measuring the total absorbed acoustic power in the restricted volume of water using the calorimetric method. In the electromechanical characterization, calculated electroacoustic efficiency factor from equivalent electrical circuits is between 40-60%, the same as one obtained measuring the derived acoustic power in an anechoic tank when there is no cavitation. When cavitation activity is present in the front of the sonotrode tip the bubble cloud has a significant influence on the derived acoustic power and decreases electroacoustic efficiency. The measured output acoustic power using calorimetric method is greater then derived acoustic power, due to a large amount of heat energy released in the cavitation process.
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January 2011

Potential error in ventriculocisternal perfusion method for determination of cerebrospinal fluid formation rate in cats.

Coll Antropol 2011 Jan;35 Suppl 1:73-7

University of Zagreb, Dubrava University Hospital, Department of Neurosurgery, Zagreb, Croatia.

The cerebrospinal fluid (CSF) formation rate (Vf) has been extensively studied by the ventriculocisternal perfusion, a method still regarded as the most precise one. This method as well as the equation for the calculation of the CSF formation rate (Vf) was established by Heisey et al on indicator dilution in perfusate. They assumed that the dilution of the indicator substance in perfusion is a consequence of newly formed CSF i.e. a higher CSF formation rate would result in a higher degree of dilution of the indicator substance. Therefore, such method is indirect and any mistake in the interpretation of the degree of indicator dilution would lead to questionable and often contradictory results regarding CSF formation rates. According to Heisey's equation, Vf shoud not depend on the rate of ventriculocisternal perfusion. However it has been shown that Vf is perfusion dependt value, and also that during perfusion the indicator substance is partially absorbed into surrounding tissue. It is possible that obtained Vf dependence on perfusion rate was caused by observed absorption of indicator substances. For that reason, in anaesthetised cats ventriculocisternal perfusion was performed at higher (252.0 microL/min) and at lower perfusion rate (65.5 microL/min) and Vf was calculated at both experimental and corrected (just for absorbed amount) values of indicator substance. Since (inspite of the correction) the difference of 12.4 microL/min between lower (15.0 microL/min) and higher perfusion rate (27.4 microL/min) was obtained, it is obvious that ventriculocisternal perfusion method cannot be considered reliable for measuring CSF formation rate.
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January 2011

Physical characteristics in the new model of the cerebrospinal fluid system.

Coll Antropol 2011 Jan;35 Suppl 1:51-6

University of Zagreb, School of Medicine, Department of Pharmacology and Croatian Institute for Brain Research, Zagreb, Croatia.

It is unknown which factors determine the changes in cerebrospinal fluid (CSF) pressure inside the craniospinal system during the changes of the body position. To test this, we have developed a new model of the CSF system, which by its biophysical characteristics and dimensions imitates the CSF system in cats. The results obtained on a model were compared to those in animals observed during changes of body position. A new model was constructed from two parts with different physical characteristics. The "cranial" part is developed from a plastic tube with unchangeable volume, while the "spinal" part is made of a rubber baloon, with modulus of elasticity similar to that of animal spinal dura. In upright position, in the "cranial" part of the model the negative pressure appears without any measurable changes in the fluid volume, while in "spinal" part the fluid pressure is positive. All of the observed changes are in accordance to the law of the fluid mechanics. Alterations of the CSF pressure in cats during the changes of the body position are not significantly different compared to those observed on our new model. This suggests that the CSF pressure changes are related to the fluid mechanics, and do not depend on CSF secretion and circulation. It seems that in all body positions the cranial volume of blood and CSF remains constant, which enables a good blood brain perfusion.
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January 2011

The application of ultrasound in neuroendoscopic procedures: first results with the new tool "NECUP-2".

Coll Antropol 2011 Jan;35 Suppl 1:45-9

University of Zagreb, Zagreb University Hospital Centre, School of Medicine, Department of Neurosurgery, Zagreb, Croatia.

