Dietary nitrate supplementation increases nitrate and nitrite concentrations in human skin interstitial fluid.

Acute dietary nitrate (NO3-) supplementation can increase [NO3-], but not nitrite ([NO2-]), in human skeletal muscle, though its effect on [NO3-] and [NO2-] in skin remains unknown. In an independent group design, 11 young adults ingested 140 mL of NO3--rich beetroot juice (BR; 9.6 mmol NO3-), and 6 young adults ingested 140 mL of a NO3--depleted placebo (PL). Skin dialysate, acquired through intradermal microdialysis, and venous blood samples were collected at baseline and every hour post-ingestion up to 4 h to assess dialysate and plasma [NO3-] and [NO2-]. The relative recovery rate of NO3- and NO2- through the microdialysis probe (73.1% and 62.8%), determined in a separate experiment, was used to estimate skin interstitial [NO3-] and [NO2-]. Baseline [NO3-] was lower, whereas baseline [NO2-] was higher in the skin interstitial fluid relative to plasma (both P < 0.001). Acute BR ingestion increased [NO3-] and [NO2-] in the skin interstitial fluid and plasma (all P < 0.001), with the magnitude being smaller in the skin interstitial fluid (e.g., 183 ± 54 vs. 491 ± 62 µM for Δ[NO3-] from baseline and 155 ± 190 vs. 217 ± 204 nM for Δ[NO2-] from baseline at 3 h post BR ingestion, both P ≤ 0.037). However, due to the aforementioned baseline differences, skin interstitial fluid [NO2-] post BR ingestion was higher, whereas [NO3-] was lower relative to plasma (all P < 0.001). These findings extend our understanding of NO3- and NO2- distribution at rest and indicate that acute BR supplementation increases [NO3-] and [NO2-] in human skin interstitial fluid.

Revealing drug release and diffusion behavior in skin interstitial fluid by surface-enhanced Raman scattering microneedles.

Microneedle (MNs), as a novel dermal drug delivery formulation, have drawn a lot of attention in recent years. Drug release and diffusion behavior in dermal interstitial fluid (ISF) determines the pharmacokinetics and effectiveness of MNs, which have not been clearly elucidated until now. Herein, we develop surface-enhanced Raman scattering (SERS)-based detection MNs (D-MNs) for the sensitive analysis of model drugs in ISF. The surface of the D-MNs was deposited with a high density of hotspot-rich core-satellite gold nanoparticles, which would generate a sensitive SERS signal of a model drug (3,3'-diethylthiatricarbocyanine, DTTC) released by therapeutic MNs (T-MNs). Furthermore, the D-MNs produced an internal-standard signal for drug signal calibration, increasing the accuracy of detection. Taking advantage of the D-MNs, the release and diffusion behavior of the drug from T-MNs in the ISF of living mice was systematically studied. It was found that DTTC diffused without directional preference in ISF up to a distance of 1.5 cm. The intensities at diffusion sites decreased sharply with increasing distance from the release site (less than 0.3% at 1.5 cm). These results indicated that drug concentration gradient rather than ISF fluidity was a major driving force for the diffusion. Moreover, the application of water-soluble MN polymers, hydrophilic model drugs in T-MNs, as well as a heating or cupping treatment of mouse skin, enhanced drug diffusion in ISF. This work provides a new tool for in situ and real-time detection of molecules in ISF, which would be beneficial for the development and evaluation of MN-based therapeutic systems.

A Randomized Controlled Trial of Changes in Fluid Distribution across Menstrual Phases with Creatine Supplementation.

This study examined the effects of creatine (Cr) loading on body mass (BM) and fluid markers of total body water (TBW), extra-cellular fluid (ECF), and intra-cellular fluid (ICF) across the menstrual cycle (MC). Thirty moderately active females, either naturally-menstruating (NM) or using hormonal contraceptives (HC), were randomized to Cr (Cr; 4 × 5 g/day of creatine monohydrate for 5 days; n = 15) or a non-caloric placebo (PL; n = 15) using a double-blind, placebo-controlled design, with a menstrual phase crossover. BM, TBW, ECF, and ICF were measured at pre- and post-supplementation in randomized order of follicular phase (FP; NM: MC days 0−8, HC: inactive pill days) or luteal phase (LP; NM: ≤15 days from next projected cycle start date, HC: active pill days) using bioelectrical impedance spectroscopy. Acute hydration status and salivary estrogen were used as covariates. Change in BM was not different between groups across MC ([PL-Cr] Δ 0.40 ± 0.50 kg; p = 0.427) or between MC phase across groups ([FP-LP] Δ 0.31 ± 0.48 kg; p = 0.528). TBW (p = 0.802), ECF (p = 0.373), and ICF (p = 0.795) were not different between supplement groups at pre-supplementation/FP time points. There were no significant differences between the NM and HC subjects at any time point, for any outcome (p > 0.05). Following LP supplementation, significant changes were observed in TBW (Cr: Δ 0.83 ± 0.38 L, PL: Δ −0.62 ± 0.38 L; p = 0.021), ECF (Cr: Δ 0.46 ± 0.15 L, PL: Δ −0.19 ± 0.15 L; p = 0.013), and ICF (Cr: Δ 0.74 ± 0.23 L, PL: Δ −0.02 ± 0.23 L; p = 0.041). These data demonstrate an increase in all fluid compartments in the LP following Cr loading, without observed alterations in body weight for females.

