Modifying the ICP pulse wave: effects on parenchymal blood flow pulsatility.

Pulsation of the cerebral blood flow (CBF) produces intercranial pressure (ICP) waves. The aim of this study is to determine whether externally modifying ICP pulsatility alters parenchymal blood flow pulsatility. A cardiac-gated inflatable device was inserted in the lateral epidural space of 12 anesthetized canines (canis familiaris) and used to cause reduction, inversion, and augmentation of the ICP pulse. CBF in each hemisphere was measured using laser Doppler velocimetry. A significant increase in both mean CBF and its amplitude was observed for reduction as well as inversion of the ICP pulse, with larger changes observed for the inversion protocol. Significant increases in the mean CBF were also observed ipsilaterally for the augmentation protocol together with indications of reduced CBF amplitude contralaterally. External alteration of the ICP pulse thus caused significant changes in parenchymal blood flow pulsatility. The inverse relationship between the ICP and CBF amplitude suggests that the changes did not occur via modification of the intracranial Windkessel mechanism. Thus, the effects likely occurred in the low-pressure vessels, i.e., capillaries and/or venules, rather than the high-pressure arteries. Future MRI studies are however required to map and quantify the effects on global cerebral blood flow.NEW & NOTEWORTHY This study demonstrated that external modification of ICP pulsatility, using a cardiac-gated inflatable device implanted epidurally in canines, alters brain tissue blood flow pulsatility. Specifically, decreasing systolic ICP increased blood flow pulsatility in brain tissue. The results suggest that the altered CBF pulsatility is unlikely to depend on modification of the Windkessel effect on the feeding arterial system but was rather an effect directly on tissue and the lower pressure distal vessels.

"Living Well with Chronic Pain": Integrative Pain Management via Shared Medical Appointments.

OBJECTIVE: To evaluate the effectiveness of a multidisciplinary, nonpharmacological, integrative approach that uses shared medical appointments to improve health-related quality of life and reduce opioid medication use in patients with chronic pain. DESIGN: This is a retrospective, pre-post review of "Living Well with Chronic Pain" shared medical appointments (August 2016 through May 2018). SETTING: The appointments included eight 3-hour-long visits held once per week at an outpatient wellness facility. SUBJECTS: Patients with chronic, non-cancer-related pain. METHODS: Patients received evaluation and evidence-based therapies from a team of integrative and lifestyle medicine professionals, as well as education about nonpharmacological therapeutic approaches, the etiology of pain, and the relationship of pain to lifestyle factors. Experiential elements focused on the relaxation techniques of meditation, yoga, breathing, and hypnotherapy, while patients also received acupuncture, acupressure, massage, cognitive behavioral therapy, and chiropractic education. Patients self-reported data via the Patient-Reported Outcomes Measurement Information System (PROMIS-57) standardized questionnaire. Use of opioid medications was evaluated in morphine milligram equivalents. RESULTS: A total of 178 participants completed the PROMIS-57 questionnaire at the first and the last visits. Statistically significant improvements in all domains (Physical Functioning, Anxiety, Depression, Fatigue, Social Roles, Pain Interference, and Sleep Disturbance) were observed (P < 0.001) between the pre-intervention (visit 1) and post-intervention (visit 8) scores. Average opioid use decreased nonsignificantly over the 8-week intervention, but the lower rate of opioid use was not sustained at 6 and 12 months' follow-up. CONCLUSIONS: Patients suffering from chronic pain who participated in a multidisciplinary, nonpharmacological treatment approach delivered via shared medical appointments experienced reduced pain and improved measures of physical, mental, and social health without increased use of opioid pain medications.

Epidural Oscillating Cardiac-Gated Intracranial Implant Modulates Cerebral Blood Flow.

