Cerebrospinal Fluid Pterins, Pterin-Dependent Neurotransmitters, and Mortality in Pediatric Cerebral Malaria.

BACKGROUND: Cerebral malaria (CM) pathogenesis remains incompletely understood. Having shown low systemic levels of tetrahydrobiopterin (BH4), an enzymatic cofactor for neurotransmitter synthesis, we hypothesized that BH4 and BH4-dependent neurotransmitters would likewise be low in cerebrospinal fluid (CSF) in CM. METHODS: We prospectively enrolled Tanzanian children with CM and children with nonmalaria central nervous system conditions (NMCs). We measured CSF levels of BH4, neopterin, and BH4-dependent neurotransmitter metabolites, 3-O-methyldopa, homovanillic acid, and 5-hydroxyindoleacetate, and we derived age-adjusted z-scores using published reference ranges. RESULTS: Cerebrospinal fluid BH4 was elevated in CM (n = 49) compared with NMC (n = 51) (z-score 0.75 vs -0.08; P < .001). Neopterin was increased in CM (z-score 4.05 vs 0.09; P < .001), and a cutoff at the upper limit of normal (60 nmol/L) was 100% sensitive for CM. Neurotransmitter metabolite levels were overall preserved. A higher CSF BH4/BH2 ratio was associated with increased odds of survival (odds ratio, 2.94; 95% confidence interval, 1.03-8.33; P = .043). CONCLUSION: Despite low systemic BH4, CSF BH4 was elevated and associated with increased odds of survival in CM. Coma in malaria is not explained by deficiency of BH4-dependent neurotransmitters. Elevated CSF neopterin was 100% sensitive for CM diagnosis and warrants further assessment of its clinical utility for ruling out CM in malaria-endemic areas.

Secondary biogenic amine deficiencies: genetic etiology, therapeutic interventions, and clinical effects.

Monoamine neurotransmitter disorders present predominantly with neurologic features, including dystonic or dyskinetic cerebral palsy and movement disorders. Genetic conditions that lead to secondary defects in the synthesis, catabolism, transport, and metabolism of biogenic amines can lead to neurotransmitter abnormalities, which can present with similar features. Eleven patients with secondary neurotransmitter abnormalities were enrolled between 2011 and 2015. All patients underwent research-based whole exome and/or whole genome sequencing (WES/WGS). A trial of treatment with levodopa/carbidopa and 5-hydroxytryptophan was initiated. In six families with abnormal neurotransmitter profiles and neurological phenotypes, variants in known disease-causing genes (KCNJ6, SCN2A, CSTB in 2 siblings, NRNX1, KIF1A and PAK3) were identified, while one patient had a variant of uncertain significance in a candidate gene (DLG4) that may explain her phenotype. In 3 patients, no compelling candidate genes were identified. A trial of neurotransmitter replacement therapy led to improvement in motor and behavioral symptoms in all but two patients. The patient with KCNJ6 variant did not respond to L-dopa therapy, but rather experienced increased dyskinetic movements even at low dose of medication. The patient's symptoms harboring the NRNX1 deletion remained unaltered. This study demonstrates the utility of genome-wide sequencing in further understanding the etiology and pathophysiology of neurometabolic conditions, and the potential of secondary neurotransmitter deficiencies to serve as novel therapeutic targets. As there was a largely favorable response to therapy in our case series, a careful trial of neurotransmitter replacement therapy should be considered in patients with cerebrospinal fluid (CSF) monoamines below reference range.

Cerebrospinal fluid neurotransmitter levels and central nervous system depression in a rat drug overdose model.

A neuropsychiatric drug overdose impairs physiological function via central nervous system (CNS) depression. In drug-related deaths, only the drug concentration can currently provide information regarding CNS depression in victims. In this study, using a drug overdose model, we investigated the ability of neurotransmitters in the cerebrospinal fluid (CSF) to serve as biomarkers for CNS depression. Four groups of rats were orally administered diazepam (200 mg/kg) and/or phenobarbital (100 mg/kg) or vehicle. In a hot plate test performed to assess physiological impairment, drug-administered animals showed prolongation of the response latency. Serum drug concentrations were also sufficient to observe the effect of drug overdose. The levels of benzoyl-derivatized neurotransmitters were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Noradrenaline, adrenaline, serotonin, melatonin, phosphoethanolamine, and histamine levels in the CSF decreased as the response latencies in the hot plate test increased. These reduced CSF neurotransmitter levels may represent physiological dysfunction through CNS depression.

