Use of ketogenic diets in the treatment of central nervous system diseases: a systematic review.

BACKGROUND: Studies have consistently shown that patients with epilepsy could benefit from ketogenic diets (KDs). Recent evidence suggests that KD could be used in the treatment of central nervous system (CNS) diseases. The aim of this systematic review was to investigate the use and efficacy of KD, modified Atkins diet (MAD) and medium-chain triglyceride (MCT) diet in infants, children, adolescents, and adults with CNS diseases. METHODS: This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Main databases, i.e. EMBASE, PubMed and PsycINFO, were searched on 4 December 2019. Only randomized clinical trials (RCTs) were included and only if they reported KD, MCT or MAD interventions on patients with CNS diseases. RESULTS: Twenty-four publications were eligible for inclusion (n = 1221). Twenty-one publications concerned epilepsy, two concerned Alzheimer's disease (AD), and one concerned Parkinson's disease (PD). All studies regarding epilepsy reported of seizure reduction compared to baseline. MCT did not significantly change regional cerebral blood flow (rCBF) in patients with AD, but MAD significantly improved memory at 6 weeks (p = .03). KD significantly improved motor and nonmotor functions in patients with PD at 8 weeks (p < .001). There was a trend towards fewer adverse effects in MAD compared to KD. CONCLUSION: In conclusion, various forms of KDs seem tolerable and effective as part of the treatment for epilepsy, AD and PD, although more investigation concerning the mechanism, efficacy and adverse events is necessary.

Experimental investigation of Gaussian random phase screen model for x-ray diffusers.

The beam diffusing properties of stacked layers of diffuser material were evaluated experimentally and compared to a Gaussian random phase screen model. The model was found to give promising accuracy in combination with a Lorentzian auto-correlation model. The tail behaviour of the angular scattering distribution as a function of number of diffusing layers was particularly well described by the model, and in the case of an amorphous carbon diffuser, the model could describe the whole of the scattering distribution convincingly.

Engineering Biocatalytic Solar Fuel Production: The PHOTOFUEL Consortium.

The EU Horizon2020 consortium PHOTOFUEL joined academic and industrial partners from biology, chemistry, engineering, engine design, and lifecycle assessment, making tremendous progress towards engine-ready fuels from CO2 via engineered photosynthetic microbes. Technical, environmental, economic, and societal opportunities and challenges were explored to frame future technology realization at scale.

Feasibility of the consultation-based reassurance questionnaire in Danish chiropractic practice.

Background: Reassuring information is recommended in clinical guidelines for the treatment of low back pain (LBP), but has not been clearly defined. The Consultation-based Reassurance Questionnaire (CRQ) was developed as a tool for measuring to what extent reassurance is present in back pain consultations and may provide important information about the clinical encounter. Until now the CRQ has only been tested in general practice patients in the UK although many patients with LBP are seen outside of this setting. The objectives of this study were to translate the CRQ into Danish, test its feasibility in chiropractic practice, and determine if CRQ scores were associated with satisfaction with care and perceived pain control. Methods: On the day of the first visit for a LBP episode, patients received an electronic survey including the CRQ. Distributions and completeness of responses on the four subscales of the CRQ (data-gathering, relationship-building, generic reassurance, cognitive reassurance) were assessed, and internal consistency for each subscale calculated as Cronbach's alpha. Outcomes at 2 weeks were; satisfaction with care (5-point Likert scale dichotomised into yes/no) and ability to control pain (0-10). Associations of the CRQ with patient characteristics and outcomes were determined in mixed models to account for dependency of observations within clinics. Results: From 964 patients visiting between November 2016 and October 2017 with new episodes of LBP, 717 completed the CRQ with no more than 1% missing values on any single item. The internal consistency was acceptable for all subscales (0.67-0.86). Scores were generally high, and more so in patients visiting a chiropractor for the first time. All four subscales were positively associated with satisfaction (Odds ratios 1.08-1.23) and generic reassurance was weakly associated with pain control (ß = 0.07 [95% CI 0.03-0.11]). Conclusions: The CRQ was feasible for use in a Danish chiropractic setting and scores on all four reassurance subscales related positively to patients' satisfaction. Patients who had visited a chiropractor previously reported slightly lower levels of reassuring information, and it should be explored if this is in accordance with the patients' needs. The potential impact on patient outcomes needs investigation.

A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants.