BACKGROUND: We have previously reported a method and device capable of manipulating ICP pulsatility while minimally effecting mean ICP. OBJECTIVE: To test the hypothesis that different modulations of the intracranial pressure (ICP) pulse waveform will have a differential effect on cerebral blood flow (CBF). METHODS: Using an epidural balloon catheter attached to a cardiac-gated oscillating pump, 13 canine subjects underwent ICP waveform manipulation comparing different sequences of oscillation in successive animals. The epidural balloon was implanted unilaterally superior to the Sylvian sulcus. Subjects underwent ICP pulse augmentation, reduction and inversion protocols, directly comparing time segments of system activation and deactivation. ICP and CBF were measured bilaterally along with systemic pressure and heart rate. CBF was measured using both thermal diffusion, and laser doppler probes. RESULTS: The activation of the cardiac-gate balloon implant resulted in an ipsilateral/contralateral ICP pulse amplitude increase with augmentation (217%/202% respectively, P < .0005) and inversion (139%/120%, P < .0005). The observed changes associated with the ICP mean values were smaller, increasing with augmentation (23%/31%, P < .0001) while decreasing with inversion (7%/11%, P = .006/.0003) and reduction (4%/5%, P < .0005). CBF increase was observed for both inversion and reduction protocols (28%/7.4%, P < .0001/P = .006 and 2.4%/1.3%, P < .0001/P = .003), but not the augmentation protocol. The change in CBF was correlated with ICP pulse amplitude and systolic peak changes and not with change in mean ICP or systemic variables (heart rate, arterial blood pressure). CONCLUSION: Cardiac-gated manipulation of ICP pulsatility allows the study of intracranial pulsatile dynamics and provides a potential means of altering CBF.

Reciprocal Signaling between Glioblastoma Stem Cells and Differentiated Tumor Cells Promotes Malignant Progression.

Glioblastoma is the most lethal primary brain tumor; however, the crosstalk between glioblastoma stem cells (GSCs) and their supportive niche is not well understood. Here, we interrogated reciprocal signaling between GSCs and their differentiated glioblastoma cell (DGC) progeny. We found that DGCs accelerated GSC tumor growth. DGCs preferentially expressed brain-derived neurotrophic factor (BDNF), whereas GSCs expressed the BDNF receptor NTRK2. Forced BDNF expression in DGCs augmented GSC tumor growth. To determine molecular mediators of BDNF-NTRK2 paracrine signaling, we leveraged transcriptional and epigenetic profiles of matched GSCs and DGCs, revealing preferential VGF expression by GSCs, which patient-derived tumor models confirmed. VGF serves a dual role in the glioblastoma hierarchy by promoting GSC survival and stemness in vitro and in vivo while also supporting DGC survival and inducing DGC secretion of BDNF. Collectively, these data demonstrate that differentiated glioblastoma cells cooperate with stem-like tumor cells through BDNF-NTRK2-VGF paracrine signaling to promote tumor growth.

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling.

Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1). Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.

Brain Cancer Stem Cells in Adults and Children: Cell Biology and Therapeutic Implications.

Brain tumors represent some of the most malignant cancers in both children and adults. Current treatment options target the majority of tumor cells but do not adequately target self-renewing cancer stem cells (CSCs). CSCs have been reported to resist the most aggressive radiation and chemotherapies, and give rise to recurrent, treatment-resistant secondary malignancies. With advancing technologies, we now have a better understanding of the genetic, epigenetic and molecular signatures and microenvironmental influences which are useful in distinguishing between distinctly different tumor subtypes. As a result, efforts are now underway to identify and target CSCs within various tumor subtypes based on this foundation. This review discusses progress in CSC biology as it relates to targeted therapies which may be uniquely different between pediatric and adult brain tumors. Studies to date suggest that pediatric brain tumors may benefit more from genetic and epigenetic targeted therapies, while combination treatments aimed specifically at multiple molecular pathways may be more effective in treating adult brain tumors which seem to have a greater propensity towards microenvironmental interactions. Ultimately, CSC targeting approaches in combination with current clinical therapies have the potential to be more effective owing to their ability to compromise CSCs maintenance and the mechanisms which underlie their highly aggressive and deadly nature.

Novel method for dynamic control of intracranial pressure.

