BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).
- MeSH
- antiparkinsonika * aplikace a dávkování škodlivé účinky farmakologie terapeutické užití MeSH
- aplikace orální MeSH
- chelátory železa * aplikace a dávkování škodlivé účinky farmakologie terapeutické užití MeSH
- deferipron * aplikace a dávkování škodlivé účinky farmakologie terapeutické užití MeSH
- dopaminové látky aplikace a dávkování škodlivé účinky farmakologie terapeutické užití MeSH
- dvojitá slepá metoda MeSH
- levodopa terapeutické užití MeSH
- lidé MeSH
- mozek - chemie MeSH
- mozek diagnostické zobrazování MeSH
- neutropenie chemicky indukované MeSH
- Parkinsonova nemoc * farmakoterapie metabolismus patofyziologie MeSH
- progrese nemoci MeSH
- substantia nigra * chemie diagnostické zobrazování účinky léků metabolismus MeSH
- železo * analýza metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
PURPOSE: Reliable detection and fitting of macromolecules (MM) are crucial for accurate quantification of brain short-echo time (TE) 1 H-MR spectra. An experimentally acquired single MM spectrum is commonly used. Higher spectral resolution at ultra-high field (UHF) led to increased interest in using a parametrized MM spectrum together with flexible spline baselines to address unpredicted spectroscopic components. Herein, we aimed to: (1) implement an advanced methodological approach for post-processing, fitting, and parametrization of 9.4T rat brain MM spectra; (2) assess the concomitant impact of the LCModel baseline and MM model (ie, single vs parametrized); and (3) estimate the apparent T2 relaxation times for seven MM components. METHODS: A single inversion recovery sequence combined with advanced AMARES prior knowledge was used to eliminate the metabolite residuals, fit, and parametrize 10 MM components directly from 9.4T rat brain in vivo 1 H-MR spectra at different TEs. Monte Carlo simulations were also used to assess the concomitant influence of parametrized MM and DKNTMN parameter in LCModel. RESULTS: A very stiff baseline (DKNTMN ≥ 1 ppm) in combination with a single MM spectrum led to deviations in metabolite concentrations. For some metabolites the parametrized MM showed deviations from the ground truth for all DKNTMN values. Adding prior knowledge on parametrized MM improved MM and metabolite quantification. The apparent T2 ranged between 12 and 24 ms for seven MM peaks. CONCLUSION: Moderate flexibility in the spline baseline was required for reliable quantification of real/experimental spectra based on in vivo and Monte Carlo data. Prior knowledge on parametrized MM improved MM and metabolite quantification.
- MeSH
- krysa rodu rattus MeSH
- makromolekulární látky metabolismus MeSH
- mozek - chemie * MeSH
- mozek * diagnostické zobrazování metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Léčba bolesti – algeziologie – je nástavbovým oborem, který se zabývá základní obtíží, pro niž přichází pacient k lékaři, tj. bolestí. Jasné stanovení definice a vysvětlení pojmu bolest je zásadní pro všechny lékařské obory. Definice bolesti byla na základě nových poznatků upravena právě v letošním roce. K nové formulaci definice přispěly nové teorie o podílu CNS na vnímání bolesti i nově stanovené patofyziologické pojmy, jimiž jsou neuromatrix a nociplastický typ bolesti. Vzhledem k rostoucímu významu chronické bolesti při nárůstu jejího výskytu v populaci i s ohledem na nové poznatky se stále více propaguje multidisciplinární pojetí jako základ léčby chronické bolesti, a to i přes rychlý rozvoj technologií zaměřených pouze na invazivní léčbu a operační postupy v léčbě bolestivého stavu. Tyto postupy však často vycházejí pouze z periferních mechanismů při vzniku a progresi bolesti.
Pain management‑algesiology is a medical speciality that deals with the basic problem for which the patient comes to the doctor – pain. A clear definition and explanation of the term pain is essential for all medical disciplines. The definition of pain was modified this year on the basis of new findings. New theories about the role of the CNS in pain perception as well as newly established pathophysiological concepts such as neuromatrix and nociplastic type of pain contributed to the new formulation of the definition. Due to the growing importance of chronic pain in the increase of its incidence in the population and in view of new knowledge, the multidisciplinary concept is increasingly being promoted as the basis for the treatment of chronic pain, despite the rapid development of technologies focused only on invasive treatment and surgical procedures in pain management. However, these procedures are often based only on peripheral mechanisms in the onset and progression of pain.