Positive Allosteric Modulation as a Potential Therapeutic Strategy in Anti-NMDA Receptor Encephalitis.

N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors important for synaptic plasticity, memory, and neuropsychiatric health. NMDAR hypofunction contributes to multiple disorders, including anti-NMDAR encephalitis (NMDARE), an autoimmune disease of the CNS associated with GluN1 antibody-mediated NMDAR internalization. Here we characterize the functional/pharmacological consequences of exposure to CSF from female human NMDARE patients on NMDAR function, and we characterize the effects of intervention with recently described positive allosteric modulators (PAMs) of NMDARs. Incubation (48 h) of rat hippocampal neurons of both sexes in confirmed NMDARE patient CSF, but not control CSF, attenuated NMDA-induced current. Residual NMDAR function was characterized by lack of change in channel open probability, indiscriminate loss of synaptic and extrasynaptic NMDARs, and indiscriminate loss of GluN2B-containing and GluN2B-lacking NMDARs. NMDARs tagged with N-terminal pHluorin fluorescence demonstrated loss of surface receptors. Thus, function of residual NMDARs following CSF exposure was indistinguishable from baseline, and deficits appear wholly accounted for by receptor loss. Coapplication of CSF and PAMs of NMDARs (SGE-301 or SGE-550, oxysterol-mimetic) for 24 h restored NMDAR function following 24 h incubation in patient CSF. Curiously, restoration of NMDAR function was observed despite washout of PAMs before electrophysiological recordings. Subsequent experiments suggested that residual allosteric potentiation of NMDAR function explained the persistent rescue. Further studies of the pathogenesis of NMDARE and intervention with PAMs may inform new treatments for NMDARE and other disorders associated with NMDAR hypofunction.SIGNIFICANCE STATEMENT Anti-N-methyl-d-aspartate receptor encephalitis (NMDARE) is increasingly recognized as an important cause of sudden-onset psychosis and other neuropsychiatric symptoms. Current treatment leaves unmet medical need. Here we demonstrate cellular evidence that newly identified positive allosteric modulators of NMDAR function may be a viable therapeutic strategy.

Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease.

OBJECTIVES: To describe the spectrum of movement disorders and cerebrospinal fluid (CSF) neurotransmitter profiles in paediatric patients with POLG disease. METHODS: We identified children with genetically confirmed POLG disease, in whom CSF neurotransmitter analysis had been undertaken. Clinical data were collected retrospectively. CSF neurotransmitter levels were compared to both standardised age-related reference ranges and to non-POLG patients presenting with status epilepticus. RESULTS: Forty-one patients with POLG disease were identified. Almost 50% of the patients had documented evidence of a movement disorder, including non-epileptic myoclonus, choreoathetosis and ataxia. CSF neurotransmitter analysis was undertaken in 15 cases and abnormalities were seen in the majority (87%) of cases tested. In many patients, distinctive patterns were evident, including raised neopterin, homovanillic acid and 5-hydroxyindoleacetic acid levels. CONCLUSIONS: Children with POLG mutations can manifest with a wide spectrum of abnormal movements, which are often prominent features of the clinical syndrome. Underlying pathophysiology is probably multifactorial, and aberrant monoamine metabolism is likely to play a role.

The importance of biochemical and genetic findings in the diagnosis of atypical Norrie disease.

BACKGROUND: Norrie disease (ND) is a rare X-linked disorder characterized by bilateral congenital blindness. ND is caused by a mutation in the Norrie disease pseudoglioma (NDP) gene, which encodes a 133-amino acid protein called norrin. Intragenic deletions including NDP and adjacent genes have been identified in ND patients with a more severe neurologic phenotype. We report the biochemical, molecular, clinical and radiological features of two unrelated affected males with a deletion including NDP and MAO genes. METHODS: Biochemical and genetic analyses were performed to understand the atypical phenotype and radiological findings. Biogenic amines in cerebrospinal fluid (CSF) were measured by high-performance liquid chromatography. The coding exons of NDP gene were amplified by polymerase chain reaction. Multiplex ligation-dependent probe amplification and chromosomal microarray were carried out on both affected males. Computed tomography and magnetic resonance imaging were performed on the two patients. RESULTS: In one patient, the serotonin and catecholamine metabolite levels in CSF were virtually undetectable. In both patients, genetic studies revealed microdeletions in the Xp11.3 region, involving the NDP, MAOA and MAOB genes. Radiological examination demonstrated brain and cerebellar atrophy. CONCLUSIONS: We suggest that alterations caused by MAO deficit may remain during the first years of life. Clinical phenotype, biochemical findings and neuroimaging can guide the genetic study in patients with atypical ND and help us to a better understanding of this disease.