[Epidural photobiomodulation accelerates the drainage of brain interstitial fluid and its mechanism].

OBJECTIVE: To evaluate the effect of photobiomodulation (PBM) on the drainage of brain interstitial fluid (ISF) and to investigate the possible mechanism of the positive effect of PBM on Alzheimer's disease (AD). METHODS: Twenty-four SD male rats were randomly divided into PBM group (n=12), sham PBM group (n=6), and negative control group (n=6). According to the injection site of tracer, the PBM group was further divided into PBM-ipsilateral traced group (n=6) and PBM-contralateral traced group (n=6). Rats in the PBM group and the sham PBM group were exposed to the dura minimally invasively on the skull corresponding to the frontal cortical area reached by ISF drainage from caudate nucleus region. The PBM group was irradiated by using 630 nm red light (5-6 mW/cm2), following an irradiation of 5 min with a 2 min pause, and a total of 5 times; the sham PBM group was kept in the same position for the same time using the light without power. The negative control group was kept without any measure. After PBM, tracer was injected into caudate nucleus of each group. The changes of ISF drainage in caudate nucleus were observed according to the diffusion and distribution of tracer molecule by tracer-based magnetic resonance imaging, and the structural changes of brain extracellular space (ECS) were analyzed by diffusion rate in ECS-mapping (DECS-mapping) technique. Finally, parameters reflecting the structure of brain ECS and the drainage of ISF were obtained: volume fraction (α), tortuo-sity (λ), half-life (T1/2), and DECS. The differences of parameters among different groups were compared to analyze the effect of PBM on brain ECS and ISF. One-Way ANOVA post hoc tests and independent sample t test were used for statistical analysis. RESULTS: The parameters including T1/2, DECS, and λ were significantly different among the PBM-ipsilateral traced group, the PBM-contralateral traced group, and the sham PBM group (F=79.286, P < 0.001; F=13.458, P < 0.001; F=10.948, P=0.001), while there was no difference in the parameter α of brain ECS among the three groups (F=1.217, P=0.324). Compared with the sham PBM group and the PBM-contralateral traced group, the PBM-ipsilateral traced group had a significant decrease in the parameter T1/2 [(45.45±6.76) min vs. (76.01±3.44) min, P < 0.001; (45.45±6.76) min vs. (78.07±4.27) min, P < 0.001], representing a significant acceleration of ISF drainage; the PBM-ipsilateral traced group had a significant increase in the parameter DECS [(4.51±0.77)×10-4 mm2/s vs. (3.15±0.44)×10-4 mm2/s, P < 0.001; (4.51±0.77)×10-4 mm2/s vs. (3.01±0.38)×10-4 mm2/s, P < 0.001], representing a significantly increased molecular diffusion rate of in the brain ECS; the PBM-ipsilateral traced group had a significant decrease in the parameter λ (1.51±0.21 vs. 1.85±0.12, P=0.001; 1.51±0.21 vs. 1.89±0.11, P=0.001), representing a significant decrease in the degree of tortuosity in the brain ECS. CONCLUSION: PBM can regulate the brain ISF drainage actively, which may be one of the potential mechanisms of the effect of PBM therapy on AD. This study provides a new method for enhancing the brain function via ECS pathway.

Oryeongsan (Wulingsan) ameliorates impaired ANP secretion of atria from spontaneously hypertensive rats.

