Value of drug level concentrations of brivaracetam, lacosamide, and perampanel in care of people with epilepsy.

OBJECTIVE: The aim of this study was to determine whether clinical efficacy and reported adverse effects (AEs) of the newer antiseizure medications (ASMs) brivaracetam (BRV), lacosamide (LCM), and perampanel (PER) have been associated with plasma levels of these ASMs. We also investigated whether plasma levels outside the reference range has led to dose adjustments. METHODS: Plasma levels of 300 people with epilepsy (PWE) seen at our tertiary epilepsy center were determined by liquid chromatography-tandem mass spectrometry. PWE received BRV (n = 100), LCM (n = 100), or PER (n = 100), in most cases in polytherapy. Demographic and clinical data were retrospectively analyzed and related to plasma levels. Clinical efficacy of BRV, LCM, or PER was assessed retrospectively by comparing seizure frequency at the time of current blood draw with seizure frequency at the time of first administration. AEs were also recorded and, if reported, compared retrospectively with the time of first administration. RESULTS: No significant associations were found between plasma levels of BRV, LCM, or PER and seizure freedom (BRV, p = 1.000; LCM, p = .243; PER, p = .113) or responder status (BRV, p = .118; LCM, p = .478; PER, p = .069) at presentation. There was also no pattern between plasma levels and the occurrence of AEs. In the majority of cases, drug levels outside the reference ranges have not led to adjustments in the daily doses of BRV (93.5%), LCM (93.9%), or PER (89.1%). SIGNIFICANCE: Plasma levels at a given time point did not allow conclusions to be drawn about seizure control or the occurrence of AEs. Our findings indicate that efficacy and tolerability cannot be predicted based on averaged data from a single plasma measurement due to high interindividual variability. Instead, individual reference values should be established when sufficient clinical data are available, in line with the 2008 International League Against Epilepsy position paper on therapeutic drug monitoring.

Levels of Alzheimer's disease blood biomarkers are altered after food intake-A pilot intervention study in healthy adults.

INTRODUCTION: Blood biomarkers accurately identify Alzheimer's disease (AD) pathophysiology and axonal injury. We investigated the influence of food intake on AD-related biomarkers in cognitively healthy, obese adults at high metabolic risk. METHODS: One-hundred eleven participants underwent repeated blood sampling during 3 h after a standardized meal (postprandial group, PG). For comparison, blood was sampled from a fasting subgroup over 3 h (fasting group, FG). Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), amyloid-beta (Aß) 42/40, phosphorylated tau (p-tau) 181 and 231, and total-tau were measured via single molecule array assays. RESULTS: Significant differences were found for NfL, GFAP, Aß42/40, p-tau181, and p-tau231 between FG and PG. The greatest change to baseline occurred for GFAP and p-tau181 (120 min postprandially, p < 0.0001). CONCLUSION: Our data suggest that AD-related biomarkers are altered by food intake. Further studies are needed to verify whether blood biomarker sampling should be performed in the fasting state. HIGHLIGHTS: Acute food intake alters plasma biomarkers of Alzheimer's disease in obese, otherwise healthy adults. We also found dynamic fluctuations in plasma biomarkers concentration in the fasting state suggesting physiological diurnal variations. Further investigations are highly needed to verify if biomarker measurements should be performed in the fasting state and at a standardized time of day to improve the diagnostic accuracy.

Exogenous estradiol and oxytocin modulate sex differences in hippocampal reactivity during the encoding of episodic memories.

Considerable evidence supports sex differences in episodic memory. The hormones estradiol and oxytocin both affect episodic memory and may contribute to these sex differences, but possible underlying hormonal interactions have not been tested in a sample involving both sexes. To this end, we conducted a randomized, placebo-controlled, parallel-group functional magnetic resonance imaging (fMRI) study including healthy free-cycling women (n = 111) and men (n = 115). The fMRI session was conducted under four experimental conditions: 1. transdermal estradiol (2 mg) and intranasal oxytocin (24 IU), 2. transdermal placebo and intranasal oxytocin, 3. transdermal estradiol and intranasal placebo, 4. transdermal placebo and intranasal placebo. Participants were scanned during the encoding of positive, neutral, and negative scenes. Recognition memory was tested three days following the scanning sessions without additional treatments. Under placebo, women showed a significantly better recognition memory and increased hippocampal responses to subsequently remembered items independent of the emotional valence compared to men. The separate treatments with either hormone significantly diminished this mnemonic sex difference and reversed the hippocampal activation pattern. However, the combined treatments produced no significant effect. Collectively, the results suggest that both hormones play a crucial role in modulating sex differences in episodic memory. Furthermore, possible antagonistic interactions between estradiol and oxytocin could explain previously observed opposing hormonal effects in women and men.