Secondary Abnormal CSF Neurotransmitter Metabolite Profiles in a Pediatric Tertiary Care Centre.

BACKGROUND: Secondary neurotransmitter deficiencies have been reported in several reviews. Our primary aim was to assess the relationship among epilepsy, antiseizure medications, and specific neurotransmitter abnormalities. We also evaluated movement disorders and brain abnormalities via magnetic resonance imaging scans in patients with secondary neurotransmitter defects. METHODS: This is a retrospective case series of 376 patients who underwent neurotransmitter analysis at BC Children's Hospital between 2009 and 2013, for a variety of neurological presentations. The biochemical genetics laboratory database was interrogated for results of cerebrospinal fluid neurotransmitter analyses. Clinical data for patients with abnormal results were collected from the hospital charts. Statistical analysis included one-way analysis of variance, chi-square, and a two-way contingency table. RESULTS: Abnormal neurotransmitter values were identified in 67 (17.8%) patients, two (0.53%) of which were attributable to a congenital neurotransmitter disorder and 11 (16.9%) secondary to other genetic diagnoses. Of 64 patients with secondary abnormal neurotransmitter values, 38 (59%) presented with epilepsy and 20 (31%) with movement disorders. A combination of epilepsy and movement disorder was less frequent. DISCUSSION: Acknowledging the limitations of this retrospective chart review, we conclude that, in our cohort, in addition to patients with movement disorders, a considerable number of patients with epilepsy and epileptic encephalopathy also showed secondary neurotransmitter mono-amine abnormalities. There is no clear relation, however, between clinical phenotype and type of neurotransmitter affected. In addition, no association was identified between the type of antiseizure medications and affected neurotransmitter type. We outline the need for prospective studies to further enrich our understanding of the relation between epilepsy and neurotransmitters with a focus on improving treatments and patient outcomes.

Photo-renewable electroanalytical sensor for neurotransmitters detection in body fluid mimics.

A composite electrode with a sandwich structure combining the properties of silver nanoparticles and a titania photoactive layer was used for the electroanalytical detection, by differential pulse voltammetry, of three neurotransmitters: dopamine, norepinephrine, and serotonin. The three analytes were determined at low detection limits (around 0.03 µM) also in the presence of conventional interferents, such as uric and ascorbic acids. The fouling of the electrode surface was overcome by irradiating the device with UVA light, restoring the initial sensor sensitivity. Dopamine, norepinephrine, and serotonin were determined also in simulated biological matrices: liquor (artificially reproduced cerebrospinal fluid) and serum. Moreover, the contemporaneous detection of dopamine and norepinephrine in simulated human urine solutions was also demonstrated, representing the first step towards clinical applications of the proposed methodology. Graphical abstract The photo-renewable electroanalytical sensor.

Neurotransmitter measures in the cerebrospinal fluid of patients with Alzheimer's disease: a review.

BACKGROUND: Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by progressive cognitive and functional decline, as well as by a variety of neuropsychiatric and psychological symptoms and behavioral dysfunctions. Various studies proposed the role of different neurotransmitter systems not only in AD-related cognitive, but also psychotic symptoms and behavioral and emotional deficits. Due to the close proximity, pathological neurochemical changes in brain occurring in AD are likely to be reflected in the cerebrospinal fluid (CSF). The purpose of this review is to provide a summary of the CSF neurotransmitter correlates of AD in order to get further insights into the potential role of altered neurotransmitters in the pathophysiology of AD and to offer novel AD biomarkers. METHODS: PubMed and MEDLINE data bases were searched for English-language articles by using "Alzheimer's disease", "CSF" and "neurotransmitter" as primary terms. No time or article type constraints were applied. Moreover, the lists of references were searched manually for additional articles. RESULTS: Changes in various correlates of cholinergic, monoaminergic and amino acid neurotransmitter systems, as well as neuropeptides, have been observed in CSF of AD patients. However, as the results of these studies have been controversial, the importance of CSF neurotransmitter parameters as potential biomarkers in AD remains quite unclear. The observed discrepancies could be bypassed by implementation of new sensitive methods, such as novel proteomics approaches that include protein separation techniques, mass spectroscopy and targeted multiplex panels of specific analytes. CONCLUSION: Although no individual CSF neurotransmitter correlate was demonstrated as suitable biomarker of AD, a combined profile of several CSF neurochemical parameters might show enhanced sensitivity and specificity and thus contribute to earlier and more accurate diagnosis of AD, crucial for application of effective treatments.

