A high-resolution real-time quantification of astrocyte cytokine secretion under shear stress for investigating hydrocephalus shunt failure.
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ABSTRACT:
SUBMITTER: Khodadadei F
PROVIDER: S-EPMC7988003 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Pediatric hydrocephalus is a devastating and costly disease. The mainstay of treatment is still surgical shunting of cerebrospinal fluid (CSF). These shunts fail at a high rate and impose a significant burden on patients, their families and society. The relationship between clinical decision making and shunt failure is poorly understood and multifaceted, but catheter occlusion remains the most frequent cause of shunt complications. In order to investigate factors that affect shunt failure, we have established the Wayne State University (WSU) shunt biobank. METHODS:To date, four hospital centers have contributed various components of failed shunts and CSF from patients diagnosed with hydrocephalus before adulthood. The hardware samples are transported in paraformaldehyde and transferred to phosphate-buffered saline with sodium azide upon deposit into the biobank. Once in the bank, they are then available for study. Informed consent is obtained by the local center before corresponding clinical data are entered into a REDCap database. Data such as hydrocephalus etiology and details of shunt revision history. All data are entered under a coded identifier. RESULTS:293 shunt samples were collected from 228 pediatric patients starting from May 2015 to September 2019. We saw a significant difference in the number of revisions per patient between centers (Kruskal-Wallis H test, p value?<?0.001). The leading etiology at all centers was post-hemorrhagic hydrocephalus, a fisher's exact test showed there to be statistically significant differences in etiology between center (p?=?0.01). Regression showed age (p?<?0.01), race (p?=?0.038) and hospital-center (p?<?0.001) to explain significant variance in the number of revisions. Our model accounted for 31.9% of the variance in revisions. Generalized linear modeling showed hydrocephalus etiology (p?<?0.001), age (p?<?0.001), weight and physician (p?<?0.001) to impact the number of ventricular obstructions. CONCLUSION:The retrospective analysis identified that differences exist between currently enrolled centers, although further work is needed before clinically actionable recommendations can be made. Moreover, the variables collected from this chart review explain a meaningful amount of variance in the number of revision surgeries. Future work will expand on the contribution of different site-specific and patient-specific factors to identify potential cause and effect relationships.
| S-EPMC7368709 | biostudies-literature
Project description:Quiescence is commonly used to describe the inactive state of endothelial cells (ECs) in monolayers that have reached homeostasis. Experimentally quiescence is usually described in terms of the relative change in cell activity (e.g. turnover, speed, etc.) in response to a perturbation (e.g. solute, shear stress, etc.). The objective of this study is to provide new insight into EC quiescence by quantitatively defining the morphology and activity of confluent cell monolayers in response to shear stress and vascular modulators. Confluent monolayers of human umbilical vein ECs (HUVECs) were subjected to a range of shear stresses (4-16 dyne cm-2) under steady flow. Using phase contrast, time-lapse microscopy and image analysis, we quantified EC morphology, speed, proliferation, and apoptosis rates over time and detected differences in monolayer responses under various media conditions: basal media supplemented with growth factors, interleukin-8, or cyclic AMP. In all conditions, we observed a transition from cobblestone to spindle-like morphology in a dose-dependent manner due to shear stress. Cyclic AMP enhanced the elongation and alignment of HUVECs due to shear stress and reduced steady state cell speed. We observed the lowest proliferation rates below 8 dyne cm-2 and found that growth factors and cyclic AMP reduced proliferation and apoptosis; interleukin-8 similarly decreased proliferation, but increased apoptosis. We have quantified the response of ECs in confluent monolayers to shear stress and vascular modulators in terms of morphology, speed, proliferation and apoptosis and have established quantifiable metrics of cell activity to define vascular quiescence under shear stress.
| S-EPMC5490251 | biostudies-literature
Project description:Background and purposeTo examine the effect of delayed compared to early planning of shunt surgery on survival, in patients with idiopathic normal pressure hydrocephalus (iNPH), a long-term follow-up case-control study of patients exposed to a severe delay of treatment was performed.MethodsIn 2010-2011 our university hospital was affected by an administrative and economic failure that led to postponement of several elective neurosurgical procedures. This resulted in an unintentional delay of planning of treatment for a group of iNPH patients, referred to as iNPHDelayed (n = 33, waiting time for shunt surgery 6-24 months). These were compared to patients treated within 3 months, iNPHEarly (n = 69). Primary outcome was mortality. Dates and underlying causes of death were provided by the Cause of Death Registry. Survival was analysed by Kaplan-Meier plots and a Cox proportional hazard model adjusted for potential confounders.ResultsMedian follow-up time was 6.0 years. Crude 4-year mortality was 39.4% in iNPHDelayed compared to 10.1% in iNPHEarly (p = 0.001). The adjusted hazard ratio in iNPHDelayed was 2.57; 95% confidence interval 1.13-5.83, p = 0.024. Causes of death were equally distributed between the groups except for death due to malignancy which was not seen in iNPHDelayed but in 4/16 cases in iNPHEarly (p = 0.044).ConclusionsThe present data indicate that shunt surgery is effective in iNPH and that early treatment increases survival.