OBJECT Intracranial pressure (ICP) pulsations are generally considered a passive result of the pulsatility of blood flow. Active experimental modification of ICP pulsations would allow investigation of potential active effects on blood and CSF flow and potentially create a new platform for the treatment of acute and chronic low blood flow states as well as a method of CSF substance clearance and delivery. This study presents a novel method and device for altering the ICP waveform via cardiac-gated volume changes. METHODS The novel device used in this experiment (named Cadence) consists of a small air-filled inelastic balloon (approximately 1.0 ml) implanted into the intracranial space and connected to an external programmable pump, triggered by an R-wave detector. Balloons were implanted into the epidural space above 1 of the hemispheres of 19 canines for up to 10 hours. When activated, the balloons were programed to cyclically inflate with the cardiac cycle with variable delay, phase, and volume. The ICP response was measured in both hemispheres. Additionally, cerebral blood flow (heat diffusion and laser Doppler) was studied in 16 canines. RESULTS This system, depending on the inflation pattern of the balloon, allowed a flattening of the ICP waveform, increase in the ICP waveform amplitude, or phase shift of the wave. This occurred with small mean ICP changes, typically around ± 2 mm Hg (15%). Bilateral ICP effects were observed with activation of the device: balloon inflation at each systole increased the systolic ICP pulse (up to 16 mm Hg, 1200%) and deflation at systole decreased or even inverted the systolic ICP pulse (-0.5 to -19 mm Hg, -5% to -1600%) in a dose-(balloon volume) dependent fashion. No aphysiological or deleterious effects on systemic pressure (≤ ±10 mm Hg; 13% change in mean pressure) or cardiac rate (≤ ± 17 beats per minute; 16% change) were observed during up to 4 hours of balloon activity. CONCLUSIONS The results of these initial studies using an intracranially implanted, cardiac-gated, volume-oscillating balloon suggest the Cadence device can be used to modify ICP pulsations, without physiologically deleterious effects on mean ICP, systemic vascular effects, or brain injury. This device and technique may be used to study the role of ICP pulsatility in intracranial hemo- and hydrodynamic processes and introduces the creation of a potential platform of a cardiac-gated system for treatment of acute and chronic low blood flow states, and diseases requiring augmentation of CSF substance clearance or delivery.

Mitochondrial control by DRP1 in brain tumor initiating cells.

Brain tumor initiating cells (BTICs) co-opt the neuronal high affinity glucose transporter, GLUT3, to withstand metabolic stress. We investigated another mechanism critical to brain metabolism, mitochondrial morphology, in BTICs. BTIC mitochondria were fragmented relative to non-BTIC tumor cell mitochondria, suggesting that BTICs increase mitochondrial fission. The essential mediator of mitochondrial fission, dynamin-related protein 1 (DRP1), showed activating phosphorylation in BTICs and inhibitory phosphorylation in non-BTIC tumor cells. Targeting DRP1 using RNA interference or pharmacologic inhibition induced BTIC apoptosis and inhibited tumor growth. Downstream, DRP1 activity regulated the essential metabolic stress sensor, AMP-activated protein kinase (AMPK), and targeting AMPK rescued the effects of DRP1 disruption. Cyclin-dependent kinase 5 (CDK5) phosphorylated DRP1 to increase its activity in BTICs, whereas Ca(2+)-calmodulin-dependent protein kinase 2 (CAMK2) inhibited DRP1 in non-BTIC tumor cells, suggesting that tumor cell differentiation induces a regulatory switch in mitochondrial morphology. DRP1 activation correlated with poor prognosis in glioblastoma, suggesting that mitochondrial dynamics may represent a therapeutic target for BTICs.

Biocompatibility evaluation of a thermoplastic rubber for wireless telemetric intracranial pressure sensor coating.

This study investigated the biocompatibility of the experimental thermoplastic rubber Arbomatrix(™) that will be used as the protective coating on a novel intracranial pressure (ICP) sensor silicon chip. Arbomatrix(™) was benchmarked against biocompatible commercial silicone rubber shunt tubing in the brain via a rat model with 60-day implant duration. A bare silicon chip was also implanted. The results showed similar cellular distribution in the brain-implant boundary and surrounding tissues. Quantitative analysis of neuron and glia density did not show significant difference between implants. Through histological and immunohistochemical evaluation we conclude that Arbomatrix(™) is well tolerated by the brain. Due to its exceptional barrier properties Arbomatrix(™) has already been shown to be an excellent protective coating for new ICP monitoring chip.

Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression.

Tissue-specific alternative splicing is critical for the emergence of tissue identity during development, yet the role of this process in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily conserved, alternative exons that represent only a minority of the total alternative exons identified. Many of these conserved exons have functional features that influence signaling pathways to profound biological effect. Here, we determined that lineage-specific splicing of a brain-enriched cassette exon in the membrane-binding tumor suppressor annexin A7 (ANXA7) diminishes endosomal targeting of the EGFR oncoprotein, consequently enhancing EGFR signaling during brain tumor progression. ANXA7 exon splicing was mediated by the ribonucleoprotein PTBP1, which is normally repressed during neuronal development. PTBP1 was highly expressed in glioblastomas due to loss of a brain-enriched microRNA (miR-124) and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that glioblastoma cells inherit the trait from a potential tumor-initiating ancestor and that these cells exploit this trait through accumulation of mutations that enhance EGFR signaling. Our data illustrate that lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates tumor suppressor functions and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones.

