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.

[Functional prediction of Tanreqing Injection in brain diseases].

The study explores the application of Tanreqing Injection into brain components in brain diseases. The components of Tanreqing Injection and its existing components in rat cerebrospinal fluid were qualitatively analyzed by liquid chromatography-mass spectrometry(LC-MS). The possible mechanism of action of Tanreqing Injection into brain on brain diseases was predicted by network pharmacological theory. In this study, 17 brain-entry components of Tanreqing Injection were founded, and 222 core targets were obtained from network pharmacological results. The biological processes include 31 items such as negative regulation of apoptotic process, MAPK cascade, Ras protein signal transduction, and 22 items such as PI3 K-Akt signal transduction, MAPK signal transduction and neurotrophic factor signal transduction. Nine brain diseases including stroke, migraine and meningioma were screened out by predicting the effect of Tanreqing Injection on brain components, which provide ideas and directions for further study of a certain encephalopathy and lay a theoretical foundation for further revealing its molecular mechanism.

Using Multifunctional Peptide Conjugated Au Nanorods for Monitoring ß-amyloid Aggregation and Chemo-Photothermal Treatment of Alzheimer's Disease.

Development of sensitive detectors of Aß aggregates and effective inhibitors of Aß aggregation are of diagnostic importance and therapeutic implications for Alzheimer's disease (AD) treatment. Herein, a novel strategy has been presented by self-assembly of peptide conjugated Au nanorods (AuP) as multifunctional Aß fibrillization detectors and inhibitors. Our design combines the unique high NIR absorption property of AuNRs with two known Aß inhibitors, Aß15-20 and polyoxometalates (POMs). The synthesized AuP can effectively inhibit Aß aggregation and dissociate amyloid deposits with NIR irradiation both in buffer and in mice cerebrospinal fluid (CSF), and protect cells from Aß-related toxicity upon NIR irradiation. In addition, with the shape and size-dependent optical properties, the nanorods can also act as effective diagnostic probes to sensitively detect the Aß aggregates. This is the first report to integrate 3 segments, an Aß-targeting element, a reporter and inhibitors, in one drug delivery system for AD treatment.

Effects of feeding two RRR-α-tocopherol formulations on serum, cerebrospinal fluid and muscle α-tocopherol concentrations in horses with subclinical vitamin E deficiency.

BACKGROUND: Alpha-tocopherol (α-TP) supplementation is recommended for the prevention of various equine neuromuscular disorders. Formulations available include RRR-α-TP acetate powder and a more expensive but rapidly water-dispersible liquid RRR-α-TP (WD RRR-α-TP). No cost-effective means of rapidly increasing serum and cerebrospinal fluid (CSF) α-TP with WD RRR-α-TP and then sustaining concentrations with RRR-α-TP acetate has yet been reported. OBJECTIVES: To evaluate serum, CSF and muscle α-TP concentrations in an 8-week dosing regimen in which horses were transitioned from WD RRR-α-TP to RRR-α-TP acetate. STUDY DESIGN: Non-randomised controlled trial. METHODS: Healthy horses with serum α-TP of <2 µg/mL were divided into three groups and followed for 8 weeks. In the control group (n = 5), no α-TP was administered. In the second group (Group A; n = 7), 5000 IU/day RRR-α-TP acetate was administered. In the third group (Group WD-A; n = 7), doses of 5000 IU/day of WD RRR-α-TP were administered over 3 weeks, followed by a 4-week transition from WD RRR-α-TP to RRR-α-TP acetate, and a final 1 week of treatment with RRR-α-TP acetate. Serum samples were obtained weekly; muscle biopsies were obtained before, at 2.5 weeks and after supplementation. CSF samples were obtained before and after the 8-week period of supplementation. RESULTS: Serum α-TP increased significantly in Group WD-A at week 1 and remained significantly higher than in Group A and the control group throughout the transition, with inter-individual variation in response. Serum α-TP increased significantly by week 7 in Group A. CSF α-TP increased significantly in Group WD-A only. Muscle α-TP concentrations did not differ significantly across groups. Serum and CSF α-TP were closely correlated (r = 0.675), whereas serum and muscle-α-TP concentrations were not correlated. MAIN LIMITATIONS: The study duration was short and data on pre-transition CSF was lacking. CONCLUSIONS: The administration of 5000 IU/day of water-dispersible RRR-α-TP rapidly increases serum α-TP. Serum and CSF α-TP concentrations are sustained with a gradual transition to 5000 IU/day of RRR-α-TP acetate. Periodic evaluation of serum α-TP concentrations is recommended because responses vary among individuals.

