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The leading cause of ventricular shunt failure in pediatric patients is proximal catheter occlusion. Here, we evaluate various types of shunt catheters to assess in vitro cellular adhesion and obstruction. The following four types of catheters were tested: (1) antibiotic- and barium-impregnated, (2) polyvinylpyrrolidone, (3) barium stripe, and (4) barium impregnated. Catheters were either seeded superficially with astrocyte cells to test cellular adhesion or inoculated with cultured astrocytes into the catheters to test catheter performance under obstruction conditions. Ventricular catheters were placed into a three-dimensional printed phantom ventricular replicating system through which artificial CSF was pumped. Differential pressure sensors were used to measure catheter performance. Polyvinylpyrrolidone catheters had the lowest median cell attachment compared to antibiotic-impregnated (18 cells), barium stripe (17 cells), and barium-impregnated (21.5 cells) catheters after culture (p < 0.01). In addition, polyvinylpyrrolidone catheters had significantly higher flow in the phantom ventricular system (0.12 mL/min) compared to the antibiotic coated (0.10 mL/min), barium stripe (0.02 mL/min) and barium-impregnated (0.08 mL/min; p < 0.01) catheters. Polyvinylpyrrolidone catheters showed less cellular adhesion and were least likely to be occluded by astrocyte cells. Our findings can help suggest patient-appropriate proximal ventricular catheters for clinical use.

Hypertension is the leading cause of cardiovascular affection and premature death worldwide. The spontaneously hypertensive rat (SHR) is the most common animal model of hypertension, which is characterized by secondary ventricular dilation and hydrocephalus. Aquaporin (AQP) 1 and 4 are the main water channels responsible for the brain’s water balance. The present study focuses on defining the expression of AQPs through the time course of the development of spontaneous chronic hypertension. We performed immunofluorescence and ELISA to examine brain AQPs from 10 SHR, and 10 Wistar–Kyoto (WKY) rats studied at 6 and 12 months old. There was a significant decrease in AQP1 in the choroid plexus of the SHR-12-months group compared with the age-matched control (p < 0.05). In the ependyma, AQP4 was significantly decreased only in the SHR-12-months group compared with the control or SHR-6-months groups (p < 0.05). Per contra, AQP4 increased in astrocytes end-feet of 6 months and 12 months SHR rats (p < 0.05). CSF AQP detection was higher in the SHR-12-months group than in the age-matched control group. CSF findings were confirmed by Western blot. In SHR, ependymal and choroidal AQPs decreased over time, while CSF AQPs levels increased. In turn, astrocytes AQP4 increased in SHR rats. These AQP alterations may underlie hypertensive-dependent ventriculomegaly.

Objective: One of the major causes of cerebral ventricular shunt failure is proximal catheter occlusion. We describe a novel ventricular cerebrospinal fluid (CSF) flow replicating system that assesses pressure and flow responses to varying degrees of catheter occlusion. Methods: Ventricular catheter performance was assessed during conditions of partial and complete occlusion. The catheters were placed into a three-dimensionally-printed phantom ventricular replicating system. Artificial CSF was pumped through the ventricular system at a constant rate of 1 mL/min to mimic CSF flow, with the proximal end of the catheter in the phantom ventricle. Pressure transducer and flow rate sensors were used to measure intra-phantom pressure, outflow pressure, and CSF flow rates. The catheters were also inserted into silicone tubing and pressure was measured in the same manner for comparison with the phantom. Results: Pressure measured in the ventricle phantom did not change when the outflow of the ventricular catheter was partially occluded. However, the intraventricular phantom pressure significantly increased when the outflow catheter was 100% occluded. The flow through the catheter showed no significant difference in rate with any degree of partial occlusion of the catheter. At the distal end of the partially occluded catheters, there was less pressure compared with the nonoccluded catheters. This difference in pressure in partially occluded catheters correlated with the percentage of catheter hole occlusion. Conclusions: Our model mimics the physiological dynamics of the CSF flow in partially and completely obstructed ventricular catheters. We found that partial occlusion of the catheter had no effect on the CSF flow rate, but did reduce outflow pressure from the catheter.