Behavioral correlates of cerebrospinal fluid amino acid and biogenic amine neurotransmitter alterations in dementia.

BACKGROUND: Behavioral and psychological signs and symptoms of dementia (BPSD) are a heterogeneous group of behavioral and psychiatric disturbances occurring in dementia patients of any etiology. Research suggests that altered activities of dopaminergic, serotonergic, (nor)adrenergic, as well as amino acid neurotransmitter systems play a role in the etiopathogenesis of BPSD. In this study we attempted to identify cerebrospinal fluid (CSF) neurochemical correlates of BPSD to provide further insight into its underlying neurochemical pathophysiological mechanisms. METHODS: Patients with probable Alzheimer's disease (AD; n = 202), probable AD with cerebrovascular disease (n = 37), probable frontotemporal dementia (FTD; n = 32), and probable dementia with Lewy bodies (DLB; n = 26) underwent behavioral assessment and lumbar puncture. CSF levels of six amino acids and several biogenic amines and metabolites were analyzed using ultraperformance liquid chromatography with fluorescence detection and reversed-phase high-performance liquid chromatography with fluorescence detection. RESULTS: In the AD patients, CSF homovanillic acid/5-hydroxyindoleacetic acid (HVA/5HIAA) ratios correlated positively with anxieties/phobias, whereas CSF levels of taurine correlated negatively with depression and behavioral disturbances in general. In FTD patients, CSF levels of glutamate correlated negatively with verbally agitated behavior. In DLB patients, CSF levels of HVA correlated negatively with hallucinations. CONCLUSIONS: Several neurotransmitter systems can be linked to one specific behavioral syndrome depending on the dementia subtype. In addition to biogenic amines and metabolites, amino acids seem to play a major role in the neurochemical etiology of BPSD as well.

[Present and future of the transcranial magnetic stimulation]. / Presente y futuro de la estimulación magnética transcraneal.

Magnetic stimulation has called the attention of neuroscientists and the public due to the possibility to stimulate and "control" the nervous system in a non-invasive way. It has helped to make more accurate diagnosis, and apply more effective treatments and rehabilitation protocols in several diseases that affect the nervous system. Likewise, this novel tool has increased our knowledge about complex neural behavior, its connections as well as its plastic modulation. Magnetic stimulation applied in simple or paired-pulse protocols is a useful alternative in the diagnosis of diseases such as multiple sclerosis, Parkinson disease, epilepsy, dystonia, amyotrophic lateral sclerosis, cerebrovascular disease, and sleep disorders. From the therapeutic perspective, magnetic stimulation applied repetitively has been found useful, with different degrees of efficacy, in treating resistant depression, tinnitus, psychogenic dysphonia, Alzheimer disease, autism, Parkinson disease, dystonia, stroke, epilepsy, generalized anxiety as well as post traumatic stress disorder, auditory hallucinations, chronic pain, aphasias, obsessive-compulsive disorders, L-dopa induced dyskynesia, mania and Rasmussen syndrome, among others. The potential of magnetic stimulation in neurorehabilitation is outstanding, with excellent range of safety and, in practical terms, without side effects.

Neurotransmitter abnormalities and response to supplementation in SPG11.

OBJECTIVE: To report the detection of secondary neurotransmitter abnormalities in a group of SPG11 patients and describe treatment with l-dopa/carbidopa and sapropterin. DESIGN: Case reports. SETTING: National Institutes of Health in the Undiagnosed Disease Program; Children's National Medical Center in the Myelin Disorders Bioregistry Program. PATIENTS: Four SPG11 patients with a clinical picture of progressive spastic paraparesis complicated by extrapyramidal symptoms and maculopathy. INTERVENTIONS: L-Dopa/carbidopa and sapropterin. RESULTS: 3/4 patients presented secondary neurotransmitter abnormalities; 4/4 partially responded to L-dopa as well as sapropterin. CONCLUSIONS: In the SPG11 patient with extrapyramidal symptoms, a trial of L-dopa/carbidopa and sapropterin and/or evaluation of cerebrospinal fluid neurotransmitters should be considered.

Novel mutations in the tyrosine hydroxylase gene in the first Czech patient with tyrosine hydroxylase deficiency.