In this paper, our experience with originally constructed Neurosurgical Endoscopic Contact Ultrasound Probe "NECUP-2" in neuroendoscopy is reported. Between June 1997 and June 2007, 132 neuroendoscopic procedures have been performed: 102 endoscopic thrid ventriculostomies (ETV), 15 arachnoid cysts and 5 intraventricular tumours operations. The "NECUP-2" was applied effectively in all cases in which blunt perforation was not possible: 38/102 ETY, 10/10 septostomies, 15/15 arachnoid cysts. In five cases of intraventricular tumours, neuroendoscopic procedure was combined with open microsurgery for tumour removal with preservation of vascular structures. There were no "NECUP-2" related complications. Of postoperative complications, we had liquorrhea (9 patients), and symptoms of meningitis (6 patients). In the follow-up period (6 months to 6 years), we had a patency rate of 80% (50/63 patients). All patients improved in clinical status. According to the first results, it seems that ultrasonic contact probe NECUP-2 presents a new device in neurosurgical armamentarium that can be used in various fields of neurosurgery. With minimal and controlled lesion that is produced at the tip of the probe, it can be used in highly demanding operations such as third ventriculostomy and tumour resection.
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January 2011

Recent insights into a new hydrodynamics of the cerebrospinal fluid.

Brain Res Rev 2011 Jan 29;65(2):99-112. Epub 2010 Sep 29.

University of Zagreb School of Medicine, Department of Pharmacology and Croatian Institute for Brain Research, 10 000 Zagreb, Croatia.

According to the traditional hypothesis, the cerebrospinal fluid (CSF) is secreted inside the brain ventricles and flows unidirectionally along subarachnoid spaces to be absorbed into venous sinuses across arachnoid villi and/or via paraneural sheaths of nerves into lymphatics. However, according to recent investigations, it appears that interstitial fluid (ISF) and CSF are formed by water filtration across the walls of arterial capillaries in the central nervous system (CNS), while plasma osmolytes are sieved (retained) so that capillary osmotic counterpressure is generated, which is instrumental in ISF/CSF water absorption into venous capillaries and postcapillary venules. This hypothesis is supported by experiments showing that water, which constitutes 99% of CSF and ISF bulk, does not flow along CSF spaces since it is rapidly absorbed into adjacent CNS microvessels, while distribution of other substances along CSF spaces depends on the rate of their removal into microvessels: faster removal means more limited distribution. Furthermore, the acute occlusion of aqueduct of Sylvius does not change CSF pressure in isolated ventricles, suggesting that the formation and the absorption of CSF are in balance. Multidirectional distribution of substances inside CSF, as well as between CSF and ISF, is caused by to-and-fro pulsations of these fluids and their mixing. Absorption of CSF into venous sinuses and/or lymphatics under the physiological pressure should be of minor importance due to their minute surface area in comparison to the huge absorptive surface area of microvessels.
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http://dx.doi.org/10.1016/j.brainresrev.2010.08.002DOI Listing
January 2011

Effect of osmolarity on CSF volume during ventriculo-aqueductal and ventriculo-cisternal perfusions in cats.

Neurosci Lett 2010 Oct 30;484(2):93-7. Epub 2010 Jul 30.

Department of Neurosurgery, Dubrava University Hospital, Avenija G. Suska 6, 10000 Zagreb, Croatia.