| S-EPMC7986742 | biostudies-literature
Project description: Not available
| S-EPMC9276358 | biostudies-literature
Project description:Molecular biomarkers for neurodegenerative diseases are critical for advancing diagnosis and therapy. Normal pressure hydrocephalus (NPH) is a neurological disorder characterized by progressive neurodegeneration, gait impairment, urinary incontinence and cognitive decline. In contrast to most other neurodegenerative disorders, NPH symptoms can be improved by the placement of a ventricular shunt that drains excess CSF. A major challenge in NPH management is the identification of patients who benefit from shunt surgery. Here, we perform genome-wide RNA sequencing of extracellular vesicles in CSF of 42 NPH patients, and we identify genes and pathways whose expression levels correlate with gait, urinary or cognitive symptom improvement after shunt surgery. We describe a machine learning algorithm trained on these gene expression profiles to predict shunt surgery response with high accuracy. The transcriptomic signatures we identified may have important implications for improving NPH diagnosis and treatment and for understanding disease aetiology.
2023-06-02 | GSE212236 | GEO
Project description:Normal pressure hydrocephalus is a frequently missed clinical entity with the typical symptom triad of gait disturbance, urinary incontinence and dementia (Hakim's triad) and occurs mostly from the 6th decade of life onwards. Early therapy can lead to a complete reversal of the symptoms. The present case report is intended to draw attention to the clinical entity normal pressure hydrocephalus (NPH) since the afflicted patients often primarily consult a gynaecologist on account of the urinary bladder disorders.
| S-EPMC4168357 | biostudies-literature
Project description:BackgroundApproximately 30% of cerebrospinal fluid (CSF) shunt systems for hydrocephalus fail within the first year and 98% of all patients will have shunt failure in their lifetime. Obstruction remains the most common reason for shunt failure. Previous evidence suggests elevated pro-inflammatory cytokines in CSF are associated with worsening clinical outcomes in neuroinflammatory diseases. The aim of this study was to determine whether cytokines and matrix metalloproteinases (MMPs) contribute towards shunt failure in hydrocephalus.MethodsUsing multiplex ELISA, this study examined shunt failure through the CSF protein concentration profiles of select pro-inflammatory and anti-inflammatory cytokines, as well as select MMPs. Interdependencies such as the past number of previous revisions, length of time implanted, patient age, and obstruction or non-obstruction revision were examined. The pro-inflammatory cytokines were IL-1?, IL-2, IL-5, IL-6, IL-8, IL-12, IL-17, TNF-?, GM-CSF, IFN-?. The anti-inflammatory cytokines were IL-4 and IL-10, and the MMPs were MMP-2, MMP-3, MMP-7, MMP-9. Protein concentration is reported as pg/mL for each analyte.ResultsPatient CSF was obtained at the time of shunt revision operation; all pediatric (<?18), totaling n?=?38. IL-10, IL-6, IL-8 and MMP-7 demonstrated significantly increased concentrations in patient CSF for the non-obstructed subgroup. Etiological examination revealed IL-6 was increased in both obstructed and non-obstructed cases for PHH and congenital hydrocephalic patients, while IL-8 was higher only in PHH patients. In terms of number of past revisions, IL-10, IL-6, IL-8, MMP-7 and MMP-9 progressively increased from zero to two past revisions and then remained low for subsequent revisions. This presentation was notably absent in the obstruction subgroup. Shunts implanted for three months or less showed significantly increased concentrations of IL-6, IL-8, and MMP-7 in the obstruction subgroup. Lastly, only patients aged six months or less presented with significantly increased concentration of IL-8 and MMP-7.ConclusionNon-obstructive cases are reported here to accompany significantly higher CSF cytokine and MMP protein levels compared to obstructive cases for IL-10, IL-6, IL-8, MMP-7 and MMP-9. A closer examination of the definition of obstruction and the role neuroinflammation plays in creating shunt obstruction in hydrocephalic patients is suggested.