Aquaporin 4 (AQP4) is a cerebral glial marker that labels ependymal cells and astrocytes’ endfeet and is the main water channel responsible for the parenchymal fluid balance. However, in brain development, AQP4 is a marker of glial stem cells and plays a crucial role in the pathophysiology of pediatric hydrocephalus. Gliogenesis characterization has been hampered by a lack of biomarkers for precursor and intermediate stages and a deeper understanding of hydrocephalus etiology is needed. This manuscript is a focused review of the current research landscape on AQP4 as a possible biomarker for gliogenesis and its influence in pediatric hydrocephalus, emphasizing reactive astrogliosis. The goal is to understand brain development under hydrocephalic and normal physiologic conditions.

Aquaporin 1 (AQP1) and aquaporin 4 (AQP4) have been identified in the eye as playing an essential role in the formation of the aqueous humor along with the Na+/K+ ATPase pump. Different authors have described the relationship between blood pressure, aqueous humor production, and intraocular pressure with different conclusions, with some authors supporting a positive correlation between blood pressure and intraocular pressure while others disagree. The aim of this work was to study the effect of high blood pressure on the proteins involved in the production of aqueous humor in the ciliary body (CB) and iris. For this purpose, we used the eyes of spontaneously hypertensive rats (SHR) and their control Wistar-Kyoto rats (WKY). Immunofluorescence was performed in different eye structures to analyze the effects of hypertension in the expression of AQP1, AQP4, and the Na+/K+ ATPase α1 and α2 subunits. The results showed an increase in AQP1 and Na+/K+ ATPase α1 and a decrease in AQP4 and Na+/K+ ATPase α2 in the CB of SHR, while an increase in AQP4 and no significant differences in AQP1 were found in the iris. Therefore, systemic hypertension produced changes in the proteins implicated in the movement of water in the CB and iris that could influence the production rate of aqueous humor, which would be affected depending on the duration of systemic hypertension.

Introduction: Dimethyl sulfoxide (DMSO), a widely utilized solvent in the medical industry, has been associated with various adverse effects, even at low concentrations, including damage to mitochondrial integrity, altered membrane potentials, caspase activation, and apoptosis. Notably, therapeutic molecules for central nervous system treatments, such as embolic agents or some chemotherapy drugs that are dissolved in DMSO, have been associated with hydrocephalus as a secondary complication. Our study investigated the potential adverse effects of DMSO on the brain, specifically focusing on the development of hydrocephalus and the effect on astrocytes. Methods: Varied concentrations of DMSO were intraventricularly injected into 3-day-old mice, and astrocyte cultures were exposed to similar concentrations of DMSO. After 14 days of injection, magnetic resonance imaging (MRI) was employed to quantify the brain ventricular volumes in mice. Immunofluorescence analysis was conducted to delineate DMSO-dependent effects in the brain. Additionally, astrocyte cultures were utilized to assess astrocyte viability and the effects of cellular apoptosis. Results: Our findings revealed a dose-dependent induction of ventriculomegaly in mice with 2%, 10%, and 100% DMSO injections (p

Abstract Background Hydrocephalus is a neurological disease with an incidence of 80–125 per 100,000 births in the United States. Neuropathology comprises ventriculomegaly, periventricular white matter (PVWM) alterations, inflammation, and gliosis. We hypothesized that hydrocephalus in a pig model is associated with subventricular and PVWM cellular alterations and neuroinflammation that could mimic the neuropathology described in hydrocephalic infants. Methods Hydrocephalus was induced by intracisternal kaolin injections in 35-day old female pigs (n = 7 for tissue analysis, n = 10 for CSF analysis). Age-matched sham controls received saline injections (n = 6). After 19–40 days, MRI scanning was performed to measure the ventricular volume. Stem cell proliferation was studied in the Subventricular Zone (SVZ), and cell death and oligodendrocytes were examined in the PVWM. The neuroinflammatory reaction was studied by quantifying astrocytes and microglial cells in the PVWM, and inflammatory cytokines in the CSF. Results The expansion of the ventricles was especially pronounced in the body of the lateral ventricle, where ependymal disruption occurred. PVWM showed a 44% increase in cell death and a 67% reduction of oligodendrocytes. In the SVZ, the number of proliferative cells and oligodendrocyte decreased by 75% and 57% respectively. The decrease of the SVZ area correlated significantly with ventricular volume increase. Neuroinflammation occurred in the hydrocephalic pigs with a significant increase of astrocytes and microglia in the PVWM, and high levels of inflammatory interleukins IL-6 and IL-8 in the CSF. Conclusion The induction of acquired hydrocephalus produced alterations in the PVWM, reduced cell proliferation in the SVZ, and neuroinflammation.