Oryeongsan (ORS), a herbal medicine formula, has long been used for the treatment of impaired body water balance in Asian countries. Recently, it was shown that ORS administration modulates the renin-angiotensin system (RAS). Purpose of the present study was to determine characteristics of atrial ANP secretion and effects of ORS on the secretion in the atria from spontaneously hypertensive rats (SHR). Normotensive WKY groups (WKY-V, WKY-ORS, WKY-LOS) and hypertensive SHR groups (SHR-V, SHR-ORS, SHR-LOS) treated with vehicle, ORS, and losartan as a positive control group, respectively, were used. Experiments were performed in perfused beating atria (1.3 Hz) allowing atrial distension, acetylcholine (ACh) stimulation, and serial collection of atrial perfusates. The secreted ANP concentration was measured using radioimmunoassay. Interstitial fluid (ISF) translocation was measured using [3H]inulin clearance. Stepwise increase in atrial distension by 1.1, 2.0, and 2.7 cmH2O above basal distension further increased ANP secretion proportionally in the atria from WKY-V, but the response was significantly suppressed in the atria from SHR-V. Cardiomyocyte ANP release, the first step of atrial ANP secretion, was suppressed in the atria from SHR-V compared to those from WKY-V (-8.02 ±â€¯2.86, -15.86 ±â€¯2.27, and -20.09 ±â€¯3.62%; n = 8, for SHR-V vs. 8.59 ±â€¯2.81, 15.65 ±â€¯7.14, and 38.12 ±â€¯8.28%; n = 8, for WKY-V; p < 0.001 for all stepwise distension, respectively). Chronic treatment with ORS reversed the suppressed ANP release in atria from SHR-ORS group (6.76 ±â€¯3.92, 9.12 ±â€¯2.85, and 28.79 ±â€¯1.79% for SHR-ORS; n = 5 vs. SHR-V; n = 8; p = 0.01, p < 0.001, p < 0.001, respectively). The effects of ORS were comparable to those of losartan. Trans-endocardial translocation of ISF, the second step of atrial ANP secretion was similar in the atria from the hypertensive SHR-V and normotensive WKY-V. ACh-induced ANP secretion and cardiomyocyte ANP release were also suppressed in the atria from SHR-V compared to WKY-V and ORS reversed the suppression. These findings were accompanied with accentuation of the AT1 receptor expression and suppression of the AT2/Mas receptor, M2 mACh receptor and GIRK4, a molecular component of KACh channel, expression in the atria from SHR-V. Further, treatment with ORS or losartan reversed the expressions in the groups of SHR-ORS and SHR-LOS. These results show that ANP secretion is suppressed in the atria from SHR in association with accentuation of AT1 receptor and suppression of AT2/Mas receptor and KACh channel expression. Treatment with ORS ameliorates impaired ANP secretion through improving cardiomyocyte ANP release with modulation of the cardiac RAS and muscarinic signaling. These findings provide experimental evidence which supports the effect of ORS on the regulation of atrial ANP secretion in the atria from SHR.

Thermal therapy induced fluid pressure and stress reductions in a solid tumor.

This paper presents an investigation on the interstitial fluid pressure and stress reductions in a vascularized solid tumor using a thermal therapy approach. The solid tumor is modeled as a fluid infiltrated poroelastic medium with a pressure source subjected to spatial heating. The distributions of temperature, interstitial fluid pressure, strains and stresses in a spherical tumor are obtained using a thermoporoelasticity theory in which the extracellular solid matrix and the interstitial fluid have different coefficient of thermal expansion (CTE). The numerical results for a solid tumor subjected to uniform spatial heating indicate that the CTE of the solid matrix of the tumor plays a crucial role in the reductions in the fluid pressure and effective stresses caused by the thermal therapy. The pore pressure and effective stresses are reduced when the CTE of the solid matrix is higher than that of the interstitial fluid. The reductions in fluid pressure and stresses may become significant depending on the difference between the CTEs of the solid matrix and interstitial fluid. The reductions reach the maximum at the tumor center and decrease with increasing radial distance from the tumor center. Finally, the thermally induced fluid flow is directed from the surface towards the center thereby potentially improving the microcirculation in the solid tumor.

Prevalence and correlates of low plasma selenium concentrations in peritoneal dialysis patients.

