Prostaglandin analog effects on cerebrospinal fluid reabsorption via nasal mucosa

Introduction Cerebrospinal fluid (CSF) outflow has been demonstrated along nasal lymphatics via olfactory nerve projections; flow may be increased by stimulating lymphatic contractility using agents such as noradrenaline and the thromboxane A2 analog U46619. Lymphatics elsewhere in the body show increased contractility upon exposure to the prostaglandin F2alpha analog isoprostane-8-epi-prostaglandin. We investigated the ability of ophthalmic prostaglandin F2alpha analogs to increase CSF outflow when applied to the nasal mucosa by inhalation. Methods Latanoprost (0.1, 0.5, or 1mg/ml), bimatoprost (0.3 or 3mg/ml), travoprost (0.04 or 0.4mg/ml), latanoprostene bunod (0.24 or 2.4mg/ml), tafluprost (0.25 or 2.5mg/ml), or control vehicle (10% DMSO) was administered to awake adult C57B/6 mice by nasal inhalation of 2μl droplets. Multiday dosing (daily for 3 days) of latanoprost also was evaluated. A total of 81 animals were studied including controls. General anesthesia was induced by injection, and fluorescent tracer (AlexaFluor647-labelled ovalbumin) was injected under stereotaxic guidance into the right lateral ventricle. Nasal turbinate tissue was harvested and homogenized after 1 hour for tracer detection by ELISA and fluorometric analysis. Results Inhalation of latanoprost 0.5mg/ml and 1mg/ml led to a 11.5-fold increase in tracer recovery from nasal turbinate tissues compared to controls (3312 pg/ml vs 288 pg/ml, p<0.001 for 0.5mg/ml; 3355 pg/ml vs 288 pg/ml, p<0.001 for 1mg/ml), while latanoprost 0.1 mg/ml enhanced recovery 6-fold (1713 pg/ml vs 288 pg/ml, p<0.01). Tafluprost 0.25mg/ml and bimatoprost 0.3mg/ml showed a modest (1.4x, p<0.05) effect, and the remaining agents showed no significant effect on tracer recovery. After 3 days of daily latanoprost treatment and several hours after the last dose, a persistently increased recovery of tracer was found. Conclusions Prostaglandin F2alpha analogs delivered by nasal inhalation resulted in increased nasal recovery of a CSF fluorescent tracer, implying increased CSF outflow via the nasal lymphatics. The greatest effect, partially dose-dependent, was observed using latanoprost. Further studies are needed to determine the efficacy of these agents in reducing ICP in short and long-term applications.

An Operators Investigation of Performance Drivers Using Diagnostics and Data Analytics

In multi-stage plug-and-perf horizontal well completions, there are a multitude of moving parts and variables to consider when evaluating performance drivers. Properly identifying performance drivers allows an operator to focus their efforts to maximize the rate of return of resource development. Typically, well-to-well comparisons are made to help identify performance drivers, but in many cases the differences are not clear. Identifying these drivers may require a better understanding of performance variability along a single lateral. Data analytics can help to identify performance drivers using existing data from development activities. In the case study below, multiple diagnostics are utilized to identify performance drivers. A combination of completion diagnostics including oil and water tracers, stimulation data, reservoir data, 3D seismic, and borehole image logs were collected on a set of wells in the early appraisal phase of a field. Using oil tracers as the best indication of stage level performance along the laterals, data analytics is applied to uncover the relationships between the tracers and the numerous diagnostics. After smoothing was applied to the dataset, trends between oil tracer recovery, several independent variables and features seen in image logs and 3D seismic were identified. All the analyses pointed to decreasing tracer recovery, and likely decreased oil production, near faulted areas along each lateral. A random forest model showed a moderate prediction power, where the model's predicted tracer recovery on blind stages was able to explain 54% of the variance seen in the tracer response (r2=0.54). This analysis suggests the identification of certain faulted areas along the wellbore could lead to ways of improving individual well economics by adjusting completion design in these areas.

Prostaglandin analog effects on cerebrospinal fluid reabsorption via nasal mucosa