Correlation between a quantitative anti-SARS-CoV-2 IgG ELISA and neutralization activity.

In the current COVID-19 pandemic, a better understanding of the relationship between merely binding and functionally neutralizing antibodies is necessary to characterize protective antiviral immunity following infection or vaccination. This study analyzes the level of correlation between the novel quantitative EUROIMMUN Anti-SARS-CoV-2 QuantiVac ELISA (IgG) and a microneutralization assay. A panel of 123 plasma samples from a COVID-19 outbreak study population, preselected by semiquantitative anti-SARS-CoV-2 IgG testing, was used to assess the relationship between the novel quantitative ELISA (IgG) and a microneutralization assay. Binding IgG targeting the S1 antigen was detected in 106 (86.2%) samples using the QuantiVac ELISA, while 89 (72.4%) samples showed neutralizing antibody activity. Spearman's correlation analysis demonstrated a strong positive relationship between anti-S1 IgG levels and neutralizing antibody titers (rs = 0.819, p < 0.0001). High and low anti-S1 IgG levels were associated with a positive predictive value of 72.0% for high-titer neutralizing antibodies and a negative predictive value of 90.8% for low-titer neutralizing antibodies, respectively. These results substantiate the implementation of the QuantiVac ELISA to assess protective immunity following infection or vaccination.

Influence of a proinflammatory state on postprandial outcomes in elderly subjects with a risk phenotype for cardiometabolic diseases.

PURPOSE: Low-grade inflammation in obesity is associated with insulin resistance and other metabolic disturbances. In response to high-energy meal intake, blood concentrations of inflammatory markers, glucose and insulin rise. The aim of this study was to examine whether a basal inflammatory state influences postprandial responses. METHODS: A randomized crossover trial was performed in 60 participants with a cardiometabolic risk phenotype (age 70 ± 5 years; BMI 30.9 ± 3.1 kg/m2). Each participant consumed three different iso-energetic meals (4300 kJ): a Western diet-like high-fat meal (WDHF), a Western diet-like high-carbohydrate meal (WDHC) and a Mediterranean diet-like meal (MED). Blood samples were collected when fasted and hourly for 5 h postprandially and analyzed for glucose, insulin, interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and endothelial adhesion molecules. Based on fasting serum C-reactive protein (CRP) concentrations, participants were assigned to a high inflammation (CRP ≥ 2.0 mg/L; n = 30) or low inflammation (CRP < 2.0 mg/L; n = 30) group, and postprandial outcomes were compared. RESULTS: Plasma IL-6, glucose and serum insulin increased after all meals, while IL-1ß and endothelial adhesion molecules were unchanged. The high inflammation group had higher fasting and postprandial IL-6 concentrations than the low inflammation group, although the IL-6 response slope was similar between groups. In response to the WDHC meal, participants in the high inflammation group experienced a higher glycaemic response than those in the low inflammation group. CONCLUSION: A basal proinflammatory state results in higher absolute fasting and postprandial IL-6 concentrations, but the increase in IL-6 relative to basal levels is not different between high and low inflammation groups. Elevated glycaemic response in the high inflammation group may be due to inflammation-induced short-term insulin resistance. The trial was registered at http://www.germanctr.de and http://www.drks.de under identifier DRKS00009861 (registration date, January 22, 2016).

Fortifying a meal with oyster mushroom powder beneficially affects postprandial glucagon-like peptide-1, non-esterified free fatty acids and hunger sensation in adults with impaired glucose tolerance: a double-blind randomized controlled crossover trial.