BACKGROUND AND OBJECTIVE: Many drugs, including proton pump inhibitors and certain antidepressants, are metabolized by the polymorphic cytochrome P450 (CYP) 2C19 enzyme. A significant portion of extensive metabolizers do not reach appropriate drug levels, and our objective was to investigate any genetic background. METHODS: The 5'-flanking region of the CYP2C19 gene from subjects with rapid omeprazole metabolism was sequenced, and CYP2C19 phenotype-genotype associations were analyzed in Swedish (n = 107) and Ethiopian (n = 126) extensive metabolizers. The relationship of the metabolic ratio of omeprazole (omeprazole/5-hydroxyomeprazole in plasma 3 hours after drug intake) with the area under the plasma concentration-time curve was used for prediction studies. Electrophoretic mobility shift assays were conducted by use of human nuclear protein extracts. Hepatic reporter vector transfections were carried out in CD1 mice. RESULTS: We identified a novel allele (CYP2C19*17) carrying -806C>T and -3402C>T, with a frequency of 18% in both Swedes and Ethiopians and 4% in Chinese subjects. In Swedes the metabolic ratio of omeprazole was higher in subjects homozygous for CYP2C19*1 (median, 0.50 [interquartile range, 0.37-0.73]) than in those homozygous for CYP2C19*17 (median, 0.25 [interquartile range, 0.15-0.33]) (P = .010). In Ethiopians a similar difference in the S/R-mephenytoin ratio was observed between individuals homozygous for CYP2C19*1 (median, 0.20 [interquartile range, 0.12-0.37]) and those homozygous for CYP2C19*17 (median, 0.05 [interquartile range, 0.03-0.06]) (P = .013). Electrophoretic mobility shift assays showed specific binding of human hepatic nuclear proteins to an element carrying -806T but not -806C. Reporter vector experiments showed an increased transcriptional activity of the CYP2C19*17 allele in vivo in mice. Predictions revealed that CYP2C19*17 homozygotes would attain 35% to 40% lower omeprazole area under the plasma concentration-time curve values than subjects homozygous for CYP2C19*1 taking standard doses of omeprazole. CONCLUSION: CYP2C19*17 is likely to cause therapeutic failures in drug treatment with, for example, proton pump inhibitors and antidepressants.

Adaptations to Speed Endurance Training in Highly Trained Soccer Players.

PURPOSE: The present study examined whether a period of additional speed endurance training would improve intense intermittent exercise performance in highly trained soccer players during the season and whether the training changed aerobic metabolism and the level of oxidative enzymes in type I and type II muscle fibers. METHODS: During the last 9 wk of the season, 13 semiprofessional soccer players performed additional speed endurance training sessions consisting of two to three sets of 8-10 repetitions of 30-m sprints with 10 s of passive recovery (SET). Before and after SET, subjects completed a double-step exercise protocol that included transitions from standing to moderate-intensity running (~75% HRmax), followed by transitions from moderate- to high-intensity running (~90% HRmax) in which pulmonary oxygen uptake (V˙O2) was determined. In addition, the yo-yo intermittent recovery test level 1 was performed, and a muscle biopsy was obtained at rest. RESULTS: The yo-yo intermittent recovery test level 1 performance was 11.6% ± 6.4% (mean ± SD) better (2803 ± 330 vs 3127 ± 383 m, P < 0.05) after SET compared with before SET. In the transition from standing to moderate-intensity running, phase II pulmonary V˙O2 kinetics was 11.4% ± 16.5% faster (P < 0.05), and the running economy at this intensity was 2.3% ± 3.0% better (P < 0.05). These improvements were apparent despite the content of muscle proteins regulating oxidative metabolism (3-hydroxyacyl CoA dehydrogenase, COX IV, and OXPHOS), and capillarization was reduced (P < 0.05). The content of 3-hydroxyacyl CoA dehydrogenase and citrate synthase in type I and type II fibers did not change. CONCLUSION: In highly trained soccer players, additional speed endurance training is associated with an improved ability to perform repeated high-intensity work. To what extent the training-induced changes in V˙O2 kinetics and mechanical efficiency in type I fibers caused the improvement in performance warrants further investigation.

Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19).

