Decreased Intracranial Pressure Elevation and Cerebrospinal Fluid Outflow Resistance: A Potential Mechanism of Hypothermia Cerebroprotection Following Experimental Stroke

Background: Elevated intracranial pressure (ICP) occurs 18–24 h after ischaemic stroke and is implicated as a potential cause of early neurological deterioration. Increased resistance to cerebrospinal fluid (CSF) outflow after ischaemic stroke is a proposed mechanism for ICP elevation. Ultra-short duration hypothermia prevents ICP elevation 24 h post-stroke in rats. We aimed to determine whether hypothermia would reduce CSF outflow resistance post-stroke. Methods: Transient middle cerebral artery occlusion was performed, followed by gradual cooling to 33 °C. At 18 h post-stroke, CSF outflow resistance was measured using a steady-state infusion method. Results: Hypothermia to 33 °C prevented ICP elevation 18 h post-stroke (hypothermia ∆ICP = 0.8 ± 3.6 mmHg vs. normothermia ∆ICP = 4.4 ± 2.0 mmHg, p = 0.04) and reduced infarct volume 24 h post-stroke (hypothermia = 78.6 ± 21.3 mm3 vs. normothermia = 108.1 ± 17.8 mm3; p = 0.01). Hypothermia to 33 °C did not result in a significant reduction in CSF outflow resistance compared with normothermia controls (0.32 ± 0.36 mmHg/µL/min vs. 1.07 ± 0.99 mmHg/µL/min, p = 0.06). Conclusions: Hypothermia treatment was protective in terms of ICP rise prevention, infarct volume reduction, and may be implicated in CSF outflow resistance post-stroke. Further investigations are warranted to elucidate the mechanisms of ICP elevation and hypothermia treatment.

A Predictive Test of Outflow Enhancement by Ab Interno Trabeculectomy

Purpose: To investigate trabeculopuncture (TP) for predicting the outcome of ab interno trabeculectomy (AIT). AIT is an effective, low-risk procedure for open angle glaucoma. Despite widespread utilization, it fails in patients with an unidentified distal outflow resistance. Methods: We bisected 81 enucleated porcine eyes and perfused them for 72 hours. They were assigned to two groups: trial (n=42) and control (n=39). Intraocular pressure (IOP) was measured continuously. At 24 hours, four YAG-laser trabeculopunctures on the nasal trabecular meshwork were performed, followed by a 180° AIT at the same site at 48 hours. Eyes were divided into TP and AIT responders and non-responders; the proportion of TP responders between both AIT groups was compared. Results: Both post-TP and post-AIT IOPs were lower than baseline IOP (p=0.015 and p<0.01, respectively). The success rates of TP and AIT were 69% and 85.7%, respectively. The proportion of TP responders among AIT responders was greater than that of AIT non-responders (p<0.01). Sensitivity and specificity values of TP as predictive test for AIT success were 77.7% and 83.3%, respectively. The positive and negative predictive values were 96.6% and 38.5%, respectively. Conclusion: A 10% reduction in IOP after TP can be used as predictor for the success (>20% IOP decrease) of 180° AIT in porcine eyes.

Suppression of TGF-β1 signaling by Matrigel via FAK signaling in cultured human trabecular meshwork cells

The trabecular meshwork (TM) is composed of TM cells and beams of the extracellular matrix, together contributing to aqueous humor (AH) outflow resistance. Herein, we validated that our culture system on 2D Matrigel expressed putative TM markers and myocilin, of which the latter was upregulated by dexamethasone. Continuous passage of these cells on 2D Matrigel resulted in a gradual loss of expression of these markers. However, such a loss was restored by seeding cells in 3D Matrigel where expression of TM markers was further upregulated upon continuous passage. In contrast, TM cells seeded on fibronectin, collagen I/IV, or laminin lost expression of these markers and turned into myofibroblasts with expression of αSMA, which were dose-dependently upregulated by TGF-β1/TGF-β2. TM cells in 3D Matrigel also expressed TGF-β1/TGF-β3 despite challenge of TGF-β1. The maintenance of TM phenotype by 3D Matrigel was linked to inhibition of canonical TGF-β signaling and activation of pFAK-pSrc-pP190RhoGAP-P120RasGAP signaling. These findings indicate that basement membrane matrix with low rigidity plays an active role in maintaining TM phenotype in the presence of TGF-β1 and shed light on its physiological role. Furthermore, abnormal matrices may perpetuate the pathological TM phenotype when the level of TGF-β2 is elevated in glaucoma patients.