PURPOSE: Impaired glucose tolerance (IGT) is a pathophysiological condition characterized by insulin resistance with known metabolic consequences such as postprandial hyperglycemia and hypertriglyceridemia. We hypothesized that fortifying a meal with mushrooms rich in ß-glucans may diminish glucose and triglyceride responses by improving postprandial gastrointestinal hormone release. METHODS: In a randomized controlled crossover study, 22 subjects with IGT ingested a meal either enriched with 20 g powder (8.1 g ß-glucans) of oven-dried Pleurotus ostreatus (enriched meal, EN) or without enrichment (control meal, CON). Blood was collected before and repeatedly within 4 h after the meal to determine AUC of glucose (primary outcome), insulin, triglycerides, non-esterified free fatty acids (NEFAs), glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP) and ghrelin. Appetite sensations (hunger, satiety, fullness, and desire to eat) were assessed before and after meal consumption by visual analog scales. RESULTS: Postprandial glucose, insulin, triglycerides, GIP and ghrelin concentrations as well as the corresponding AUCs did not differ between EN and CON. NEFAs-AUC was 14% lower (P = 0.026) and GLP-1-AUC 17% higher (P = 0.001) after EN compared to CON. Appetite ratings did not differ between treatments, except for hunger (AUC 22% lower after EN vs. CON; P = 0.031). CONCLUSION: The observed immediate postprandial metabolic changes indicate that an easily manageable fortification of a single meal with powder from dried oyster mushrooms as ß-glucan source may improve postprandial metabolism. If the effect is preserved long term, this measure can diminish the risk for further development of overweight/obesity and type 2 diabetes in subjects with IGT. CLINICAL TRIAL REGISTRATION: German Clinical Trial Register on 09/08/2018; trial-ID: DRKS00015244.

Comparison of Perioperative High-Sensitive Troponin T and Troponin I Assays in Cardiac Surgery.

BACKGROUND: Troponin measurements are among the standard parameters for monitoring perioperative myocardial ischaemia after cardiosurgical procedures. As high-sensitive assays continue to replace older analytic parameters with lower sensitivity, this study aimed to compare perioperative profiles of a high-sensitive troponin T assay (hsTnT, Roche Diagnostics, Mannheim, Germany) with a troponin I assay (sTnI, Siemens Healthcare Diagnostics, Eschborn, Germany). METHODS: A total of 287 consecutive patients undergoing a typical spectrum of cardiac procedures from August 2017 to March 2018 monitored with the hsTnT assay were compared with a propensity-matched collective analysed with the sTnI assay. For side-by side comparison, the peak troponin (Tmax) values were scaled to a z-score distribution before comparison. RESULTS: Despite absolute postoperative hsTnT and sTnI values differing by an order of magnitude, parameters could be scaled to a common distribution with kernel density curves overlapping 92%. Both parameters showed equal behaviour in subgroup analyses regarding relevant perioperative factors, such as type of procedure, cross-clamping time, and type of cardioplegic solution. However, there were some differences regarding pre-existing renal impairment between both parameters. In both groups, renal failure patients with chronic kidney disease stages IV or V as well as patients on haemodialysis exhibited a marked Tmax increase of >100% compared with normal kidney function (hsTnT, +121%; 2,383.5 vs 1,078.8 ng/L; p=0.0006; and sTnI, +149%; 27.3 ng/mL vs 11.0 ng/mL; p=0.009). However, in patients with moderately impaired renal function, those in the hsTnT group, but not in the sTnI cohort, showed significantly increased Tmax values (CKD stages II or III, 1,233.5 ng/L [+14%] and 1,314.1 ng/L [+22%] vs 1,078.8 ng/L; p=0.01 and p=0.03). In these patients, the postoperative interval until Tmax was reached was also significantly increased (14.4 and 19.0 hrs vs 12.4 hrs for chronic kidney disease stages II and III; p=0.0038 and p<0.001), indicating a higher rate of accumulation in the hsTnT parameter. CONCLUSION: In the context of cardiac surgery, this study found that both parameters behaved in a similar manner under most relevant circumstances. Despite significant difference in the absolute serum concentration, hsTnT and sTnI can be scaled to virtually identical distributions. However, renal impairment did affect both parameters differently with troponin T but not troponin I, showing evidence of accumulation in moderately impaired renal disease.

Testosterone serum levels are not predictive of maternal virilization in hyperreactio luteinalis.