OBJECTIVE: Selenium is a key component in multiple enzyme systems, and dialysis patients with lower levels have been reported to have increased mortality. Low selenium levels were commonly reported in historic hemodialysis patients, but not in recent studies. There have been very few studies in peritoneal dialysis (PD) patients, and with the increasing age and frailty of our PD population we wished to review factors associated with lower selenium in PD patients. DESIGN & METHODS: We retrospectively reviewed plasma selenium, normal laboratory >0.8 umol/L, measurements from a cohort of PD patients, attending for routine peritoneal membrane assessments, along with measurement of dialysis adequacy (Kt/Vurea), and normalized nitrogen appearance rate (nPNA) and bioimpedance measured extracellular water (ECW)/total body water (TBW), and skeletal muscle mass indexed for height (SMMI). RESULTS: The median plasma selenium was 0.84 (IQR-0.72-1.01) umol/L in 406 PD patients, 61.1 % male, mean age 59.0 ± 15.5 years, 44.9 % diabetic with 15.8 % designated as clinically frail (CFS). 41.4 % had selenium deficiency (<0.8 umol/L), and was more common with increasing CFS (χ2-6.8, p < 0.009), comorbidity grade(χ2-26.74, p < 0.001).Plasma selenium correlated with serum total protein (TP) (r = 0.352), albumin (r = 0.358), nPNA (r = 0.263), and negatively with ECW/TBW (r= -0.321) all p < 0.001, and positively with SMMI (rho = 0.109, p = 0.03). On multivariable analysis selenium was independently associated with TP (ß 0.799 ± 0.15,95 % confidence limits (95CL) (0.505-1.093), p=<0.001), and negatively with C reactive protein (CRP) (ß -0.02 ± 0.01, (95CL -0.047 to -0.005) p = 0.01), and ECW/TBW (ß -1.499 ± 0.42 (95CL -2.33 to -0.666) p=<0.001). CONCLUSIONS: Compared to recent studies in hemodialysis patients, we report a 41 % prevalence for low selenium levels. Plasma selenium was positively associated with total serum protein, and negatively with CRP and ECW/TBW. Thus, lower selenium concentrations were linked to reduced dietary protein intake, and increasing frailty, inflammation and ECW/TBW ratios.

Costs Associated with Laser Interstitial Thermal Therapy Are Lower Than Anterior Temporal Lobectomy for Treatment of Temporal Lobe Epilepsy.

BACKGROUND: Laser interstitial thermal therapy (LITT) is a minimally invasive alternative to anterior temporal lobectomy (ATL) for treatment of temporal lobe epilepsy. It has gained popularity as familiarity with technique increases and outcomes are better characterized. There has been no direct cost comparison between the 2 techniques in literature to date. The current study directly compares hospital costs associated with LITT with those of ATL patients and analyzes the factors potentially responsible for those costs. METHODS: Patients who underwent ATL (27) and LITT (15) were retrospectively reviewed for total hospital costs along with demographic, surgical, and postoperative factors potentially affecting cost. T-tests were used to compare costs and independent linear regressions, and hierarchical regressions were used to examine predictors of cost for each procedure. RESULTS: Mean hospital costs of admission for single-trajectory LITT ($104,929.88) were significantly less than for ATL ($134,980.04) (P = 0.001). In addition, length of stay, anesthesia costs, operative room costs, and postoperative hospitalization costs were all significantly lower in LITT. CONCLUSIONS: Given the minimally invasive nature of LITT, it is associated with shorter length of stay and lower hospital costs than ATL in the first head-to-head comparison of procedural costs in literature to date. Long-term efficacy as it relates to these costs associated with LITT and ATL should be further investigated to better characterize the utility of LITT in temporal lobe epilepsy patients.

The effects of gastric cancer interstitial fluid on tumors based on traditional Chinese medicine 'phlegm' theory and the investigation on the mechanism through microRNA-21 regulation.

This study aimed to investigate the effects of gastric cancer interstitial fluid (GCIF) on tumors and explore the possible mechanism of Xiaotan Sanjie decoction (XTSJ) on treatment of gastric cancer from the view of regulating microRNA-21 (miR-21) expression. The GCIF was extracted and identified by measuring the levels of interleukin-8 (IL-8), intercellular adhesion molecule 1 (ICAM-1) and miR-21. The effects of GCIF on the proliferation of SGC-7901 cells and tumor growing were assessed by cell counting kit-8 (CCK-8) assay and subcutaneously transplanted tumor-bearing nude mice model, respectively. Additionally, inhibition effect of XTSJ decoction on proliferation of SGC-7901 cells intervened by GCIF were assessed in vitro and anti-cancer effect of it was further assessed using orthotopic transplanted tumor-bearing nude mice model. The concentration of SGC-7901 gastric cancer cells were dependent on the concentration of the added GCIF. After 72 hours of continuous culture, the interstitial fluid had an obvious proliferative effect on the SGC-7901 tumor cells, which was the most significant in the high concentration group. XTSJ decoction could inhibit the growth-promoting effect (P < 0.01) of GCIF on gastric cancer cells. Intervention of the GCIF might promote the growth (P < 0.05) of the subcutaneously transplanted tumors in nude mice and decrease the net weight of the tumor-bearing nude mice (P < 0.05) after tumor removal. The GCIF was able to up-regulate the expression (P < 0.001) of miR-21 in the subcutaneously transplanted tumors. XTSJ decoction could downregulate the expression (P < 0.05) of miR-21 in SGC-7901 orthotopically transplanted tumors. XTSJ decoction can inhibit the multiplicative effect of GCIF on gastric cancer cells, growth of gastric tumor and promotion effect of GCIF on tumors, probably due to the down-regulating miR-21 expression in tumor tissues.