Cerebrospinal fluid flow impedance is elevated in Type I Chiari malformation.

Diagnosis of Type I Chiari malformation (CMI) is difficult because the most commonly used diagnostic criterion, cerebellar tonsillar herniation (CTH) greater than 3-5 mm past the foramen magnum, has been found to have little correlation with patient symptom severity. Thus, there is a need to identify new objective measurement(s) to help quantify CMI severity. This study investigated longitudinal impedance (LI) as a parameter to assess CMI in terms of impedance to cerebrospinal fluid motion near the craniovertebral junction. LI was assessed in CMI patients (N = 15) and age-matched healthy controls (N = 8) using computational fluid dynamics based on subject-specific magnetic resonance imaging (MRI) measurements of the cervical spinal subarachnoid space. In addition, CTH was measured for each subject. Mean LI in the CMI group (551 ± 66 dyn/cm5) was significantly higher than in controls (220 ± 17 dyn/cm5, p < 0.001). Mean CTH in the CMI group was 9.0 ± 1.1 mm compared to -0.4 ± 0.5 mm in controls. Regression analysis of LI versus CTH found a weak relationship (R2 = 0.46, p < 0.001), demonstrating that CTH was not a good indicator of the impedance to CSF motion caused by cerebellar herniation. These results showed that CSF flow impedance was elevated in CMI patients and that LI provides different information than a standard CTH measurement. Further research is necessary to determine if LI can be useful in CMI patient diagnosis.

Vascular endothelial growth factor in the CSF of elderly patients with ventriculomegaly: variability, periodicity and levels in drainage responders and non-responders.

OBJECTIVES: The aim of this study was to examine lumbar CSF-VEGF levels from elderly patients with ventriculomegaly to evaluate the possible circadian or periodic concentration profile and relevance to the prediction of drainage response. METHODS: Lumbar CSF samples were collected in 1-h interval over 35 h from 22 patients with ventriculomegaly. CSF-VEGF levels were measured to elucidate the possible circadian or periodic concentration profiles. These VEGF levels were evaluated for correlations with clinical response to CSF drainage, ventricle size and other clinical information. RESULTS: The 35-h CSF-VEGF levels demonstrated a periodic concentration pattern with significant episodic fluctuation with 3-5h intervals. CSF-VEGF levels in non-responder group in which patients did not show clinical improvement with CSF drainage were significantly higher than these in responder group. CONCLUSION: VEGF variation in hydrocephalus patients suggests its possible pathophysiological role in hydrocephalus. The periodic concentration pattern of CSF-VEGF must be considered when choosing the most appropriate time for sample collection or clinical manipulation. Increased VEGF level in patients who showed no improvement with CSF drainage suggests that a possible greater ischemic or vascular injury may play a role in these patients. Pending further studies, these results suggest that high VEGF levels have a potential application in predicting non-responder patients with CSF drainage and so reducing the morbidity and cost of drainage and shunting in these patients.

Hydrodynamics of the Certas™ programmable valve for the treatment of hydrocephalus.

BACKGROUND: The new Certas™ shunt for the treatment of hydrocephalus has seven standard pressure settings that according to the manufacturer range from 36 to 238 mmH2O, and an additional "Virtual Off" setting with an opening pressure >400 mmH2O. Information on actual pressure response and reliability of shunt performance is important in clinical application, especially the "Virtual Off" setting as a non-surgical replacement for shunt ligation. The objective of this study was to evaluate the in-vitro hydrodynamic performance of the Certas™ shunt. METHODS: Six new Certas™ shunts with proximal and distal catheters were tested with an automated, computerized test system that raised the pressure from zero to a maximum pressure and back to zero at each valve setting. Opening pressure and flow resistance were determined. RESULTS: For settings 1-7 the measured opening pressure range was 26 to 247 mmH2O, and the mean change in opening pressure for a one-step adjustment was between 33 and 38 mmH2O. For setting 8 ("Virtual Off") the measured mean opening pressure was 494 ± 34 mmH2O (range 451 to 556 mmH2O). The mean outflow resistance was 7.0 mmHg/ml/min (outflow conductance 17.9 µl/s/kPa). CONCLUSIONS: The six shunts had similar characteristics and closely matched the manufacturer's specifications for opening pressure at settings 1-7. The opening pressure for the "Virtual Off" setting was nearly 500 mmH2O, which is 100 mmH2O higher than the manufacturer's specification of ">400" and should be functionally off for most patients with communicating hydrocephalus. Clinical studies are needed to evaluate if the CSF dynamic profile persists after implantation in patients.