BACKGROUND: Elevated concentrations of circulating testosterone are present in hyperreactio luteinalis (HL), a pregnancy-specific, self-limited condition. HL is associated with maternal virilization in about 30% of cases. The correlation between testosterone levels and maternal virilization has not yet been quantified. Our aim was to identify a testosterone cut-off level which may allow to predict maternal virilization. METHODS: A literature research was performed. Publications were chosen if serum testosterone concentrations and presence or absence of maternal virilization was mentioned. Additionally, we report serial levels of steroids analyzed by Liquid chromatography-tandem mass spectrometry (LC-MS/MS) in one case of HL managed at our institution. RESULTS: In all, 31 cases fulfilled the search criteria. We found significant overlap between testosterone levels in asymptomatic women and women with signs of virilization (range 6.2-37.3 nmol/l and 13.7-197.5 nmol/l, respectively). The method applied for testosterone analysis was mentioned in three reports only. Peak serum testosterone concentration in our case was 120.3 nmol/l. CONCLUSION: From the available data, maternal virilization in HL cannot be predicted by the level of circulating testosterone. However, comparability of results is hampered by the analytical methods applied. LC-MS/MS should preferably be used for reporting concentrations of circulating testosterone.

IGF-I in cord blood is predictive of final height in monozygotic twins with intra-twin birth weight differences.

OBJECTIVE: Adverse prenatal conditions can exert a long-lasting impact on growth up to final height (FH). Due to different prenatal nutrient availability, monozygotic twin pairs with discordant birth weight (bw) provide an excellent model to examine the impact of genes and environment and to analyse the predictive value of bw, birth length (bl) and cord blood (cb) concentration of IGF-I on FH. PATIENTS AND METHODS: Twenty eight monozygotic twin pairs with intra-twin bw-/bl-differences were studied at birth and longitudinally until FH. Intra-twin bw difference >1 SDS was defined "discordant" (n = 10 pairs). IGF-I was analysed in cord blood in all twins. Intra-twin differences (∆) in bw, bl and cord blood IGF-I were correlated with ∆FH. RESULTS: Throughout growth and up until FH intra-twin length/height differences remained for all but two (26/28) twins and for all (10/10) discordant twins. In the discordant group, a highly significant intra-twin difference for FH-SDS was found with a mean intra-twin Δheight- SDS of 1.23 (range, 0.29-2.34). This corresponds to a mean Δintra-twin difference at FH of 7.9 cm (3.1 inch; range, 2-15 cm [0.79-5.9 inch]). Correlation coefficients were calculated to identify factors predicting FH: ∆bw (r = .678; P = .0005), ∆bl (r = .333; P = .0002) and ∆IGF-I in cb (r = .418; P = .0023). Interaction terms showed that IGF-I is an additional factor to the auxological data, leading to an improvement of the ∆FH modelling. CONCLUSION: Prenatal environment leading to bw-/bl- and cbIGF-I differences in monozygotic twins had a long-lasting impact on growth until FH. Both, anthropometric data at birth and cbIGF-I are predictive of FH.

Evidence for shrunken pore syndrome in children.

The link between cystatin C and mortality independent of glomerular filtration rate (GFR) in adults has prompted the "Shrunken Pore Syndrome" (SPS) hypothesis, where high serum cystatin C with normal creatinine is explained by smaller glomerular pores, through which creatinine can pass freely, while the larger cystatin C, beta-trace protein (BTP) and pro-inflammatory molecules are retained. This study set out to apply the definition of SPS to children. In 294 children who underwent inulin clearance (Cin) test, serum creatinine, cystatin C and BTP were measured. For all three markers eGFRx was calculated using the full age spectrum equations. The ratio eGFRcys/eGFRcrea was plotted against the error of eGFRBTP(%) (i.e. eGFRBTP-Cin)/Cin*100%). Patients with and without SPS according to different cut-off points of eGFRcys/eGFRcrea and eGFRcys/Cin (i.e. ≤0.6,0.7,0.8) were compared in terms of eGFRx, Cin, error of eGFRx(%) and eGFRBTP/eGFRcrea-ratio. The ratio eGFRcys/eGFRcrea and error of eGFRBTP(%) were positively correlated. The prevalence of SPS by eGFRcys/eGFRcrea with a cut-off of 0.6 was 4.8%. Patients with SPS had a more negative error of eGFRcys(%) and eGFRBTP(%) and higher Cin regardless of the definition. Overestimation of eGFRcrea in patients with SPS was only present when using the eGFRcys/eGFRcrea rather than the eGFRcys/Cin definition. Cystatin C and BTP are related independent of creatinine, suggesting glomerular pore size as a common denominator. The prevalence of SPS in children is comparable to adults. For research in SPS, a definition based on eGFRcys/exogenous clearance study may be useful to study the effect of SPS on creatinine metabolism.