Differential fatty acid analysis of cerebrospinal fluid in infants and young children with suspected meningitis.

PURPOSE: Meningitis is relatively common in infants and young children and can cause permanent brain damage. The aim of this study was to determine whether meningitis is associated with fatty acids in cerebrospinal fluid (CSF). METHODS: CSF samples from children between 3 months and 6 years of age admitted to the Tabriz public hospitals who met clinical criteria of meningitis were collected at enrollment. A total of 81 samples were analyzed for fatty acid profile by gas-liquid chromatography. RESULTS: Children with a purulent meningitis demonstrated a higher percentage of oleic acid (p < 0.05, >10 %) and lower percentages of omega-3 polyunsaturated fatty acids (p < 0.001, <-40 %) than aseptic meningitis and nonmeningitis groups did. There was an inverse relationship between CSF long-chain omega-3 fatty acids and the total number of leukocytes and differential counts of neutrophils and lymphocytes in the purulent meningitis group. Moreover, significantly lower omega-3 fatty acids (p = 0.001, -37 %) and higher ratio of n-6/n-3 (p = 0.02, -29 %) were found in patients with purulent meningitis with sepsis than in those with meningitis and no sepsis. CONCLUSIONS: This study provides evidence that purulent meningitis and its complication with sepsis are associated with important disturbances in CSF fatty acids, mainly deficiency in long-chain omega-3 polyunsaturated fatty acids.

Integral equations and boundary-element solution for static potential in a general piece-wise homogeneous volume conductor.

Boundary element methods (BEM) are used for forward computation of bioelectromagnetic fields in multi-compartment volume conductor models. Most BEM approaches assume that each compartment is in contact with at most one external compartment. In this work, I present a general surface integral equation and BEM discretization that remove this limitation and allow BEM modeling of general piecewise-homogeneous medium. The new integral equation allows positioning of field points at junctioned boundary of more than two compartments, enabling the use of linear collocation BEM in such a complex geometry. A modular BEM implementation is presented for linear collocation and Galerkin approaches, starting from the standard formulation. The approach and resulting solver are verified in four ways, including comparisons of volume and surface potentials to those obtained using the finite element method (FEM), and the effect of a hole in skull on electroencephalographic scalp potentials is demonstrated.

Cerebrospinal fluid reconstitution via a perfusion-based cadaveric model: feasibility study demonstrating surgical simulation of neuroendoscopic procedures.

Cadaveric surgical simulation carries the advantage of realistic anatomy and haptic feedback but has been historically difficult to model for intraventricular approaches given the need for active flow of CSF. This feasibility study was designed to simulate intraventricular neuroendoscopic approaches and techniques by reconstituting natural CSF flow in a cadaveric model. In 10 fresh human cadavers, a simple cervical laminectomy and dural opening were made, and a 12-gauge arterial catheter was introduced. Saline was continuously perfused at physiological CSF pressures to reconstitute the subarachnoid space and ventricles. A neuroendoscope was subsequently inserted via a standard right frontal bur hole. In 8 of the 10 cadavers, adequate reconstitution and endoscopic access of the lateral and third ventricles were achieved. In 2 cadavers, ventricular access was not feasible, perhaps because of a small ventricle size and/or deteriorated tissue quality. In all 8 cadavers with successful CSF flow reconstitution and endoscopic access, identifying the foramen of Monro was possible, as was performing septum pellucidotomy and endoscopic third ventriculostomy. Furthermore, navigation of the cerebral aqueduct, fourth ventricle, prepontine cistern, and suprasellar cistern via the lamina terminalis was possible, providing a complementary educational paradigm for resident education that cannot typically be performed in live surgery. Surgical simulation plays a critical and increasingly prominent role in surgical education, particularly for techniques with steep learning curves including intraventricular neuroendoscopic procedures. This novel model provides feasible and realistic surgical simulation of neuroendoscopic intraventricular procedures and approaches.

Effect of dexamethasone on the efficacy of daptomycin in the therapy of experimental pneumococcal meningitis.