Abstract Background Intraventricular hemorrhage (IVH) and post-hemorrhagic hydrocephalus (PHH) have a complex pathophysiology involving inflammatory response, ventricular zone and cell–cell junction disruption, and choroid-plexus (ChP) hypersecretion. Increased cerebrospinal fluid (CSF) cytokines, extracellular matrix proteins, and blood metabolites have been noted in IVH/PHH, but osmolality and electrolyte disturbances have not been evaluated in human infants with these conditions. We hypothesized that CSF total protein, osmolality, electrolytes, and immune cells increase in PHH. Methods CSF samples were obtained from lumbar punctures of control infants and infants with IVH prior to the development of PHH and any neurosurgical intervention. Osmolality, total protein, and electrolytes were measured in 52 infants (18 controls, 10 low grade (LG) IVH, 13 high grade (HG) IVH, and 11 PHH). Serum electrolyte concentrations, and CSF and serum cell counts within 1-day of clinical sampling were obtained from clinical charts. Frontal occipital horn ratio (FOR) was measured for estimating the degree of ventriculomegaly. Dunn or Tukey’s post-test ANOVA analysis were used for pair-wise comparisons. Results CSF osmolality, sodium, potassium, and chloride were elevated in PHH compared to control (p = 0.012 −

Abstract Background Many animal models have been used to study the pathophysiology of hydrocephalus; most of these have been rodent models whose lissencephalic cerebral cortex may not respond to ventriculomegaly in the same way as gyrencephalic species and whose size is not amenable to evaluation of clinically relevant neurosurgical treatments. Fewer models of hydrocephalus in gyrencephalic species have been used; thus, we have expanded upon a porcine model of hydrocephalus in juvenile pigs and used it to explore surgical treatment methods. Methods Acquired hydrocephalus was induced in 33–41-day old pigs by percutaneous intracisternal injections of kaolin (n = 17). Controls consisted of sham saline-injected (n = 6) and intact (n = 4) animals. Magnetic resonance imaging (MRI) was employed to evaluate ventriculomegaly at 11–42 days post-kaolin and to plan the surgical implantation of ventriculoperitoneal shunts at 14–38-days post-kaolin. Behavioral and neurological status were assessed. Results Bilateral ventriculomegaly occurred post-induction in all regions of the cerebral ventricles, with prominent CSF flow voids in the third ventricle, foramina of Monro, and cerebral aqueduct. Kaolin deposits formed a solid cast in the basal cisterns but the cisterna magna was patent. In 17 untreated hydrocephalic animals. Mean total ventricular volume was 8898 ± 5917 SD mm3 at 11–43 days of age, which was significantly larger than the baseline values of 2251 ± 194 SD mm3 for 6 sham controls aged 45–55 days, (p

Abstract Background Severe intraventricular hemorrhage (IVH) is one of the most devastating neurological complications in preterm infants, with the majority suffering long-term neurological morbidity and up to 50% developing post-hemorrhagic hydrocephalus (PHH). Despite the importance of this disease, its cytopathological mechanisms are not well known. An in vitro model of IVH is required to investigate the effects of blood and its components on the developing ventricular zone (VZ) and its stem cell niche. To address this need, we developed a protocol from our accepted in vitro model to mimic the cytopathological conditions of IVH in the preterm infant. Methods Maturing neuroepithelial cells from the VZ were harvested from the entire lateral ventricles of wild type C57BL/6 mice at 1–4 days of age and expanded in proliferation media for 3–5 days. At confluence, cells were re-plated onto 24-well plates in differentiation media to generate ependymal cells (EC). At approximately 3–5 days, which corresponded to the onset of EC differentiation based on the appearance of multiciliated cells, phosphate-buffered saline for controls or syngeneic whole blood for IVH was added to the EC surface. The cells were examined for the expression of EC markers of differentiation and maturation to qualitatively and quantitatively assess the effect of blood exposure on VZ transition from neuroepithelial cells to EC. Discussion This protocol will allow investigators to test cytopathological mechanisms contributing to the pathology of IVH with high temporal resolution and query the impact of injury to the maturation of the VZ. This technique recapitulates features of normal maturation of the VZ in vitro, offering the capacity to investigate the developmental features of VZ biogenesis.