Changes in PUFA and eicosanoid metabolism during/after apnea diving: a prospective single-center study.

Background: The popularity of apneic diving is continually growing. As apnea diving substantially burdens the cardiovascular system, special focus is warranted. Regarding inflammation processes and associated inflammatory-related diseases (e.g., cardiovascular diseases), eicosanoids play an important role. This study aims to investigate polyunsaturated fatty acids (PUFAs) and eicosanoids in voluntary apnea divers, and so to further improve understanding of pathophysiological processes focusing on proinflammatory effects of temporarily hypercapnic hypoxia.. Methods: The concentration of PUFAs and eicosanoids were investigated in EDTA plasma in apnea divers (n=10) before and immediately after apnea, 0.5 hour and four hours later, applying liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Mean age was 41±10 years, and divers performed a mean breath-hold time of 317±111 seconds. PUFAs, eicosanoids and related lipids could be classified in four different kinetical reaction groups following apnea. The first group (e.g., Ω-6 and Ω-3-PUFAs) showed an immediate concentration increase followed by a decrease below baseline four hours after apnea. The second group (e.g., thromboxane B2) showed a slower increase, with its maximum concentration 0.5 hour post-apnea followed by a decrease four hours post-apnea. Group 3 (9- and 13-hydroxyoctadecadienoic acid) is characterized by two concentration increase peaks directly after apnea and four hours afterward compared to baseline. Group 4 (e.g., prostaglandin D2) shows no clear response. Conclusion: Changes in the PUFA metabolism after even a single apnea revealed different kinetics of pro- and anti-inflammatory regulations and changes for oxidative stress levels. Due to the importance of these mediators, apnea diving should be evaluated carefully and be performed only with great caution against the background of cardiovascular diseases and inflammation processes.

Oxytocin enhances the pain-relieving effects of social support in romantic couples.

Social support plays a vital role in physical and mental well-being. The neuropeptide hormone oxytocin (OXT) has been implicated in modulating pair-bonding and affiliative behaviors, but whether OXT contributes to the analgesic effects of a romantic partner's touch remains elusive. In the present randomized placebo-controlled, between-group, functional magnetic resonance imaging study involving 194 healthy volunteers (97 heterosexual couples), we tested the effects of intranasal OXT (24 IU) on handholding as a common mode of expressing emotional support in romantic couples. We scanned the subjects while brief electric shocks were administered. The subjects assumed that they received social support from either their romantic partner or an unfamiliar person. Unbeknown to the subject, in the partner and stranger support conditions, the same male experimenter always held the subject's left hand. Partner support was most effective in reducing the unpleasantness of electric shocks, and OXT further attenuated the unpleasantness across conditions. On the neural level, OXT significantly augmented the beneficial effects of partner support, as evidenced by a stronger decrease of neural responses to shocks in the anterior insula (AI), a stronger activity increase in the middle frontal gyrus (MFG), and a strengthened functional coupling between the AI and MFG. Our results support the notion that OXT specifically modulates the beneficial effects of social support in romantic couples by concomitantly reducing pain-associated activity and increasing activity linked to cognitive control and pain inhibition. We hypothesize that impaired OXT signaling may contribute to the experience of a lack of partner support.

Saliva molecular inflammatory profiling in female migraine patients responsive to adjunctive cervical non-invasive vagus nerve stimulation: the MOXY Study.