Acupuncture modulates extracellular ATP levels in peripheral sensory nervous system during analgesia of ankle arthritis in rats.

As an ancient analgesia therapy, acupuncture has been practiced worldwide nowadays. A good understanding of its mechanisms will offer a promise for its rational and wider application. As the first station of pain sensation, peripheral sensory ganglia express pain-related P2X receptors that are involved in the acupuncture analgesia mechanisms transduction pathway. While the role of their endogenous ligand, extracellular ATP (eATP), remains less studied. This work attempted to clarify whether acupuncture modulated eATP levels in the peripheral sensory nerve system during its analgesia process. Male Sprague-Dawley rats underwent acute inflammatory pain by injecting Complete Freund's Adjuvant in the unilateral ankle joint for 2 days. A twenty-minute acupuncture was applied to ipsilateral Zusanli acupoint. Thermal hyperalgesia and tactile allodynia were assessed on bilateral hind paws to evaluate the analgesic effect. eATP of bilateral isolated lumbar 4-5 dorsal root ganglia (DRGs) and sciatic nerves were determined by luminescence assay. Nucleotidases NTPDase-2 and -3 in bilateral ganglia and sciatic nerves were measured by real-time PCR to explore eATP hydrolysis process. Our results revealed that acute inflammation induced bilateral thermal hyperalgesia and ipsilateral tactile allodynia, which were accompanied by increased eATP levels and higher mechano-sensitivity of bilateral DRGs and decreased eATP levels of bilateral sciatic nerves. Acupuncture exerted anti-nociception on bilateral hind paws, reversed the increased eATP and mechanosensitivity of bilateral DRGs, and restored the decreased eATP of bilateral sciatic nerves. NTPDase-2 and -3 in bilateral ganglia and sciatic nerves were inconsistently modulated during this period. These observations indicate that eATP metabolism of peripheral sensory nerve system was simultaneously regulated during acupuncture analgesia, which might open a new frontier for acupuncture research.

Molecular mechanisms of brain water transport.

Our brains consist of 80% water, which is continuously shifted between different compartments and cell types during physiological and pathophysiological processes. Disturbances in brain water homeostasis occur with pathologies such as brain oedema and hydrocephalus, in which fluid accumulation leads to elevated intracranial pressure. Targeted pharmacological treatments do not exist for these conditions owing to our incomplete understanding of the molecular mechanisms governing brain water transport. Historically, the transmembrane movement of brain water was assumed to occur as passive movement of water along the osmotic gradient, greatly accelerated by water channels termed aquaporins. Although aquaporins govern the majority of fluid handling in the kidney, they do not suffice to explain the overall brain water movement: either they are not present in the membranes across which water flows or they appear not to be required for the observed flow of water. Notably, brain fluid can be secreted against an osmotic gradient, suggesting that conventional osmotic water flow may not describe all transmembrane fluid transport in the brain. The cotransport of water is an unconventional molecular mechanism that is introduced in this Review as a missing link to bridge the gap in our understanding of cellular and barrier brain water transport.

Propofol rather than Isoflurane Accelerates the Interstitial Fluid Drainage in the Deep Rat Brain.