OBJECTIVES: Fluvoxamine is metabolized by the polymorphic cytochrome P450 (CYP) 2D6 and the smoking-inducible CYP1A2. Therapeutic doses of fluvoxamine inhibit both CYP1A2 and CYP2C19. In this study we used extensive metabolizers (EMs) and poor metabolizers (PMs) of debrisoquin (INN, debrisoquine) (CYP2D6) and two probes, caffeine (CYP1A2) and omeprazole (CYP2C19), to investigate whether nontherapeutic doses of fluvoxamine inhibit CYP1A2 but possibly not CYP2C19. METHODS: Single oral doses of 100 mg caffeine and 20 mg omeprazole were given separately to 5 EMs and 5 PMs of debrisoquin to assess the activity of CYP1A2 and CYP2C19, respectively. Initially, a single oral dose of fluvoxamine (25 mg to PMs and 50 mg to EMs) was given, followed by 1 week of daily administration of 25 mg x 2 to EMs and 25 mg x 1 to PMs. Caffeine (day 6) and omeprazole (day 7) were again administered at the steady state of fluvoxamine. Later the study protocol was repeated with a lower dose of fluvoxamine, 10 mg x 2 to EMs and 10 mg x 1 to PMs for 1 week. Concentrations of fluvoxamine, caffeine, omeprazole, and their metabolites were analyzed by HPLC methods in plasma and urine. RESULTS: The kinetics of fluvoxamine were not significantly different in EMs and PMs after a single oral dose of the drug. At the higher but not the lower steady-state dose of fluvoxamine, a significantly lower clearance in PMs compared with EMs was observed (geometric mean, 0.86 versus 1.4 L/h per kilogram; P <.05). At steady state, the 25 mg x 1 or x 2 fluvoxamine dose caused a pronounced inhibition of about 75% to 80% for both CYP1A2 and CYP2C19, whereas the inhibition after the lower 10 mg x 1 or x 2 dose was about 40% to 50%. The area under the plasma concentration-versus-time curve from 0 to 24 hours [AUC(0-24)] of caffeine increased 5-fold (P <.001) after the higher dose of fluvoxamine and 2-fold (P <.05) after the lower dose. The area under the plasma concentration-time curve from time zero to 8 hours [AUC(0-8)] ratio of 5-hydroxyomeprazole/omeprazole decreased 3.4-fold (P <.001) and 2.4-fold (P <.001), respectively. One EM subject had a very low oral clearance of fluvoxamine after both single and multiple dosing of the drug. This subject might have a deficient transporter protein in the gut, leading to an increased absorption of fluvoxamine. CONCLUSION: No convincing evidence was found that CYP2D6 is an important enzyme for the disposition of fluvoxamine. Other factors seem to be more important. A nontherapeutic oral daily dose of fluvoxamine is sufficient to provide a marked inhibition of both caffeine (CYP1A2) and omeprazole (CYP2C19) metabolism. It was not possible to separate the inhibitory effects of fluvoxamine on these enzymes, even after such a low daily dose such as 10 mg x 1 or x 2 of fluvoxamine.

The Karolinska cocktail for phenotyping of five human cytochrome P450 enzymes.

OBJECTIVES: Our objectives were (1) to determine whether the drugs caffeine, losartan, omeprazole, debrisoquin (INN, debrisoquine), and quinine can be given simultaneously in low doses as a cocktail for the phenotyping of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4, respectively, and (2) to design an administration schedule to give as few sampling occasions as possible. METHODS: Twenty-four subjects were given oral doses of 100 mg caffeine, 25 mg losartan, 20 mg omeprazole, 10 mg debrisoquin, and 250 mg quinine on separate days. After a washout period of at least 4 days, all drugs were given simultaneously except for quinine, which was given 8 hours after the other drugs. Blood and urine samples were collected to determine parent drug and metabolite concentrations for assessment of phenotyping indices. Any difference between both single and cocktail doses was tested on a log-normal distribution. RESULTS: The phenotypic indices of CYP1A2 (paraxanthine/caffeine in 4-hour plasma), CYP2C9 (losartan/E-3174 [metabolite of losartan] in 0- to 8-hour urine), CYP2C19 (omeprazole/5-hydroxyomeprazole in 3-hour plasma), and CYP3A4 (quinine/3-hydroxyquinine in 16-hour plasma) were not significantly changed when probe drugs were administered alone compared with together, although a tendency toward higher concentrations of losartan was seen during simultaneous administration (95% confidence interval, 0.51-1.002; P =.051). The CYP2D6 phenotypic index (debrisoquin/4-hydroxydebrisoquin in 0- to 8-hour urine) was significantly changed when drugs were given together (95% confidence interval, 0.45-0.87; P =.007), indicating an inhibition of the debrisoquin metabolism. The within-subject coefficients of variation (8%-25%) were much lower than the between-subject coefficients of variation (34%-79%). CONCLUSIONS: The administration of drugs together suggests an inhibition of debrisoquin metabolism caused by the concurrent drugs given. By separating debrisoquin from the other cocktail drugs, this method is likely to be used as a tool to phenotype the enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 with only 2 urinary collections and 2 blood-sampling occasions.

Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and Koreans.