Recent state-of-the-art methods developed for the analysis of polar xenobiotics from different types of biological matrices usually employ liquid chromatography with mass spectrometry. However, there are limitations when a small amount of sample mass is available. For example, individual benthic invertebrates or fish tissue samples often weigh less than 100 mg (e.g., brain, liver) but are necessary to understand environmental fate and bioaccumulation dynamics. We developed ultra-fast methods based on a direct sample introduction technique. This included coupling laser diode thermal desorption with atmospheric pressure chemical ionization mass spectrometry (LDTD-APCI-MS). We then quantitated a common selective serotonin reuptake inhibitor (citalopram) in brain tissues of individual juvenile fish after in vivo exposure to environmentally relevant concentration. Two mass spectrometric methods based on low (LDTD-APCI-triple quadrupole (QqQ)-MS/MS) and high (LDTD-APCI-high-resolution product scan (HRPS)) resolutions were developed and evaluated. Individual instrument conditions were optimized to achieve an accurate and robust analytical method with minimum sample preparation requirements. We achieved very good recovery (97-108%) across the range of 1-100 ng g-1 for LDTD-APCI-HRPS. LDTD-APCI-QqQ-MS/MS showed poorer performance due to interferences from the matrix at the lowest concentration level. LDTD-APCI ionization was successfully validated for analysis of non-filtered sample extracts. Evaluation of final methods was performed for a set of real fish brain samples, including comparison of LDTD-APCI-HRPS with a previously validated LC-heated electrospray ionization-HRPS method. This new LDTD-APCI-HRPS method avoids the chromatographic step and provides important benefits such as analysis of limited sample masses, lower total sample volume (typically μL), and reduction in analysis time per sample run to a few seconds. Graphical abstract.
- MeSH
- antidepresiva druhé generace analýza MeSH
- chemické látky znečišťující vodu analýza MeSH
- citalopram analýza MeSH
- lasery polovodičové MeSH
- mozek - chemie * MeSH
- Oncorhynchus mykiss * metabolismus MeSH
- potrava z moře (živočišná) analýza MeSH
- selektivní inhibitory zpětného vychytávání serotoninu analýza MeSH
- spektrometrie hmotnostní - ionizace laserem za účasti matrice metody MeSH
- tandemová hmotnostní spektrometrie metody MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
According to the United States Centers for Disease Control and Prevention (CDC), as of July 11, 2016, the reported average incidence of children diagnosed with an autism spectrum disorder (ASD) was 1 in 68 (1.46%) among 8-year-old children born in 2004 and living within the 11 monitoring sites' surveillance areas in the United States of America (USA) in 2012. ASD is a multifaceted neurodevelopmental disorder that is also considered a hidden disability, as, for the most part; there are no apparent morphological differences between children with ASD and typically developing children. ASD is diagnosed based upon a triad of features including impairment in socialization, impairment in language, and repetitive and stereotypic behaviors. The increasing incidence of ASD in the pediatric population and the lack of successful curative therapies make ASD one of the most challenging disorders for medicine. ASD neurobiology is thought to be associated with oxidative stress, as shown by increased levels of reactive oxygen species and increased lipid peroxidation, as well as an increase in other indicators of oxidative stress. Children with ASD diagnosis are considered more vulnerable to oxidative stress because of their imbalance in intracellular and extracellular glutathione levels and decreased glutathione reserve capacity. Several studies have suggested that the redox imbalance and oxidative stress are integral parts of ASD pathophysiology. As such, early assessment and treatment of antioxidant status may result in a better prognosis as it could decrease the oxidative stress in the brain before it can induce more irreversible brain damage. In this review, many aspects of the role of oxidative stress in ASD are discussed, taking into account that the process of oxidative stress may be a target for therapeutic interventions.