Tyrosine hydroxylase deficiency manifests mainly in early childhood and includes two clinical phenotypes: an infantile progressive hypokinetic-rigid syndrome with dystonia (type A) and a neonatal complex encephalopathy (type B). The biochemical diagnostics is exclusively based on the quantitative determination of the neurotransmitters or their metabolites in cerebrospinal fluid (CSF). The implementation of neurotransmitter analysis in clinical praxis is necessary for early diagnosis and adequate treatment. Neurotransmitter metabolites in CSF were analyzed in 82 children (at the age 1 month to 17 years) with clinical suspicion for neurometabolic disorders using high performance liquid chromatography (HPLC) with electrochemical detection. The CSF level of homovanillic acid (HVA) was markedly decreased in three children (64, 79 and 94 nmol/l) in comparison to age related controls (lower limit 218-450 nmol/l). Neurological findings including severe psychomotor retardation, quadruspasticity and microcephaly accompanied with marked dystonia, excessive sweating in the first patient was compatible with the diagnosis of tyrosine hydroxylase (TH) deficiency (type B) and subsequent molecular analysis revealed two novel heterozygous mutations c.636A>C and c.1124G>C in the TH gene. The treatment with L-DOPA/carbidopa resulted in the improvement of dystonia. Magnetic resonance imaging studies in two other patients with microcephaly revealed postischaemic brain damage, therefore secondary HVA deficit was considered in these children. Diagnostic work-up in patients with neurometabolic disorders should include analysis of neurotransmitter metabolites in CSF.

Evidence for involvement of central noradrenergic activity in crying proneness.

Crying as a response to emotionally-charged situations varies greatly among individuals, genders, and cultures. Information on the neural systems involved in crying behavior comes mainly from studies of pathological laughing and crying in patients after brain injury. The authors assessed crying proneness (CPR) as expressed by the score on the "crying easily" item of the SCL-90 questionnaire in 65 men and 105 women subjects in whom lumbar puncture was performed for diagnostic reasons. None of the subjects showed pathological laughing or crying. The authors estimated the levels of the main metabolites of noradrenaline (MHPG), serotonin (5-HIAA), and dopamine (HVA) in CSF, and searched for associations to CPR score. Subjects with high CPR showed significantly lower MHPG levels than subjects with low CPR, and no differences in 5-HIAA or HVA levels. Higher frequencies of women were found in the subgroups with high CPR. The "crying easily" score was positively associated with the Interpersonal Sensitivity subscale of the SCL-90 questionnaire in female but not in male subjects, indicating the cultural dimension of crying behavior, while it was not associated with the Depression subscale score. It is suggested that central noradrenergic mechanisms control the threshold for tear production in normal crying behavior.

Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4-9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 × 1011 vg (n = 3), and 4.2 × 1011 vg (n = 4). Primary aims were to demonstrate the safety of the procedure and document biomarker evidence of restoration of brain AADC activity. Secondary aims were to assess clinical improvement in symptoms and motor function. Direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Twelve (12) months after surgery, 6/7 subjects gained normal head control and 4/7 could sit independently. At 18 months, 2 subjects could walk with 2-hand support. Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function.

Quantification of neurotransmitter amino acids by capillary electrophoresis laser-induced fluorescence detection in biological fluids.

The role of neurotransmitter amino acids (NAAs) in the functioning of the nervous system has been the focus of increasingly intense research over the past several years. Among the various amino acids that have important roles as neurotransmitters, there are alanine (Ala), glutamic acid (Glu), aspartic acid (Asp), serine (Ser), taurine (Tau) and glycine (Gly). NAAs are present in plasma, cells and--at trace levels--in all biological fluids, but complex components in biological matrices make it difficult to determine them in biological samples. We describe a new capillary electrophoresis (CE) method with laser-induced fluorescence detection by which analytes are resolved in less than 12 minutes in a 18 mmol/L phosphate run buffer at pH 11.6. The use of elevated temperatures during sample derivatization leads to a drastic reduction in the reaction time, down to 20 min, compared to the 6-14 h usually described for reactions between FITC and amino acids at room temperature. In order to demonstrate its wide range of applications, the method was applied to the analysis of NAA in human plasma and in other sample types, such as red blood cells, urine, cultured cells, cerebrospinal fluid, saliva and vitreous humor, thus avoiding the typical limitations of other methods, which are normally suitable for use with only one or two matrix types.

Bioanalytical methodology for determination of glutamate and aspartate for use in pharmacological sciences with application of Integrated Calibration Method.