Objective: Different anesthetics have distinct effects on the interstitial fluid (ISF) drainage in the extracellular space (ECS) of the superficial rat brain, while their effects on ISF drainage in the ECS of the deep rat brain still remain unknown. Herein, we attempt to investigate and compare the effects of propofol and isoflurane on ECS structure and ISF drainage in the caudate-putamen (CPu) and thalamus (Tha) of the deep rat brain. Methods: Adult Sprague-Dawley rats were anesthetized with propofol or isoflurane, respectively. Twenty-four anesthetized rats were randomly divided into the propofol-CPu, isoflurane-CPu, propofol-Tha, and isoflurane-Tha groups. Tracer-based magnetic resonance imaging (MRI) and fluorescent-labeled tracer assay were utilized to quantify ISF drainage in the deep brain. Results: The half-life of ISF in the propofol-CPu and propofol-Tha groups was shorter than that in the isoflurane-CPu and isoflurane-Tha groups, respectively. The ECS volume fraction in the propofol-CPu and propofol-Tha groups was much higher than that in the isoflurane-CPu and isoflurane-Tha groups, respectively. However, the ECS tortuosity in the propofol-CPu and propofol-Tha groups was much smaller than that in isoflurane-CPu and isoflurane-Tha groups, respectively. Conclusions: Our results demonstrate that propofol rather than isoflurane accelerates the ISF drainage in the deep rat brain, which provides novel insights into the selective control of ISF drainage and guides selection of anesthetic agents in different clinical settings, and unravels the mechanism of how general anesthetics function.

An Initial Cost-Effectiveness Analysis of Magnetic Resonance-Guided Laser Interstitial Thermal Therapy in Pediatric Epilepsy Surgery.

INTRODUCTION: Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is a new technology that provides a clinically efficacious and minimally invasive alternative to conventional microsurgical resection. However, little data exist on how costs compare to traditional open surgery. The goal of this paper is to investigate the cost-effectiveness of MRgLITT in the treatment of pediatric epilepsy. METHODS: We retrospectively analyzed the medical records of pediatric patients who underwent MRgLITT via the Visualase® thermal therapy system (Medtronic, Inc., Minneapolis, MN, USA) between December 2013 and September 2017. Direct costs associated with preoperative, operative, and follow-up care were extracted. Benefit was calculated in quality-adjusted life years (QALYs), and the cost-effectiveness was derived from the discounted total direct costs over QALY. Sensitivity analysis on 4 variables was utilized to assess the validity of our results. RESULTS: Twelve consecutive pediatric patients with medically refractory epilepsy underwent MRgLITT procedures. At the last postoperative follow-up, 8 patients were seizure free (Engel I, 66.7%), 2 demonstrated significant improvement (Engel II, 16.7%), and 2 patients showed worthwhile improvement (Engel III, 16.7%). The average cumulative discounted QALY was 2.11 over the lifetime of a patient. Adjusting for inflation, MRgLITT procedures had a cost-effectiveness of USD 22,211 per QALY. Our sensitivity analysis of cost variables is robust and supports the procedure to be cost--effective. CONCLUSION: Our data suggests that MRgLITT may be a cost-effective alternative to traditional surgical resection in pediatric epilepsy surgery.

Magnetic Resonance-Guided Laser Interstitial Thermal Therapy for the Treatment of Nonlesional Insular Epilepsy in Pediatric Patients: Technical Considerations.

INTRODUCTION: The insula presents anatomic challenges to surgical exploration and intervention. Open neurosurgical intervention is associated with high rates of complications despite improved seizure control. Minimally invasive techniques using novel energy delivery methods have gained popularity due to their relative safety and ability to overcome access-related barriers. The goal of this paper is to present an operative technical report and methodological considerations on the application of magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) for the treatment of nonlesional, medically refractory, insular epilepsy in pediatric patients. METHODS: Visualase laser probe(s) were implanted using ROSA robotic stereotactic guidance into the insula using a parasagittal trajectory. After confirmation of placement using intraoperative MRI, thermal energy was delivered under real-time MR guidance. Laser wire pullback was performed when the initial dose of thermal energy was insufficient to ablate the target in its entirety. Thermal ablation within the intended target was confirmed using gadolinium-enhanced brain MRI. Following removal of laser wires, a final T1-weighted axial brain MRI was performed to confirm no evidence of hemorrhage. RESULTS: Three patients underwent MRgLITT of nonlesional insular epilepsy over an 11-month period. The epileptogenic focus was localized to the insula using stereoelectroencephalography. The anterior and middle portions of the insula were accessed using a parasagittal trajectory. Laser ablation was performed for up to 3 min using an output of 10.5 W. No complications were encountered, and all patients were discharged within 24 h after the surgery. At the most recent follow-up, all patients had an Engel I outcome without any new neurologic deficits. CONCLUSION: This small cohort shows that insular ablation can be achieved safely with promising seizure outcomes in the short term.