The effect of cerebrospinal fluid (CSF) osmolarity on the CSF volume has been studied on different CSF/brain tissue contact areas. It has been shown, on anesthetized cats under normal CSF pressure, that the perfusion of CSF system (12.96 μl/min) by hyperosmolar CSF (400 mOsml/l) leads to significantly higher outflow volume (μl/min) during ventriculo-cisternal perfusion (29.36 ± 1.17 and 33.50 ± 2.78) than the ventriculo-aqueductal perfusion (19.58 ± 1.57 and 22.10 ± 2.31) in experimental period of 30 or 60 min. Both of these hyperosmolar perfusions resulted in significantly higher outflow volume than the perfusions by isoosmolar artificial CSF (12.86 ± 0.96 and 13.58 ± 1.64). These results suggest that the volume of the CSF depends on both the CSF osmolarity and the size of the contact area between CSF system and surrounding tissue exposed to hyperosmolar CSF. However, all of these facts imply that the control of the CSF volume is not in accordance with the classical hypothesis of cerebrospinal fluid hydrodynamic. According to this hypothesis, the CSF volume should be regulated by active formation of CSF (secretion) inside the brain ventricles and passive CSF absorption outside of the brain. Obtained results correspond to the new hypothesis which claims that the volume of CSF depends on the gradients of hydrostatic and osmotic forces between the blood on one side and extracellular fluid and CSF on the other. The CSF exchange between the entire CSF system and the surrounding tissue should, therefore, be determined by (patho)physiological conditions that predominate within those compartments.
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http://dx.doi.org/10.1016/j.neulet.2010.07.058DOI Listing
October 2010

Dynamics of distribution of 3H-inulin between the cerebrospinal fluid compartments.

Brain Res 2009 Jan 31;1248:127-35. Epub 2008 Oct 31.

Department of Pharmacology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, 10 000 Zagreb, Croatia.

Since the distribution of substances between various cerebrospinal fluid (CSF) compartments is poorly understood, we studied (3)H-inulin distribution, over time, after its injection into cisterna magna (CM) or lateral ventricle (LV) or cisterna corporis callosi (CCC) in dogs. After the injection into CM (3)H-inulin was well distributed to cisterna basalis (CB), lumbar (LSS) and cortical (CSS) subarachnoid spaces and less distributed to LV. When injected in LV (3)H-inulin was well distributed to all CSF compartments. However, after injection into CCC (3)H-inulin was mostly localized in CCC and adjacent CSS, while its concentrations were much lower in CM and CB and very low in LSS and LV. Concentrations of (3)H-inulin in venous plasma of superior sagittal sinus and arterial plasma were very low and did not differ significantly, while its concentration in urine was very high. In (3)H-inulin distribution it seems that two simultaneous processes are relevant: a) the pulsation of CSF with to-and-fro displacement of CSF and its mixing, carrying (3)H-inulin in all directions, and b) the passage of (3)H-inulin from CSF into nervous parenchyma and its rapid distribution to a huge surface area of capillaries by vessels pulsations. (3)H-inulin then slowly diffuses across capillary walls into the bloodstream to be eliminated in the urine.
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http://dx.doi.org/10.1016/j.brainres.2008.10.044DOI Listing
January 2009

Fluid perfusion as a method of cerebrospinal fluid formation rate--critical appraisal.

Coll Antropol 2008 Jan;32 Suppl 1:133-7

Laboratory of Neurochemistry and Molecular Neurobiology, Department of Molecular Biology, Ruder Boskovic Institute, Zagreb, Croatia.

The aim of the study was to evaluate whether or not cerebrospinal fluid formation rate (Vf) calculated according to the equation of Heisey et al., truly show the produced cerebrospinal fluid. For this reason Vf was simulated (40.6 microL/min) by an infusion pump in a plastic cylinder and the evaluation was done by comparing the results obtained between the calculated Vf and the simulated one. In both cases the result should be the same (40.6 micro/min). Other types of experiments were carried out by ventriculocisternal perfusion (92.4 microL/min) on anaesthetized and sacrificed cats. If the equation is correct, the calculated Vf for sacrificed animals should be zero, because there is no Vf in dead animals. The fact that the calculated Vf (46.5 microL/min) in the plastic cylinder was different (p < 0.0001) from the simulated one (40.6 microL/min) and that Vf was calculated even for dead animals (3-5 microL/min) clearly shows the that perfusion method may not be an accurate method for determination of Vf.
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January 2008