Effect Of Topical DLBS 1425 On Tissue Plasminogen Activator (tPA) Expression In Trabecular Meshwork Of Wistar Rats

Introduction: Tissue plasminogen activator (tPA) in the trabecular meshwork (TM) is a serine protease that important to maintain the aquos outflow resistance by activating the matrix metalloproteinase (MMP). It can cause a degradation of the extracellular matrix, which can maintain the normal flow of aquos humor. However, the use of anti-inflammatory drugs has been shown to reduce the expression of tPA, leading to an increase in the outflow resistance. Therefore, we propose the use of DLBS 1425, an extract of Phaleria macrocarpa which has been proven to have anti-inflammatory effects. Aim : This study aims to determine the expression of tPA in Wistar rats’ TM. Methods : An experimental laboratory study with post-test only randomized controlled group design was performed. Twenty-two Wistar rats were divided into two groups, the control and the experimental. The experimental group was given topical DLBS 1425 at a dose of 6 times / day, for 4 weeks. The control group was given drops of Hyalub Minidose® 6 times / day, for 4 weeks. tPA expression on TM was examined by immunohistochemical staining. Data were collected and processed using the SPSS 15.0 for Windows. Results : The mean tPA expression in TM with Allred scores in the experimental group (0.18 ± 0.60) was significantly lower (p <0.001) than the control group (6.27 ± 0.91). Conclusion : Topical DLBS 1425 suppresses the expression of tPA on the trabecular meshwork of Wistar rats. Key words: tissue plasminogen activator, trabecular meshwork, DLBS 1425, Phaleria macrocarpa.

Crosstalk between MicroRNA and Oxidative Stress in Primary Open-Angle Glaucoma

Reactive oxygen species (ROS) plays a key role in the pathogenesis of primary open-angle glaucoma (POAG), a chronic neurodegenerative disease that damages the trabecular meshwork (TM) cells, inducing apoptosis of the retinal ganglion cells (RGC), deteriorating the optic nerve head, and leading to blindness. Aqueous humor (AH) outflow resistance and intraocular pressure (IOP) elevation contribute to disease progression. Nevertheless, despite the existence of pharmacological and surgical treatments, there is room for the development of additional treatment approaches. The following review is aimed at investigating the role of different microRNAs (miRNAs) in the expression of genes and proteins involved in the regulation of inflammatory and degenerative processes, focusing on the delicate balance of synthesis and deposition of extracellular matrix (ECM) regulated by chronic oxidative stress in POAG related tissues. The neutralizing activity of a couple of miRNAs was described, suggesting effective downregulation of pro-inflammatory and pro-fibrotic signaling pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), transforming growth factor-beta 2 (TGF-β2), Wnt/β-Catenin, and PI3K/AKT. In addition, with regards to the elevated IOP in many POAG patients due to increased outflow resistance, Collagen type I degradation was stimulated by some miRNAs and prevented ECM deposition in TM cells. Mitochondrial dysfunction as a consequence of oxidative stress was suppressed following exposure to different miRNAs. In contrast, increased oxidative damage by inhibiting the mTOR signaling pathway was described as part of the action of selected miRNAs. Summarizing, specific miRNAs may be promising therapeutic targets for lowering or preventing oxidative stress injury in POAG patients.

Measurement of outflow resistance imposed by magnetic sphincter augmentation: defining normal values and clinical implication

Introduction No manometric criteria have been defined to select patients for magnetic sphincter augmentation (MSA). The first step to establish such criteria is to measure the outflow resistance at esophagogastric junction (EGJ) imposed by MSA. This resistance needs to be overcome by the esophageal contraction in order for the esophagus to empty and to avoid postoperative dysphagia. This study was designed to measure the outflow resistance caused by MSA in patients free of postoperative dysphagia. Methods Records of the patients who underwent MSA in our institution were reviewed. A group of MSA patients with excellent functional outcome, who were free of clinically significant postoperative dysphagia, were selected. These patients then underwent high-resolution impedance manometry (HRIM) at a target date of 1 year after surgery. The outflow resistance was measured by the esophageal intrabolus pressure (iBP) recorded 2 cm proximal to the lower esophageal sphincter (LES). Results The study population consisted of 43 patients. HRIM was performed at mean of 20.4 (10.4) months after surgery. The mean (SD) amplitude of the iBP was 13.5 (4.3) before surgery and increased to 19.1 (5.6) after MSA (p < 0.0001). Patients with a smaller size LINX device (≤ 14 beads) had a similar iBP when compared to those with a larger device (> 15 beads) [19.7 (4.5) vs. 18.4 (5.9), p = 0.35]. There was a significant correlation between the iBP and % incomplete bolus clearance [Spearman R: 0.44 (95% CI 0.15–0.66), p = 0.0032]. The 95th percentile value for iBP after MSA was 30.4 mmHg. Conclusion The EGJ outflow resistance measured by iBP is increased after MSA. The upper limit of normal for iBP is 30 mmHg in this cohort of patients who were free of dysphagia after MSA. This degree of resistance needs to be overcome by distal esophageal contraction and will likely be requisite to prevent persistent postoperative dysphagia.

Cerebrospinal fluid dynamics with its surgical implications

Cerebrospinal fluid (CSF) is largely (70-80%) produced by the choroids plexus of the ventricles and is considered as the plasma ultrafiltrate. While CSF formation, circulation, and composition appear to be physiological and physical, its absorption appears to be mainly physical. The formation, composition, circulation, absorption, and changes in pathological conditions of CSF are discussed briefly in this review article. The CSF pressure dynamics studies provide information about the tightness, elastance, or outflow resistance of the CSF in the CNS. We believe that the present study shall help to provide essential details of CSF physiology which are important to many disciplines including radiology, neurology, and neurosurgery.