OBJECTIVES: To investigate the CYP1A2 genotype-phenotype relationship and to compare CYP1A2 genetic polymorphisms and enzyme activity in terms of the effect of smoking and oral contraceptive (OC) use in Swedes and Koreans. METHODS: CYP1A2 enzyme activity was determined in 194 and 150 healthy Swedish and Korean subjects, respectively, on the basis of the 4-h plasma paraxanthine/caffeine (17X/137X) ratio determined using high-performance liquid chromatography. Genotyping for the -3860G>A, -2467delT, -739 T>G, -729 C>T, -163C>A and -3113A>G polymorphisms was performed by PCR-restriction fragment length polymorphism analysis. RESULTS: The mean 17X/137X ratio was 1.54-fold higher in Swedes than in Koreans (mean difference: 0.16; 95% CI of the mean difference: 0.12, 0.20; p < 0.0001). Smokers had a significantly higher 17X/137X ratio (higher CYP1A2 activity) than non-smokers, while Swedish OC users had a significantly lower 17X/137X ratio than non-users (mean difference: 0.31, 95% CI of the mean difference: 0.23, 0.39; p < 0.0001). No effect of gender differences on enzyme activity was observed. Four known (CYP1A2*1A, *1D, *1F, and *1L) and two novel haplotypes (CYP1A2*1V and CYP1A2*1W) were found. CYP1A2*1K was rare in Swedes and absent in Koreans. No significant genotype-phenotype relationship was observed, with the exception of CYP1A2*1F in Swedish smokers, where it was associated with higher enzyme inducibility (p = 0.02). Koreans displayed a significantly lower mean 17X/137X ratio than Swedes having the same CYP1A2 genotype, smoking habit and OC use. CONCLUSIONS: We found significant differences in CYP1A2 enzyme activity between Swedes and Koreans that could not be explained by environmental factors or the CYP1A2 haplotypes examined, despite differences in allele frequencies. None of the investigated CYP1A2 haplotypes are critical in inducing variations in enzyme activity, with the exception of CYP1A2*1F.

The impact of CYP2C9 genetics and oral contraceptives on cytochrome P450 2C9 phenotype.

CYP2C9-dependent drug metabolism is subject to large interindividual variation. To some extent, this is explained by genetic polymorphism with expression of enzyme variants that differ in catalytic activity. The aim of this study was to characterize the variation in CYP2C9 phenotype in relation to genotype, with further analysis of the CYP2C9 gene in metabolic outliers. A study population of 126 healthy white subjects were recruited and genotyped for the variant alleles, CYP2C9*1-3. In CYP2C9 phenotyping with losartan, three subpopulations were distinguished that differed in the number of CYP2C9*3 alleles (0, 1, or 2). A three-fold higher metabolic ratio (MR; urinary losartan/carboxymetabolite) was found comparing CYP2C9*1/*3 (n = 20) to CYP2C9*1/*1 (n = 81), but there was considerable variation within each genotype. Subjects genotyped as CYP2C9*1/*1, but with an unexpectedly slow oxidation of losartan, were selected for DNA-sequencing analysis of the CYP2C9 gene. Interestingly, single nucleotide polymorphisms (SNPs) could not be identified either in the 5'-flanking region, the nine exons, or exon-intron boundaries. However, sequencing of the CYP2C9 gene was also carried out in patients genotyped as CYP2C9*1/*1 but with an exceptionally low steady-state clearance of S-warfarin. Here, five different SNPs were identified. In further analysis of the healthy volunteers, it became evident that women on oral contraceptives (OCs) had slower oxidation of losartan (MR of losartan: 1.7) than women without OCs (MR of losartan: 0.86). This novel finding was not explained by a different frequency of variant alleles. In summary, CYP2C9 genotype and oral contraceptives both contribute to a large interindividual variation in CYP2C9 activity.

Application of a high-repetition-rate laser diagnostic system for single-cycle-resolved imaging in internal combustion engines.

High-repetition-rate laser-induced fluorescence measurements of fuel and OH concentrations in internal combustion engines are demonstrated. Series of as many as eight fluorescence images, with a temporal resolution ranging from 10 micros to 1 ms, are acquired within one engine cycle. A multiple-laser system in combination with a multiple-CCD camera is used for cycle-resolved imaging in spark-ignition, direct-injection stratified-charge, and homogeneous-charge compression-ignition engines. The recorded data reveal unique information on cycle-to-cycle variations in fuel transport and combustion. Moreover, the imaging system in combination with a scanning mirror is used to perform instantaneous three-dimensional fuel-concentration measurements.