| S-EPMC7845119 | biostudies-literature
Project description:Hydrocephalus is a frequent complication following subarachnoid hemorrhage. Few studies investigated the association between laboratory parameters and shunt-dependent hydrocephalus. This study aimed to investigate the variations of laboratory parameters after subarachnoid hemorrhage. We also attempted to identify predictive laboratory parameters for shunt-dependent hydrocephalus.Multiple imputation was performed to fill the missing laboratory data using Bayesian methods in SPSS. We used univariate and multivariate Cox regression analyses to calculate hazard ratios for shunt-dependent hydrocephalus based on clinical and laboratory factors. The area under the receiver operating characteristic curve was used to determine the laboratory risk values predicting shunt-dependent hydrocephalus.We included 181 participants with a mean age of 54.4 years. Higher sodium (hazard ratio, 1.53; 95% confidence interval, 1.13-2.07; p = 0.005), lower potassium, and higher glucose levels were associated with higher shunt-dependent hydrocephalus. The receiver operating characteristic curve analysis showed that the areas under the curve of sodium, potassium, and glucose were 0.649 (cutoff value, 142.75 mEq/L), 0.609 (cutoff value, 3.04 mmol/L), and 0.664 (cutoff value, 140.51 mg/dL), respectively.Despite the exploratory nature of this study, we found that higher sodium, lower potassium, and higher glucose levels were predictive values for shunt-dependent hydrocephalus from postoperative day (POD) 1 to POD 12-16 after subarachnoid hemorrhage. Strict correction of electrolyte imbalance seems necessary to reduce shunt-dependent hydrocephalus. Further large studies are warranted to confirm our findings.
| S-EPMC5726740 | biostudies-literature
Project description:Idiopathic normal pressure hydrocephalus (iNPH) is a syndrome characterized by gait disturbance, cognitive deterioration and urinary incontinence in elderly individuals. These symptoms can be improved by shunt operation in some but not all patients. Therefore, discovering predictive factors for the surgical outcome is of great clinical importance. We used normalized power variance (NPV) of electroencephalography (EEG) waves, a sensitive measure of the instability of cortical electrical activity, and found significantly higher NPV in beta frequency band at the right fronto-temporo-occipital electrodes (Fp2, T4 and O2) in shunt responders compared to non-responders. By utilizing these differences, we were able to correctly identify responders and non-responders to shunt operation with a positive predictive value of 80% and a negative predictive value of 88%. Our findings indicate that NPV can be useful in noninvasively predicting the clinical outcome of shunt operation in patients with iNPH.
| S-EPMC4293598 | biostudies-other
Project description:We aimed to determine whether presence of AD neuropathology predicted cognitive, gait and balance measures in patients with idiopathic normal pressure hydrocephalus (iNPH) after shunt surgery. This is a prospective study of gait and balance measured by Timed Up and Go (TUG) and Tinetti tests, and cognitive function measured by Mini Mental Status Exam (MMSE), before and after shunt surgery in participants 65 years and older with iNPH at the Johns Hopkins University. Random effects models were used and adjusted for confounders. 88 participants were included in the analysis with a median (IQR) time of 104 (57-213) days between surgery and follow-up. 23 (25%) participants had neuritic plaques present (NP+) and were significantly older [76.4 (6.0) years], but were otherwise similar in all demographics and outcome measures, when compared to the group without neuritic plaques (NP-). NP- and NP+ participants equally improved on measures of TUG (β = -3.27, 95% CI -6.24, -0.30, p = 0.03; β = -2.37, 95% CI -3.90, -0.86, p = 0.02, respectively), Tinetti-total (β = 1.95, 95% CI 1.11, 2.78, p<0.001; β = 1.72, 95% CI 0.90, 2.53, p<0.001, respectively), -balance (β = 0.81, 95% CI 0.23, 1.38, p = 0.006; β = 0.87, 95% CI 0.40, 1.34, p<0.001, respectively) and -gait (β = 1.03, 95% CI 0.61, 1.45, p<0.001; β = 0.84, 95% CI 0.16, 1.53, p = 0.02, respectively), while neither NP- nor NP+ showed significant improvement on MMSE (β = 0.10, 95% CI -0.27, 0.46, p = 0.61, β = 0.41, 95% CI -0.27, 1.09, p = 0.24, respectively). In summary, 26% of participants with iNPH had coexisting AD pathology, which does not significantly influence the clinical response to shunt surgery.
| S-EPMC5546572 | biostudies-other