This study aimed to determine the effect of dexamethasone in combination with low-dose or high-dose daptomycin for the treatment of penicillin- and cephalosporin-resistant pneumococcal meningitis. Efficacy (ΔCFU/mL) and cerebrospinal fluid (CSF) levels of daptomycin at 15mg/kg and 25mg/kg were studied in a rabbit model of pneumococcal meningitis, comparing them with the same doses in combination with dexamethasone at 0.125mg/kg every 12h over a 26-h period against two different Streptococcus pneumoniae strains, HUB 2349 and ATCC 51916 with daptomycin minimum inhibitory concentrations (MICs) of 0.09mg/L and 0.19mg/L, respectively. Daptomycin levels in CSF were lower when dexamethasone was given concurrently. Against strain HUB 2349, therapeutic failure occurred with daptomycin 15mg/kg+dexamethasone; daptomycin 25mg/kg+dexamethasone was better at reducing bacterial counts than the lower dose throughout treatment. Against the highly cephalosporin-resistant ATCC 51916 strain, daptomycin 15mg/kg+dexamethasone achieved a lower bacterial decrease than daptomycin 15mg/kg alone, and therapeutic failure at 24h occurred in the daptomycin 15mg/kg+dexamethasone group. Addition of dexamethasone to a 25mg/kg daptomycin dose did not affect the efficacy of daptomycin: it remained bactericidal throughout treatment. In conclusion, against the studied strains, low-dose (15mg/kg/day) daptomycin is affected by concomitant use of dexamethasone: CSF levels are reduced and its bacterial efficacy is affected. At a higher daptomycin dose (25mg/kg/day), however, the use of dexamethasone does not alter efficacy; the combination appears to be a good choice for the treatment of pneumococcal meningitis.

Cerebrospinal fluid metabolomics implicate bioenergetic adaptation as a neural mechanism regulating shifts in cognitive states of HIV-infected patients.

OBJECTIVES: To identify prognostic surrogate markers for change in cognitive states of HIV-infected patients. DESIGN: Longitudinal cerebrospinal fluid (CSF) samples were collected from 98 HIV-infected patients identified by temporal change in cognitive states classified as normal, stably impaired, improving and worsening. METHODS: The metabolic composition of CSF was analysed using H nuclear magnetic resonance (H NMR) spectroscopy that focused on energy metabolites. Metabolic biomarkers for cognitive states were identified using multivariate partial least squares regression modelling of the acquired spectra, combined with nonparametric analyses of metabolites with clinical features. RESULTS: Multivariate modelling and cross-validated recursive partitioning identified several energy metabolites that, when combined with clinical variables, classified patients based on change in neurocognitive states. Prognostic identification for worsening was achieved with four features that included no change in a detectable plasma viral load, elevated citrate and acetate; decreased creatine, to produce a model with a predictive accuracy of 92%, sensitivity of 88% and 96% specificity. Prognosis for improvement contained seven features that included first visit age less than 47 years, new or continued use of antiretrovirals, elevated glutamine and glucose; decreased myo-inositol, ß-glucose and creatinine to generate a model with a predictive accuracy of 92%, sensitivity of 100% and specificity of 84%. CONCLUSION: These CSF metabolic results suggest that worsening cognitive status in HIV-infected patients is associated with increased aerobic glycolysis, and improvements in cognitive status are associated with a shift to anaerobic glycolysis. Dietary, lifestyle and pharmacologic interventions that promote anaerobic glycolysis could protect the brain in setting of HIV infection with combined antiretroviral therapy.

Pediatric lumbar puncture and cerebrospinal fluid analysis.