A new calibration approach based on the adaptation of Integrated Calibration Method (ICM) to consecutive two components analysis in separation science is presented. Consecutive ICM method (C-ICM) was conceptually developed and applied to determination of two excitatory amino acids - glutamate and aspartate in cerebrospinal fluids collected by the use of brain microdialysis from freely-moving animals. Both analytes as a neurotransmitters play an important role in formation of the memory trace, and thus the processes of learning and memory. Due to their low concentration and presence of interferences, considered analytical system - animal brain - was a big challenge. High-performance liquid chromatography (HPLC) with electrochemical detection (ECD) was used in all experimental work. The most important feature of proposed method is integration of interpolative and extrapolative ways to calculate analyte concentration in single calibration procedure, which consequently leads to obtain series of six estimations of analytical result. Comparison of individual estimations with each other allows for a more in-depth analysis of systematic errors. It was proved that C-ICM approach enables diagnosis and compensation of systematic errors induced by occurrence of interference effects and improvement of accuracy of analytical results. Most of all, it was demonstrated that application of this method is efficient and useful analytical tool in analysis of complicated biological samples in pharmacology and neuroscience.

Application of NaYF4:Yb/Er/Tm UCNPs in Array-Based Sensing of Neurotransmitters: From a Single Particle to a Multichannel Sensor Array.

A novel multichannel sensor array has been designed using a single, yet multiemissive lanthanide-doped upconversion nanoparticle (UCNP). The energy levels of lanthanide ions gave rise to several emission bands which were exploited as individual sensor elements for the recognition of four important neurotransmitters (NTs): dopamine, norepinephrine, levodopa, and serotonin. At alkaline conditions, the oxidation products of these NTs quenched the fluorescence emissions of UCNPs with different quenching degrees. The resulting fingerprint multichannel emission profiles from NaYF4:Yb/Er/Tm UCNPs allowed the discrimination of NTs with excellent accuracy. The recognition was further verified in artificial cerebrospinal fluid, as a complex biological media. We believe that the designed UCNP-based multichannel sensor array offers innovative insights into the discrimination of various chemical signatures using a single measurement.

Suppression of the descending inhibitory pathway by continuous thoracic intrathecal lidocaine infusion reduces the thermal threshold of the tail-flick response in rats.

PURPOSE: For the suppression of descending inhibitory pathways in animals, single-dose lidocaine blockade is reversible and causes less damage than chronic spinal cord injury, decerebration, and cold blockade of the spinal cord. However, single-dose blockade has a variable onset and is relatively short-lived. To surmount these disadvantages, we devised a continuous thoracic intrathecal lidocaine infusion and evaluated its effects in rats. METHODS: Rats were administered continuous intrathecal infusions of 0, 0.25%, 0.5%, and 1% lidocaine at 10 &gml.h(-1) following a 10-&gml bolus. The effects of the continuous thoracic blockade on tail-flick (TF) latency (estimated by the percent maximum possible effect [%MPE]) and on the release of neurotransmitters in the cerebrospinal fluid (CSF) were evaluated. RESULTS: Continuous thoracic blockade with 0.5% and 1% lidocaine infusion reversibly shortened TF latency (%MPE, -22.0 +/- 11.0 % and -21.2 +/- 4.6 %, respectively, versus baseline; P < 0.05) during drug infusion. Compared with normal saline, thoracic intrathecal infusion of lidocaine significantly lowered norepinephrine and serotonin concentrations in the CSF at 1 h of infusion (P = 0.02 for both). CONCLUSION: Continuous thoracic blockade by local anesthetic resulted in reversible suppression of descending inhibitory pathways for varying durations. Such blockade may provide further information regarding nociceptive transmission and the mechanisms of antinociception in animals.

Potential biomarkers for persistent and neuropathic pain therapy.

Persistent, in particular neuropathic pain affects millions of people worldwide. However, the response rate of patients to existing analgesic drugs is less than 50%. There are several possibilities to increase this response rate, such as optimization of the pharmacokinetic and pharmacodynamic properties of analgesics. Another promising approach is to use prognostic biomarkers in patients to determine the optimal pharmacological therapy for each individual. Here, we discuss recent efforts to identify plasma and CSF biomarkers, as well as genetic biomarkers and sensory testing, and how these readouts could be exploited for the prediction of a suitable pharmacological treatment. Collectively, the information on single biomarkers may be stored in knowledge bases and processed by machine-learning and related artificial intelligence techniques, resulting in the optimal pharmacological treatment for individual pain patients. We highlight the potential for biomarker-based individualized pain therapies and discuss biomarker reliability and their utility in clinical practice, as well as limitations of this approach.