Abstract Hydrocephalus is a distension of the ventricular system associated with ventricular zone disruption, reactive astrogliosis, periventricular white matter ischemia, axonal impairment, and corpus callosum alterations. The condition's etiology is typically attributed to a malfunction in classical cerebrospinal fluid (CSF) bulk flow; however, this approach does not consider the unique physiology of CSF in fetal and perinatal patients. The parenchymal fluid contributes to the glymphatic system, and plays a fundamental role in pediatric hydrocephalus, with aquaporin 4 (AQP4) as the primary facilitator of these fluid movements. Despite the importance of AQP4 in the pathophysiology of hydrocephalus, it’s expression in human fetal life is not well-studied. This manuscript systematically defines the brain expression of AQP4 in human brain development under control (n = 13) and hydrocephalic conditions (n = 3). Brains from 8 postconceptional weeks (PCW) onward and perinatal CSF from control (n = 2), obstructive (n = 6) and communicating (n = 6) hydrocephalic samples were analyzed through immunohistochemistry, immunofluorescence, western blot, and flow cytometry. Our results indicate that AQP4 expression is observed first in the archicortex, followed by the ganglionic eminences and then the neocortex. In the neocortex, it is initially at the perisylvian regions, and lastly at the occipital and prefrontal zones. Characteristic astrocyte end-feet labeling surrounding the vascular system was not established until 25 PCW. We also found AQP4 expression in a subpopulation of glial radial cells with processes that do not progress radially but, rather, curve following white matter tracts (corpus callosum and fornix), which were considered as glial stem cells (GSC). Under hydrocephalic conditions, GSC adjacent to characteristic ventricular zone disruption showed signs of early differentiation into astrocytes which may affect normal gliogenesis and contribute to the white matter dysgenesis. Finally, we found that AQP4 is expressed in the microvesicle fraction (p

Holoprosencephaly (HPE) is a birth defect that occurs during the first weeks of pregnancy and as a result the prosencephalon does not clearly divide in diencephalon, two halves of the telencephalon and lateral ventricles in the brain of the fetus and, in general, HPE is accompanied by facial defects. There are three main types of holoprosencephaly according to severity; alobar, semi-lobar and lobar. We report here a case that could be defined as a semi-lobar form of HPE with hydrocephalus and scarce facial malformations. Keywords: Human foetus, Holoprosencephaly, Brain malformation, Facial defects

The choroid plexuses (ChP) are highly vascularized tissues suspended from each of the cerebral ventricles. Their main function is to secret CSF that fills the ventricles and the subarachnoid spaces, forming a crucial system for the development and maintenance of the CNS. However, despite the essential role of the ChP–CSF system to regulate the CNS in a global manner, it still remains one of the most understudied areas in neurobiology. Here we define by immunohistochemistry the expression of different proteins involved in the maturation and functionality of the ChP from the late embryological period to maturity. We found an opposite gradient of expression between AQP1 and Glut1 that define functional maturation in the ChP periphery, and PCNA and calbindin, present in the ChP roof zone with proliferative activity. We conclude that the maturation of the ChP matures from distal to proximal, starting in the areas nearest to the cortex, expressing in the distal, mature areas AQP1 and Glut1 (related to ChP functionality to support cortex development), and in the proximal immature areas (ChP root) calbindin and PCNA related to progenitor activity and proliferation.

The aim of the present work is to analyze the cerebrospinal fluid proteomic profile, trying to find possible biomarkers of the effects of hypertension of the blood to CSF barrier disruption in the brain and their participation in the cholesterol and β-amyloid metabolism and inflammatory processes. Cerebrospinal fluid (CSF) is a system linked to the brain and its composition can be altered not only by encephalic disorder, but also by systemic diseases such as arterial hypertension, which produces alterations in the choroid plexus and cerebrospinal fluid protein composition. 2D gel electrophoresis in cerebrospinal fluid extracted from the cistern magna before sacrifice of hypertensive and control rats was performed. The results showed different proteomic profiles between SHR and WKY, that α-1-antitrypsin, apolipoprotein A1, albumin, immunoglobulin G, vitamin D binding protein, haptoglobin and α-1-macroglobulin were found to be up-regulated in SHR, and apolipoprotein E, transthyretin, α-2-HS-glycoprotein, transferrin, α-1β-glycoprotein, kininogen and carbonic anhidrase II were down-regulated in SHR. The conclusion made here is that hypertension in SHR produces important variations in cerebrospinal fluid proteins that could be due to a choroid plexus dysfunction and this fact supports the close connection between hypertension and blood to cerebrospinal fluid barrier disruption.