BACKGROUND: Lumbar puncture (LP) is a commonly performed procedure in pediatrics. Accurate analysis of cerebrospinal fluid (CSF) profile is essential in diagnosing and managing a variety of infectious and inflammatory conditions involving the brain, meninges, and spinal cord. It can also provide useful diagnostic information in the evaluation of possible subarachnoid hemorrhage and demyelinating syndromes, and aid in the diagnosis and management of pseudotumor cerebri. OBJECTIVES: To review anatomic, physiologic, and pathologic aspects of performing pediatric lumbar puncture and CSF analysis. DISCUSSION: Although still a commonly performed procedure in the outpatient setting, effective vaccines to prevent invasive infection due to Streptococcus pneumoniae and Haemophilus influenzae type b have greatly reduced pediatric bacterial meningitis rates due to these pathogens, resulting in decreased opportunity for physician-trainees to perfect this important skill (among nonneonates) during the 3 years of supervised residency training. Success in performing pediatric LP is augmented by a thorough understanding of medical aspects related to this procedure. This article discusses technical aspects involved in successfully performing a lumbar puncture to obtain CSF, and interpreting a CSF profile in children. CONCLUSION: A thorough understanding of anatomic, physiologic, and pathologic considerations regarding performing lumbar puncture and CSF analysis can augment success in diagnosing a variety of potentially serious pediatric conditions.

[Study on protective effect of cerebrospinal fluid containing Qingxin Kaiqiao Fang on sodium dithionite-induced PC12 cell injury].

OBJECTIVE: To study the protective effect of cerebrospinal fluid containing Qingxin Kaiqiao Fang on sodium dithionite (Na2S2O4)-induced PC12 cell injury, in order to provide basis for clinical application of the prescription. METHOD: SD rats were orally administered with water decoction of Qingxin Kaiqiao Fang (7. 9 g . kg-1) once every 12 h, for a total of 7 times, in order to prepare cerebrospinal fluid containing Qingxin Kaiqiao Fang. The neurocyte injury model was established by adding Na2S2O4 with the final concentration of 8 m mol . L-1 into PC12 cells. With nimodipine (1 x 10(7)mol . L-1 ) as the positive control group, MTT method test was adopted to detect the impact of cerebrospinal fluid containing Qingxin Kaiqiao Fang on the activity of PC12 cells. The expression of Bax, Bel-2 and Caspase-3 mRNA was detected by RT-PCR. RESULT: The cerebrospinal fluid containing Qingxin Kaiqiao Fang groups showed a significantly higher activity in PC12 cells than the model group, with decrease in expressions of Bax mRNA and Caspase-3 mRNA and increase in expression of Bel-2 mRNA. There were significant differences compared with the model group (P< 0. 05,P <0. 01). CONCLUSION: Qingxin Kaiqiao Fang shows a notable protective effect on Na2S2 04-induced neurocyte injury.

[Preliminary construction of studies on "pharmaceutical chemistry of cerebrospinal fluid containing Chinese medicine"].

According to the research methods for pharmaceutical chemistry of serum containing Chinese medicine, we put forward the concept, research ideas and methods of "pharmaceutical chemistry of cerebrospinal fluid containing Chinese medicine" for the first time on the basis of summary of the present situation in research on the base of single and compound Chinese medicine by applying the composition analysis methods on pharmaceutical chemistry of the drug through blood brain barrier. At the same time, scientific research value and prospect of pharmaceutical chemistry of cerebrospinal fluid containing Chinese medicine were discussed. The study on "pharmaceutical chemistry of cerebrospinal fluid containing Chinese medicine" will give an important complement to the study methods of material base of traditional Chinese medicine, and promote the modernization of traditional Chinese medicine prescriptions.

Does an anti-oxidant ascorbic acid improve the condition of hippocampal formation slice preparations? A micro-EEG approach.

The objective of this study was to assess whether ascorbic acid (AA), an intracellular anti-oxidant critical for neuronal protection, when added to artificial cerebrospinal fluid (ACSF), is able to protect hippocampal (HPC) formation slice preparations from ageing. In this research, the micro-electroencephalographic (EEG) technique was applied. Experiments were performed on 72 HPC formation slices obtained from 12 male Wistar rats. Two series of experiments were conducted: the control experiment, in which ACSF was used as an incubation medium, and the research one, in which ACSF was supplemented with 200 µM AA. The experimental model of carbachol-induced EEG theta rhythm was applied. The following parameters of theta rhythm after 15, 30 and 45 min of recording were analysed: frequency, power, time duration of theta epochs and time duration of intervals between theta epochs. The results show that AA causes a statistically significant decrease in the power of theta rhythm after 15, 30 and 45 min of recording. The time duration of intervals between theta epochs was almost twice as long in slices incubated in ACSF + AA than in ACSF after 45 min of recording. The data obtained indicate that AA does not improve the condition of HPC slices. On the contrary, it worsens the ability of slice preparations to generate theta oscillations. We hypothesize that our data may result from the Fenton reaction or changes in the conformation of connexins.