BACKGROUND: Rising evidence indicate that oxytocin and IL-1ß impact trigemino-nociceptive signaling. Current perspectives on migraine physiopathology emphasize a cytokine bias towards a pro-inflammatory status. The anti-nociceptive impact of oxytocin has been reported in preclinical and human trials. Cervical non-invasive vagus nerve stimulation (nVNS) emerges as an add-on treatment for the preventive and abortive use in migraine. Less is known about its potential to modulate saliva inflammatory signaling in migraine patients. The rationale was to perform inter-ictal saliva measures of oxytocin and IL-1ß along with headache assessment in migraine patients with 10 weeks adjunctive nVNS compared to healthy controls. METHODS: 12 migraineurs and 12 suitably matched healthy control were studied with inter-ictal saliva assay of pro- and anti-neuroinflammatory cytokines using enzyme-linked immuno assay techniques along with assessment of headache severity/frequency and associated functional capacity at baseline and after 10 weeks adjunctive cervical nVNS. RESULTS: nVNS significantly reduced headache severity (VAS), frequency (headache days and total number of attacks) and significantly improved sleep quality compared to baseline (p < 0.01). Inter-ictal saliva oxytocin and IL-1ß were significantly elevated pre- as well as post-nVNS compared to healthy controls (p < 0.01) and similarly showed changes that may reflect the observed clinical effects. CONCLUSIONS: Our results add to accumulating evidence for a therapeutic efficacy of adjunct cervical non-invasive vagus nerve stimulation in migraine patients. This study failed to provide an evidence-derived conclusion addressed to the predictive value and usefulness of saliva assays due to its uncontrolled study design. However, saliva screening of mediators associated with trigemino-nociceptive traffic represents a novel approach, thus deserve future targeted headache research. Trial registration This study was indexed at the German Register for Clinical Trials (DRKS No. 00011089) registered on 21.09.2016.

Thyroid Function in Monozygotic Twins with Intra-twin Birth Weight Differences: A Prospective Longitudinal Cohort Study.

OBJECTIVE: To analyze the long-term impact of birth weight (BW) on thyroid function in genetically identical twins with intra-twin BW differences from birth to adolescence. STUDY DESIGN: In total, 52 monozygotic twin pairs underwent at least one analysis of thyroid function at mean ages of 10.1 years (27 pairs), 15.1 years (35 pairs), and 17.4 years (36 pairs); 18 pairs donated blood at all time points. BW difference of <1 SDS was defined as concordant, BW difference ≥1 SDS as discordant. RESULTS: In concordant twins, no significant differences were observed. In the discordant group, smaller twins had higher mean thyroid-stimulating hormone (TSH) than their larger co-twins at 10.1 years (3.6 vs 2.5 µU/mL; P = .04) and 15.1 years (2.6 vs 2.2 µU/mL; P = .08). Smaller twins showed lower mean thyroxine than larger co-twins at 10.1 years (7.8 vs 8.2 µg/dL P = .05) and 17.4 years (7.7 vs 8.4 µg/dL; P = .03), and a tendency at 15.1 years (6.9 vs 7.4 µg/dL; P = .09). Calculation of TSH-thyroxine ratio revealed significant differences in the discordant group, with greater ratios in the smaller twin at 10.1 years (0.5 vs 0.3; P = .006) and 15.1 years (0.4 vs 0.3; P = .04). CONCLUSIONS: In this group of monozygotic twins with intra-twin BW differences, BW seemed to exert a long-lasting impact on thyroid function. This may be due to a delay in hypothalamic-pituitary-thyroid axis maturation, with TSH resistance during childhood and early adolescence in children with low BW.

Moderate Postmeal Walking Has No Beneficial Effects Over Resting on Postprandial Lipemia, Glycemia, Insulinemia, and Selected Oxidative and Inflammatory Parameters in Older Adults with a Cardiovascular Disease Risk Phenotype: A Randomized Crossover Trial.