- MeSH
- aerobióza MeSH
- antioxidancia metabolismus MeSH
- centrální nervový systém metabolismus MeSH
- dítě MeSH
- dysbióza komplikace MeSH
- gastrointestinální nemoci komplikace MeSH
- glutathionperoxidasa metabolismus MeSH
- incidence MeSH
- lidé MeSH
- metalothionein metabolismus MeSH
- mitochondrie metabolismus MeSH
- mozek - chemie MeSH
- neurodegenerativní nemoci etiologie metabolismus MeSH
- oxidace-redukce MeSH
- oxidační stres * MeSH
- peroxidace lipidů MeSH
- poruchy autistického spektra epidemiologie imunologie metabolismus patofyziologie MeSH
- předškolní dítě MeSH
- scavengery volných radikálů metabolismus MeSH
- selen fyziologie MeSH
- selenoproteiny metabolismus MeSH
- střevní mikroflóra MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Neurotransmitters, small molecules widely distributed in the central nervous system are essential in transmitting electrical signals across neurons via chemical communication. Dysregulation of these chemical signaling molecules is linked to numerous neurological diseases including tauopathies. In this study, a precise and reliable liquid chromatography method was established with tandem mass spectrometry detection for the simultaneous determination of aspartic acid, asparagine, glutamic acid, glutamine, γ-aminobutyric acid, N-acetyl-l-aspartic acid, pyroglutamic acid, acetylcholine and choline in human brain tissue. The method was successfully applied to the analysis of human brain tissues from three different tauopathies; corticobasal degeneration, progressive supranuclear palsy and parkinsonism-dementia complex of Guam. Neurotransmitters were analyzed on ultra-high performance chromatography (UHPLC) using an ethylene bridged hybrid amide column coupled with tandem mass spectrometry (MS/MS). Identification and quantification of neurotransmitters was carried out by ESI+ mass spectrometry detection. We optimized sample preparation to achieve simple and fast extraction of all nine analytes. Our method exhibited an excellent linearity for all analytes (all coefficients of determination >0.99), with inter-day and intra-day precision yielding relative standard deviations 3.2%-11.2% and an accuracy was in range of 92.6%-104.3%. The present study, using the above method, is the first to demonstrate significant alterations of brain neurotransmitters caused by pathological processes in the brain tissues of patient with three different tauopathies.
- MeSH
- chromatografie kapalinová metody MeSH
- hmotnostní spektrometrie metody MeSH
- lidé MeSH
- limita detekce MeSH
- lineární modely MeSH
- mozek - chemie fyziologie MeSH
- neurotransmiterové látky analýza metabolismus MeSH
- reprodukovatelnost výsledků MeSH
- tauopatie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Hyperosmolar solutions have been used in neurosurgery to modify brain bulk. The aim of this animal study was to compare the short-term effects of equivolemic, equiosmolar solutions of hypertonic saline (HTS) and sodium lactate (HTL) on cerebral cortical microcirculation and brain tissue oxygenation in a rabbit craniotomy model. METHODS: Rabbits (weight, 1.5 to 2.0 kg) were anesthetized, ventilated mechanically, and subjected to a craniotomy. The animals were allocated randomly to receive a 3.75 mL/kg intravenous infusion of either 3.2% HTS (group HTS, n=9), half-molar sodium lactate (group HTL, n=10), or normal saline (group C, n=9). Brain tissue partial pressure of oxygen (PbtO2) and microcirculation in the cerebral cortex using sidestream dark-field imaging were evaluated before, 20 and 40 minutes after 15 minutes of hyperosmolar solution infusion. Global hemodynamic data were recorded, and blood samples for laboratory analysis were obtained at the time of sidestream dark-field image recording. RESULTS: No differences in the microcirculatory parameters were observed between the groups before and after the use of osmotherapy. Brain tissue oxygen deteriorated over time in groups C and HTL, this deterioration was not significant in the group HTS. CONCLUSIONS: Our findings suggest that equivolemic, equiosmolar HTS and HTL solutions equally preserve perfusion of cortical brain microcirculation in a rabbit craniotomy model. The use of HTS was better in preventing the worsening of brain tissue oxygen tension.
- MeSH
- anestezie MeSH
- hemodynamika účinky léků MeSH
- hypertonický solný roztok farmakologie MeSH
- králíci MeSH
- kraniotomie MeSH
- mikrocirkulace účinky léků MeSH
- modely u zvířat MeSH
- mozek - chemie účinky léků MeSH
- mozková kůra krevní zásobení účinky léků MeSH
- mozkový krevní oběh účinky léků MeSH
- natriumlaktát farmakologie MeSH
- osmolární koncentrace MeSH
- spotřeba kyslíku účinky léků MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Mössbauer spectrometry is a progressive method of analysis of materials which is widely used for the study of various molecular and biomolecular systems, as well as various other objects and materials containing Mössbauer nuclides. This work is focused on applications of Mössbauer spectroscopy in the area of studying iron in biological tissues. The results of the published works show that iron in this case is present in the oxidation states Fe II and Fe III , and constitutes a part of molecules, such as ferritin, ferrihydrite, hematite, and haemosiderin. Low-temperature measurements of some types of biological tissues confirmed the presence of paramagnetic and superparamagnetic components.