Impact of P-Glycoprotein-Mediated Active Efflux on Drug Distribution into Lumbar Cerebrospinal Fluid in Nonhuman Primates.

Estimation of unbound drug concentration in the brain (Cu,brain) is an essential part of central nervous system (CNS) drug development. As a surrogate for Cu,brain in humans and nonhuman primates, drug concentration in cerebrospinal fluid (CCSF) collected by lumbar puncture is often used; however, the predictability of Cu,brain by lumbar CCSF is unclear, particularly for substrates of the active efflux transporter P-glycoprotein (P-gp). Here, we measured lumbar CCSF in cynomolgus monkey after single intravenous administration of 10 test compounds with varying P-gp transport activities. The in vivo lumbar cerebrospinal fluid (CSF)-to-plasma unbound drug concentration ratios (Kp,uu,lumbar CSF) of nonsubstrates or weak substrates of P-gp were in the range 0.885-1.34, whereas those of good substrates of P-gp were in the range 0.195-0.458 and were strongly negatively correlated with in vitro P-gp transport activity. Moreover, concomitant treatment with a P-gp inhibitor, zosuquidar, increased the Kp,uu,lumbar CSF values of the good P-gp substrates, indicating that P-gp-mediated active efflux contributed to the low Kp,uu,lumbar CSF values of these compounds. Compared with the drug concentrations in the cisternal CSF and interstitial fluid (ISF) that we previously determined in cynomolgus monkeys, the lumbar CCSF were more than triple for two and all of the good P-gp substrates examined, respectively. Although lumbar CCSF may overestimate cisternal CSF and ISF concentrations of good P-gp substrates, lumbar CCSF allowed discrimination of good P-gp substrates from the weak and nonsubstrates and can be used to estimate the impact of P-gp-mediated active efflux on drug CNS penetration. SIGNIFICANCE STATEMENT: This is the first study to systematically evaluate the penetration of various P-glycoprotein (P-gp) substrates into lumbar cerebrospinal fluid (CSF) in nonhuman primates. Lumbar CSF may contain >3-fold higher concentrations of good P-gp substrates than interstitial fluid (ISF) and cisternal CSF but was able to discriminate the good substrates from the weak or nonsubstrates. Because lumbar CSF is more accessible than ISF and cisternal CSF in nonhuman primates, these findings will help increase our understanding of drug central nervous system penetration at the nonclinical stage.

Brain interstitial fluid drainage and extracellular space affected by inhalational isoflurane: in comparison with intravenous sedative dexmedetomidine and pentobarbital sodium.

Brain interstitial fluid drainage and extracellular space are closely related to waste clearance from the brain. Different anesthetics may cause different changes of brain interstitial fluid drainage and extracellular space but these still remain unknown. Herein, effects of the inhalational isoflurane, intravenous sedative dexmedetomidine and pentobarbital sodium on deep brain matters' interstitial fluid drainage and extracellular space and underlying mechanisms were investigated. When compared to intravenous anesthetic dexmedetomidine or pentobarbital sodium, inhalational isoflurane induced a restricted diffusion of extracellular space, a decreased extracellular space volume fraction, and an increased norepinephrine level in the caudate nucleus or thalamus with the slowdown of brain interstitial fluid drainage. A local administration of norepinephrine receptor antagonists, propranolol, atipamezole and prazosin into extracellular space increased diffusion of extracellular space and interstitial fluid drainage whilst norepinephrine decreased diffusion of extracellular space and interstitial fluid drainage. These findings suggested that restricted diffusion in brain extracellular space can cause slowdown of interstitial fluid drainage, which may contribute to the neurotoxicity following the waste accumulation in extracellular space under inhaled anesthesia per se.

Cell integrity indicators assessed by bioelectrical impedance: A systematic review of studies involving athletes.

INTRODUCTION: Bioelectrical impedance analysis (BIA) has been used to evaluate cellular health and integrity through bioelectrical indicators. In the sporting context, monitoring these indicators can be useful to assess the quality and vitality of cells and body tissues. OBJECTIVE: The aim of this systematic review was to investigate indicators of cellular health and integrity evaluated by BIA in athletes. METHODS: Searches were performed in December 2017 in the Lilacs, Medline, PubMed, Science Direct, Scielo, Scopus, SPORTDiscus, and Web of Science databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: The searches retrieved 31 articles (30 involving professional athletes and one involving university athletes). In longitudinal studies (n = 15), the bioelectrical parameters directly associated with cellular health and integrity were extracellular water (ECW), phase angle (PA), BIA vector analysis (BIVA), crude reactance data (Xc), resistance (R), and ECW/BCM ratio. Regarding the findings of cross-sectional studies (n = 16), the investigated parameters (ECW, PA, BIVA, Z, BCM, and ECW/BCM) were directly associated with gender, age, sports performance level, modality, and game position. CONCLUSIONS: In the included studies, the cellular health and integrity indicators were: Z, Xc, R, total water, intracellular water, ECW, PA, BIVA, BCM, and ECW/BCM.