IntroductionCerebrospinal fluid (CSF) outflow has been demonstrated along nasal lymphatics via olfactory nerve projections; flow may be increased by stimulating lymphatic contractility using agents such as noradrenaline and the thromboxane A2 analog U46619. Lymphatics elsewhere in the body show increased contractility upon exposure to the prostaglandin F2alpha analog isoprostane-8-epi-prostaglandin. We investigated the ability of ophthalmic prostaglandin F2alpha analogs to increase CSF outflow when applied to the nasal mucosa by inhalation.MethodsLatanoprost (0.1, 0.5, or 1mg/ml), bimatoprost (0.3 or 3mg/ml), travoprost (0.04 or 0.4mg/ml), latanoprostene bunod (0.24 or 2.4mg/ml), tafluprost (0.25 or 2.5mg/ml), or vehicle (10% DMSO) was administered to awake adult C57B/6 mice by nasal inhalation of 2μl droplets. A total of 67 animals were studied including controls. General anesthesia was induced by injection, and fluorescent tracer (AlexaFluor647-labelled ovalbumin) was injected under stereotaxic guidance into the right lateral ventricle. Nasal turbinate tissue was harvested and homogenized after 1 hour for tracer detection by ELISA and fluorometric analysis.ResultsInhalation of latanoprost 0.5mg/ml and 1mg/ml led to a 11.5-fold increase in tracer recovery from nasal turbinate tissues compared to controls (3312 pg/ml vs 288 pg/ml, p<0.001 for 0.5mg/ml; 3355 pg/ml vs 288 pg/ml, p<0.001 for 1mg/ml), while latanoprost 0.1 mg/ml enhanced recovery 6-fold (1713 pg/ml vs 288 pg/ml, p<0.01). Tafluprost 0.25mg/ml and bimatoprost 0.3mg/ml showed a modest (1.4x, p<0.05) effect, and the remaining agents showed no significant effect on tracer recovery.ConclusionsProstaglandin F2alpha analogs delivered by nasal inhalation resulted in increased nasal recovery of a CSF fluorescent tracer, implying increased CSF outflow via the nasal lymphatics. The greatest effect, partially dose-dependent, was observed using latanoprost. Further studies are needed to determine the efficacy of these agents in reducing ICP in short and long-term applications.

Integrated Analysis of Tracer and Pressure-Interference Tests To Identify Well Interference

Summary In ultralow-permeability reservoirs, communication between wells through connected fractures can be observed through tracer and pressure-interference tests. Understanding the connectivity between fractured horizontal wells in a multiwell pad is important for infill well drilling and parent-child well interactions. Interwell tracer and pressure-interference tests involve two or more fractured horizontal wells and provide information about hydraulic-fracture connectivity between the wells. In this work, we present an integrated approach based on the analysis of tracer and pressure interference data to obtain the degree of interference between fractured horizontal wells in a multiwell pad. We analyze well interference using tracer (chemical tracer and radioactive proppant tracer) and pressure data in an 11-well pad in the Permian Basin. Changes in pressure and tracer concentration in the monitor wells were used to identify and evaluate interference between the source and monitor wells. Extremely low tracer recovery and weak pressure response signify the absence of connected fractures and suggest that interference through matrix alone is insignificant. Combined tracer and pressure-interference data suggest connected fracture pathways between the communicating wells. The degree of interference can be estimated in terms of pressure response times and tracer recovery. An effective reservoir model was used to simulate pressure interference between wells during production. Simulation results indicate that well interference observed during production is primarily because of hydraulically connected fractures. Combined tracer and pressure-interference analysis provides a unique tool for understanding the time-dependent connectivity between communicating wells, which can be useful for optimizing infill well drilling, well spacing, and fracture sizing in future treatment designs.

Brain-blood permeability: TNF-α promotes escape of protein tracer from CSF to blood

The objective of this study was to determine the effect of tumor necrosis factor (TNF)-α on the efflux of protein from the central nervous system to blood based on assessing the clearance of radiolabeled albumin from the cerebrospinal fluid (CSF) to blood in rats. 125I-labeled human serum albumin (125I-HSA) was injected into a lateral ventricle, and venous blood was sampled hourly to determine the basal CSF protein clearance into the blood. After this, rats were intraventricularly infused with 10 μl TNF-α and 10 μl131I-HSA ( n = 6) or 10 μl saline and 10 μl 131I-HSA ( n = 6). Venous blood was sampled hourly for 3 h. 131I-HSA tracer recovery increased threefold in the venous blood and was significantly higher in the spleen, muscles, and skin in animals treated with TNF-α. No significant changes were observed in control animals treated with saline. The data suggest that TNF-α promotes the clearance of protein macromolecules from the CSF to the venous blood.

Contribution of extracranial lymphatics and arachnoid villi to the clearance of a CSF tracer in the rat

The objective of this study was to determine the relative roles of arachnoid villi and cervical lymphatics in the clearance of a cerebrospinal fluid (CSF) tracer in rats.125I-labeled human serum albumin (125I-HSA; 100 μg) was injected into one lateral ventricle, and an Evans blue dye-rat protein complex was injected intravenously. Arterial blood was sampled for 3 h. Immediately after this, multiple cervical vessels were ligated in the same animals, and plasma recoveries were monitored for a further 3 h after the intracerebroventricular injection of 100 μg131I-HSA. Tracer recovery in plasma at 3 h averaged (%injected dose) 0.697 ± 0.042 before lymphatic ligation and dropped significantly to 0.357 ± 0.060 after ligation. Estimates of the rate constant associated with the transport of the CSF tracer to plasma were also significantly lower after obstruction of cervical lymphatics (from 0.584 ± 0.072/h to 0.217 ± 0.056/h). No significant changes were observed in sham-operated animals. Assuming that the movement of the CSF tracer to plasma in lymph-ligated animals was a result of arachnoid villi clearance, we conclude that arachnoid villi and extracranial lymphatic pathways contributed equally to the clearance of the CSF tracer from the cranial vault.