Exposure levels of anti-LINGO-1 Li81 antibody in the central nervous system and dose-efficacy relationships in rat spinal cord remyelination models after systemic administration.

LINGO-1 (leucine-rich repeat and Ig domain containing NOGO receptor interacting protein-1) is a negative regulator of myelination and repair of damaged axons in the central nervous system (CNS). Blocking LINGO-1 function leads to robust remyelination. The anti-LINGO-1 Li81 antibody is currently being evaluated in clinical trials for multiple sclerosis (MS) and is the first MS therapy that directly targets myelin repair. LINGO-1 is selectively expressed in brain and spinal cord but not in peripheral tissues. Perhaps the greatest concern for Li81 therapy is the limited access of the drug to the CNS. Here, we measured Li81 concentrations in brain, spinal cord, and cerebral spinal fluid in rats after systemic administration and correlated them with dose-efficacy responses in rat lysolecithin and experimental autoimmune encephalomyelitis spinal cord models of remyelination. Remyelination was dose-dependent, and levels of Li81 in spinal cord that promoted myelination correlated well with affinity measurements for the binding of Li81 to LINGO-1. Observed Li81 concentrations in the CNS of 0.1 to 0.4% of blood levels are consistent with values reported for other antibodies. To understand the features of the antibody that affect CNS penetration, we also evaluated the pharmacokinetics of Li81 Fab2, Fab, and poly(ethylene glycol)-modified Fab. The reagents all showed similar CNS exposure despite large differences in their sizes, serum half-lives, and volumes of distribution, and area under the curve (AUC) measurements in the CNS directly correlated with AUC measurements in serum. These studies demonstrate that exposure levels achieved by passive diffusion of the Li81 monoclonal antibody into the CNS are sufficient and lead to robust remyelination.

Biochemical parameters to assess choroid plexus dysfunction in Kearns-Sayre syndrome patients.

Our aim was to assess biochemical parameters to detect choroid plexus dysfunction in Kearns-Sayre syndrome (KSS) patients. We studied CSF from 7 patients with KSS including total proteins, 5-methyltetrahydrofolate, homovanillic acid (HVA) and Selenium (Se) concentrations. High Se values, increased HVA and total protein concentrations and decreased 5-MTHF values were observed in all cases. This pattern seems very specific to KSS since it was only detected in 7 patients out of 1850 CSF samples analysed, and may represent a good biochemical model for evaluating choroid plexus dysfunction. The accumulated Se in CSF might have deleterious consequences such as toxicity effects.

Quantitative proteomics for investigating psychiatric disorders.

The underlying pathophysiology of psychiatric disorders remains elusive. The use of quantitative proteomics to investigate disease-specific protein signatures holds great promise to improve the understanding of psychiatric disorders and identify relevant biomarkers. In this review, we discuss quantitative proteomic approaches for elucidating molecular mechanisms of psychiatric disorders, i.e. anxiety, schizophrenia, bipolar disorder and depression, by studying specimens from animal models and patients. We present gel-based, label-free and stable isotope-labeling methodologies and evaluate their strengths and limitations in the context of psychiatric research, with a focus on (15)N metabolic labeling of live animals due to its increased accuracy and potential for future applications. We also review biomarker candidate validation methods and present quantitative proteomic studies from the literature that aim to disentangle the molecular pathobiology of psychiatric disorders and identify candidate biomarkers. Finally, we explore the applicability of implementing proteomic methods as a routine diagnostic tool in the clinical laboratory.

Pharmacokinetics of moxifloxacin in cerebrospinal fluid and plasma in patients with tuberculous meningitis.

Moxifloxacin cerebrospinal fluid (CSF) penetration was evaluated by obtaining full plasma and CSF time concentration curves for 4 patients with tuberculous meningitis. The geometric mean ratio of the areas under the curve for CSF to plasma were 0.82 (range, 0.70-0.94) at 400 mg once per day and 0.71 (0.58-0.84) at 800 mg once per day.