[Preliminary observation on imbalance degree of impedance in extracellular fluid of cells in the twelve meridians in healthy subjects].

OBJECTIVE: To calculate the imbalance degree (IBD) of left-right meridian (IBD-LRM), IBD of exterior-interior meridian (IBD-EIM) and IBD of hand-foot meridians (IBD-HFM) of impedance in extracellular fluid of cells in twelve meridians of healthy subjects, so as to provide foundation for meridian diagnosis. METHODS: A total of 31 healthy volunteers were enrolled and bioelectrical impedance spectroscopy (BIS) was applied. The constant current (from 1 to 100 kHz, 200 µA) was connected into the bilateral twelve meridians through two excitation electrodes with a distance of 10 cm. Two measuring electrodes, with an interval of 5 cm, were set in between the two excitation electrodes to collect the voltage amplitude and phase. The Cole-Cole curve fitting was used to calculate the impedance of extracellular fluid of cells in the twelve meridians; the IBD-LRM, IBD-EIM and IBD-HFM as well as their absolute values were calculated. RESULTS: The impedance of extracellular fluid in the left side was higher than that in right side in the large intestine meridian, the small intestine meridian and the bladder meridian (P<0.05, P<0.01). The mean value of IBD-LRM of extracellular fluid was (4.0±1.4) %; the mean value of absolute value of IBD-LRM was (15.0±1.1) %; the maximum absolute value of IBD-LRM was the bladder meridian. The mean value of IBD-EIM was (3.3±1.0) %; the mean value of absolute value of IBD-EIM was (17.9±1.6) %; the maximum absolute value of IBD-EIM was the bladder meridian and the kidney meridian. The impedance of extracellular fluid of hand jueyin meridian, hand taiyin meridian and hand shaoyin meridian were lower than those of foot meridians. The mean value of IBD-HFM was (-2.6±1.1) %; the mean value of absolute value of IBD-HFM was (19.7±1.7) %; the maximum absolute value of IBD-HFM was shaoyang meridian; the imbalance of yin meridians was greater than yang meridians. There were significant differences in impedance of extracellular fluid between left and right and between hands and feet (P<0.05, P<0.01). CONCLUSION: The extracellular fluid of left-right meridians of healthy subjects is different, but the absolute value of IBD is low; the mean value of exterior meridian and interior meridian is very close, and the absolute value of IBD is medium; the impedance of the foot meridians are greater than the hand meridians, and the absolute value of IBD is relatively high.

Pharmacokinetic comparative study of tetramethylpyrazine and ferulic acid and their compatibility with different concentration of gastrodin and gastrodigenin on blood-stasis migraine model by blood-brain microdialysis method.

Tianma pills, a traditional formula made from Ligusticum chuanxiong and Gastrodia elata, are efficacious for the treatment of primary headache. Tetramethylpyrazine (TMP) and Ferulic acid (FA) are the bioactive ingredients of Ligusticum chuanxiong, while Gastrodin and Gastrodigenin are the bioactive ingredients of Gastrodia elata. Pharmacokinetic assessment of TMP, FA, gastrodin or gastrodigenin in blood or brain interstitial fluid (BIF) has been reported in healthy animals. However, the pharmacokinetic properties of TMP and FA have not been studied when they are co-administered in a blood-stasis migraine model. The present research investigated the pharmacokinetic behavior of TMP and FA after oral administration in the presence of different concentrations of gastrodin and gastrodigenin in a blood-stasis migraine model. Pharmacokinetic parameters were determined using blood-brain microdialysis in combination with the UHPLC-MS method. Compared to the control group, in which TMP and FA were administrated without gastrodin or gastrodigenin, the T1/2, MRT, Cmax and AUC0-∞ of TMP and FA were increased. These results indicate that varying concentrations of gastrodin and gastrodigenin play an important role in affecting the pharmacokinetics of TMP and FA. Low concentrations of gastrodin and gastrodigenin (similar to those found in Tianma pills) were more efficacious, validating the utility of the ancient formulation.