Stability analysis of vascular endothelial growth factor in cerebrospinal fluid.

Vascular endothelial growth factor (VEGF) is a promising biological marker and prognostic indicator in many neurological diseases. Although VEGF concentrations in plasma and cerebrospinal fluid (CSF) are increasingly reported, CSF-VEGF stability pre- and during-assay procedures is seldom evaluated. In the current study, we investigated VEGF variability and stability in CSF related to sample preparation, storage, and routine experimental procedures. Results showed that contaminant cell breakdown or aggregation can occur gradually before sample processing. However, after the removal of contaminant cell components, CSF-VEGF levels did not show significant changes in samples incubated at room temperature for 5 h, thawed/refrozen for 6 cycles. Samples preserved at -80 °C for up to 7 years continued to show measurable levels. Since some cellular components such as platelets contain a large amount of releasable VEGF, we conclude that CSF samples should be processed as soon as possible to carefully remove all cellular components and prevent possible consequent release of VEGF into CSF. After centrifugation to remove cellular contents, VEGF in CSF was relatively stable during routine experimental procedures and storage.

Alterations of pulsation absorber characteristics in experimental hydrocephalus.

OBJECT: Analysis of waveform data in previous studies suggests that the pulsatile movement of CSF may play a role in attenuating strong arterial pulsations entering the cranium, and its effectiveness in attenuating these pulsations may be altered by changes in intracranial pressure (ICP). These findings were obtained in studies performed in canines with normal anatomy of the CSF spaces. How then would pulsation absorbance respond to changes in CSF movement under obstructive conditions such as the development of hydrocephalus? In the present study, chronic obstructive hydrocephalus was induced by the injection of cyanoacrylate gel into the fourth ventricle of canines, and pulsation absorbance was compared before and after hydrocephalus induction. METHODS: Five animals were evaluated with simultaneous recordings of ICP and arterial blood pressure (ABP) before and at 4 and 12 weeks after fourth ventricle obstruction by cyanoacrylate. To assess how the intracranial system responds to the arterial pulsatile component, ABP and ICP waveforms recorded in a time domain had to be analyzed in a frequency domain. In an earlier study the authors introduced a particular technique that allows characterization of the intracranial system in the frequency domain with sufficient accuracy and efficiency. This same method was used to analyze the relationship between ABP and ICP waveforms recorded during several acute states including hyperventilation as well as CSF withdrawal and infusion under conditions before and after inducing chronic obstructive hydrocephalus. Such a relationship is reflected in terms of a gain, which is a function of frequency. The cardiac pulsation absorbance (CPA) index, which is simply derived from a gain evaluated at the cardiac frequency, was used to quantitatively evaluate the changes in pulsation absorber function associated with the development of hydrocephalus within each of the animals, which did become hydrocephalic. To account for normal and hydrocephalic conditions within the same animal and at multiple time points, statistical analysis was performed by repeated-measures ANOVA. RESULTS: The performance of the pulsation absorber as assessed by CPA significantly deteriorated after the development of chronic hydrocephalus. In these animals the decrement in CPA was far more significant than other anticipated changes including those in ICP, compliance, or ICP pulse amplitude. CONCLUSIONS: To the extent that the free CSF movement acts as a buffer of arterial pulsation input to flow in microvessels, alterations in the pulsation absorber may play a pathophysiological role. One measure of alterations in the way the brain deals with pulsatile input-the CPA measurement-changes dramatically with the imposition of hydrocephalus. Results in the present study suggest that CPA may serve as a complementary metric to the conventional static measure of intracranial compliance in other experimental and clinical studies.

VEGF/VEGFR-2 changes in frontal cortex, choroid plexus, and CSF after chronic obstructive hydrocephalus.