Método cuantitativo para distinguir el líquido cefalorraquídeo de la solución salina en la anestesia combinada intradural-epidural / Quantitative test to distinguish spinal fluid from saline solution in combined spinalepidural anesthesia

OBJETIVOS: Proponer la utilización de un glucómetrodigital como método cuantitativo sencillo para detectarlíquido cefalorraquídeo durante la técnica de anestesiacombinada epidural-intradural y determinar su validez,a través de la sensibilidad, especificidad, valores predictivosy cocientes de probabilidad.PACIENTES Y MÉTODOS: Se realizó el estudio de validezdel test en 30 pacientes programados para cirugía conanestesia combinada intradural-epidural. Se consideróun resultado positivo si había glucosa en el líquido querefluía o se aspiraba a través de la aguja epidural eintradural, y se contrastaba con un patrón de referencia(las características del bloqueo sensitivo o motor tras laadministración de anestésico local). Tras localizar elespacio epidural con solución salina, se realizaba el testy se administraban 3 mL de anestésico local. Si no habíabloqueo sensitivo o motor, el test se consideraba verdaderonegativo. Se realizaba la punción dural, se realizabael test y se administraban 2-3 mL de anestésico local.En este caso si había bloqueo sensitivo o motor el test seconsideraba verdadero positivo. Con todo ello se realizóel análisis de validez.RESULTADOS: La sensibilidad del test fue del 100%, suespecificidad del 94%, el valor predictivo positivo de93%, y el valor predictivo negativo de 100%, la razón deprobabilidad positiva de 15,5 y la negativa de 0.CONCLUSIÓN: El glucómetro utilizado es un métodocuantitativo válido para diferenciar líquido cefalorraquídeode solución salina durante la anestesia combinada,de uso sencillo y fácilmente disponible, con una granutilidad para confirmar o descartar la presencia delíquido cefalorraquídeo(AU)

OBJECTIVES: To validate the use of a digital bloodglucose meter for detecting the presence of spinal fluidduring combined spinal-epidural anesthesia in terms ofspecificity, positive and negative predictive values, andlikelihood ratios.PATIENTS AND METHODS: Validation was studied in 30patients scheduled for surgery under combined spinalepiduralanesthesia. A positive finding, defined asdetection of spinal fluid return or aspiration by theepidural or spinal needle, was compared with results ofstandard reference tests (the pattern of sensory or motorblock after administration of the local anesthetic). Afterlocating the epidural space with saline solution, the testwas performed and 3 mL of local anesthetic wasadministered. If no sensory or motor blockade wasevident, the test was considered a true negative. Spinalpuncture was then performed, the test was repeated, and2 to 3 mL of local anesthetic was injected. The test wasconsidered a true positive if sensory or motor blockadewas evident. These findings entered into the validationanalyses.RESULTS: Sensitivity was 100%, specificity 94%,positive predictive value 93%, negative predictive value100%, the positive likelihood ratio 15.5, and negativelikelihood 0.CONCLUSION: Blood glucose meter readings provide avalid quantitative measure for distinguishing spinal fluidfrom saline solution during combined spinal-epiduralanesthesia. The method, which uses a readily availabledevice, is easy to use to rule out the presence of spinalfluid(AU)

Addressing a folate imbalance in fetal cerebrospinal fluid can decrease the incidence of congenital hydrocephalus.

Fetal-onset hydrocephalus (HC), which affects between 1:500 and 1:5000 live human births, results from unequal production and drainage of cerebrospinal fluid (CSF) and is associated with abnormal development of the cerebral cortex leading to severe neurological deficits. We previously found that in the hydrocephalic Texas rat, the CSF of affected fetuses induced a cell cycle arrest in neural progenitor cells. Here, we show that alterations in folate metabolism in the CSF of the developing cerebrum are likely responsible for this effect. We identified 3 folate enzymes in the CSF and demonstrate that low levels of one of these, 10-formyltetrahydrofolate dehydrogenase, are associated with HC in the hydrocephalic Texas rat. Therefore, we tested whether supplementation with specific folate species would improve developmental outcome. After daily administration of a combination of tetrahydrofolic and 5-formyltetrahydrofolic acids to pregnant dams, there was a significant reduction in the incidence of HC and improved brain development. By contrast, supplementation with folic acid increased the incidence of congenital HC in this model. These results indicate the complexities of folate metabolism in the developing brain and suggest that folate imbalance leading to HC in the hydrocephalic Texas rat fetuses can be treated with maternal folate supplementation using specific folate metabolites and combinations thereof.