In the present study, we aimed at determining the metabolic responses of the human visual cortex during the presentation of chromatic and achromatic stimuli, known to preferentially activate two separate clusters of neuronal populations (called "blobs" and "interblobs") with distinct sensitivity to color or luminance features. Since blobs and interblobs have different cytochrome-oxidase (COX) content and micro-vascularization level (i.e., different capacities for glucose oxidation), different functional metabolic responses during chromatic vs. achromatic stimuli may be expected. The stimuli were optimized to evoke a similar load of neuronal activation as measured by the bold oxygenation level dependent (BOLD) contrast. Metabolic responses were assessed using functional 1H MRS at 7 T in 12 subjects. During both chromatic and achromatic stimuli, we observed the typical increases in glutamate and lactate concentration, and decreases in aspartate and glucose concentration, that are indicative of increased glucose oxidation. However, within the detection sensitivity limits, we did not observe any difference between metabolic responses elicited by chromatic and achromatic stimuli. We conclude that the higher energy demands of activated blobs and interblobs are supported by similar increases in oxidative metabolism despite the different capacities of these neuronal populations.
- MeSH
- barva * MeSH
- energetický metabolismus MeSH
- glukosa metabolismus MeSH
- kyselina aspartová metabolismus MeSH
- kyselina glutamová metabolismus MeSH
- kyselina mléčná metabolismus MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- magnetická rezonanční tomografie MeSH
- mozek - chemie fyziologie MeSH
- neurony fyziologie MeSH
- oxidace-redukce MeSH
- respirační komplex IV metabolismus MeSH
- světelná stimulace * MeSH
- zdraví dobrovolníci pro lékařské studie MeSH
- zrakové evokované potenciály MeSH
- zrakové korové centrum metabolismus fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
The aim of this study was to investigate the effects of melatonin on oxidative stress, the expression of transient receptor potential melastatin-2 (TRPM2) in guinea pig brains, and the influence of melatonin on oxidative stress in lungs and airway inflammation induced by particulate matter 2.5 (PM2.5). A particle suspension (0.1 g/ml) was nasally administered to the guinea pigs to prepare a PM2.5 exposure model. Cough frequency and cough incubation period were determined through RM6240B biological signal collection and disposal system. Oxidative stress markers, including malondialdehyde (MDA), total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD), and glutathione peroxidase (GSH-Px), in the medulla oblongata were examined through spectrophotometer. Reactive oxygen species (ROS) were detected in the hypoglossal nucleus, cuneate nucleus, Botzinger complex, dorsal vagal complex, and airway through dihydroethidium fluorescence. Hematoxylin-eosin (HE) staining and substance P expression via immunohistochemistry revealed the inflammatory levels in the airway. TRPM2 was observed in the medulla oblongata through immunofluorescence and Western blot. The ultrastructure of the blood-brain barrier and neuronal mitochondria was determined by using a transmission electron microscope. Our study suggests that melatonin treatment decreased PM2.5-induced oxidative stress level in the brains and lungs and relieved airway inflammation and chronic cough. TRPM2 might participate in oxidative stress in the cough center by regulating cough.
- MeSH
- antioxidancia terapeutické užití MeSH
- hematoencefalická bariéra účinky léků patologie MeSH
- kašel chemicky indukované farmakoterapie patologie MeSH
- kationtové kanály TRPM metabolismus MeSH
- látky znečišťující vzduch škodlivé účinky MeSH
- medulla oblongata účinky léků metabolismus MeSH
- melatonin terapeutické užití MeSH
- morčata MeSH
- mozek - chemie účinky léků MeSH
- oxidační stres účinky léků MeSH
- pevné částice škodlivé účinky MeSH
- plíce účinky léků MeSH
- velikost částic MeSH
- zvířata MeSH
- Check Tag
- morčata MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