Chronic hydrocephalus (CH) is often associated with decreased cerebral blood flow (CBF) and oxygen levels. While the exact pathophysiology is not clear, vascular endothelial growth factor (VEGF) and its receptor-2 (VEGFR-2) may be involved. Because the choroid plexus (CP) is involved in cerebrospinal fluid (CSF) production and secretes numerous growth factors including VEGF, it is important to understand VEGF/VEGFR-2 levels in the CP-CSF circulatory system. Our results showed significant decreases in CBF and VEGFR-2 levels in frontal cortex (FC) in CH compared with SC; there were no significant changes in VEGF levels. CBF change in FC was positively correlated with VEGFR-2 levels (P=0.024). Immunohistochemistry (IHC) showed robust expression of VEGF/VEGFR-2 in CP. After CH induction, ventricular CSF volume and VEGF levels significantly increased. These results suggest that the decreased VEGFR-2 levels in FC may be contributed to decreased CBF and increased ventricular CSF-VEGF levels possibly reflected a hypoxic response and/or accumulation of VEGF from CP secretion after blockage of CSF outlet. Further investigation into CSF-VEGF levels in different sites may provide a better understanding of VEGF/VEGFR-2 modulation in the normal and hydrocephalic brain, and may represent a feasible approach to potential therapeutic options for hydrocephalus.

Dissociation between vascular endothelial growth factor receptor-2 and blood vessel density in the caudate nucleus after chronic hydrocephalus.

Chronic hydrocephalus (CH) is characterized by the presence of ventricular enlargement, decreased cerebral blood flow (CBF), and brain tissue oxygen delivery. Although the underlying pathophysiological role of vascular endothelial growth factor (VEGF) is not clear, ischemic-hypoxic events in CH are known to trigger its release. Previously, we have shown increased VEGF receptor-2 (VEGFR-2) and blood vessel density (BVd) in the hippocampus after CH. We investigated changes in neuronal and glial VEGFR-2 density and BVd in the caudate nucleus in an experimental model of CH. Animals with CH were divided into short term (ST, 2 to 4 weeks) and long term (LT, 12 to 16 weeks) and were compared with surgical controls (SCs, 12 to 16 weeks). The cellular and BVds were estimated using immunohistochemical and stereological counting methods. Overall, percentage (%)VEGFR-2 neurons were approximately two times greater in CH (ST, LT) than in SC. By comparison, glial cell %VEGFR-2 was greater by 10% to 17% in ST and 4% to 11% lower in LT compared with that in SC. Blood vessel density was significantly lower in CH than in SC in the superficial caudate. Changes in cerebrospinal fluid ventricular volume and pressure, as well as in CBF did not correlate with either VEGFR-2 or BVd. These observed findings suggest that destructive forces may outweigh angiogenic forces and possibly show a disassociation between VEGFR-2 and BV expressions.

An experimental in-vivo canine model for adult shunt infection.

BACKGROUND: Detailed human studies of the mechanisms and development of shunt infection in real time are not possible, and we have developed a canine hydrocephalus model to overcome this. The intention of this pilot study was to show that the canine hydrocephalus model could be shunted using conventional "human" shunts, and that a shunt infection could be established so that further studies could then be planned. METHODS: Hydrocephalus was induced in seven dogs (Canis familiaris) by fourth ventricle obstruction. Four weeks later they were shunted using a Hakim Precision valve. Four of the dogs received shunts whose ventricular catheter had been inoculated with Staphylococcus epidermidis, and three were uninoculated controls. Four weeks after shunting the dogs were sacrificed and necropsy was performed. Removed shunts and tissue samples were examined microbiologically and isolates were subjected to detailed identification and genomic comparison. RESULTS: All the dogs remained well after shunting. Examination of removed shunt components revealed S. epidermidis in the brain and throughout the shunt system in the four inoculated animals, but in two of these Staphylococcus intermedius was also found. S. intermedius was also isolated from all three "negative" controls. There were slight differences between S. intermedius strains suggesting endogenous infection rather than cross- infection from a point source. CONCLUSION: Shunt infection was established in the canine model, and had the experiment been extended beyond four weeks the typical microbiological, pathological and clinical features might have appeared. The occurrence of unplanned shunt infections in control animals due to canine normal skin flora reflects human clinical experience and underlines the usual source of bacteria causing shunt infection.