BACKGROUND: Research suggests that postprandial events, as risk factors for cardiovascular diseases (CVDs), are influenced by meal composition and exercise. OBJECTIVES: We investigated the effect of walking versus rest on postprandial metabolic, inflammatory, and oxidative events following the consumption of test meals reflecting 2 different dietary patterns in older adults with an increased CVD risk. METHODS: A randomized crossover trial was conducted in 26 men and women (aged 70 ± 5 y; BMI 30.3 ± 2.3 kg/m2). Each adult participated in 4 treatments combining 1 of 2 iso-energetic (4300 kJ) meals [Western diet high-fat meal (WD): total fat, 59.4 g; saturated fatty acids, 32.0 g, dietary fiber, 4.2 g; or Mediterranean-type diet meal (MD): total fat, 40.1 g; saturated fatty acids, 5.1 g; dietary fiber, 14.5 g] with 30 min walking (4.6 ± 0.1 km/h) or rest. Primary (serum triglycerides) and secondary [serum nonesterified fatty acids (NEFAs); parameters of glucose metabolism, inflammation, endothelial activation, oxidation; blood pressure/heart rate] outcomes were measured at fasting and 1.5, 3.0, and 4.5 h postprandially. Data were analyzed by linear mixed models. RESULTS: Triglycerides were higher after the WD than after the MD [AUC in mmol/L × min: Western diet high-fat meal plus postprandial walking (WD-W), 218 ± 15.2; Western diet high-fat meal plus postprandial resting (WD-R), 207 ± 12.6; Mediterranean-type diet meal plus postprandial walking (MD-W), 139 ± 9.83; Mediterranean-type diet meal plus postprandial resting (MD-R), 149 ± 8.15; P  < 0.001]. No meal or activity effect was observed for NEFAs based on AUC data (WD-W, -43.5 ± 7.08; WD-R, -49.2 ± 6.94; MD-W, -48.0 ± 11.6; MD-R, -67.6 ± 7.58). Plasma glucose was higher after the MD than after the WD (WD-W, 222 ± 34.9; WD-R, 177 ± 32.8; MD-W, 314 ± 44.4; MD-R, 275 ± 57.8; P  < 0.001), as was serum insulin (AUC in nmol/L × min: WD-W, 82.0 ± 10.3; WD-R, 88.6 ± 12.8; MD-W, 129 ± 14.7; MD-R, 138 ± 20.5; P < 0.001). Plasma IL-6 was higher after walking than after resting (AUC in pg/mL × min: WD-W, 72.0 ± 34.0; WD-R, 14.3 ± 38.8; MD-W, 70.8 ± 39.4; MD-R, 5.60 ± 26.0; P < 0.05). Plasma vitamin C was higher after the MD than after the WD (P < 0.001) and after walking than after resting (P < 0.05; AUC in mg/L × min: WD-W, -305 ± 59.6; WD-R, -396 ± 84.0; MD-W, 113 ± 56.4; MD-R, -44.5 ± 48.1). We observed no meal or activity effects on parameters of oxidation and endothelial adhesion molecules. Our data revealed no significant meal × activity effects on all outcomes. CONCLUSIONS: In older adults with an increased CVD risk, the MD was associated with superior effects on several postprandial parameters (e.g., triglycerides), in comparison to the WD. Data revealed no relevant differences regarding the effects of postmeal walking and resting. None of the 4 treatments can be rated as superior regarding their acute effects on the shown postprandial metabolic, oxidative, and inflammatory parameters. The trial was registered at German Clinical Trials Register (DRKS; http://www.germanctr.de and http://www.drks.de) under identifier DRKS00012409.

Selective L4 Dorsal Root Ganglion Stimulation Evokes Pain Relief and Changes of Inflammatory Markers: Part I Profiling of Saliva and Serum Molecular Patterns.

OBJECTIVES: Complex regional pain syndrome (CRPS) and associated comorbidities have been linked to a pro-inflammatory state driven by different mediators. Targeted dorsal root ganglion stimulation (DRGSTIM ) suppressed pain levels and improved functional capacity in intractable CRPS. However, clinical trials assessing the impact of DRG stimulation on the neuroimmune axis are lacking. METHODS: This study enrolled 24 subjects (12 refractory CRPS patients plus suitably matched healthy controls) and performed immunoassays of inflammatory mediators in saliva and serum along with score-based assessments of pain, mood, and sleep quality at baseline and after three months of selective L4-DRGSTIM . RESULTS: After three-month L4-DRGSTIM CRPS associated pain significantly decreased. In addition, disturbed sleep and mood improved post-DRGSTIM , although statistically not significant. Significantly increased serum values of pro-inflammatory markers were detected pre- and post L4-DRGSTIM for high-mobility group box 1, tumor-necrosis factor α, interleukin (IL) 6, and leptin. IL-1ß was significantly elevated pre-L4 DRGSTIM , but not posttreatment. Elevated anti-inflammatory IL-10 significantly decreased after three months in serum, while saliva oxytocin concentrations increased in CRPS subjects after L4-DRGSTIM (p = 0.65). No severe implantation and stimulation associated adverse events were recorded. CONCLUSIONS: Selective L4-DRGSTIM improved neuropathic pain and functional impairment in CRPS as previously reported. CRPS patients displayed a pro-inflammatory molecular pattern in serum. Serum anti-inflammatory IL-10 significantly declined, while saliva oxytocin nonsignificantly increased after L4-DRGSTIM . An evidence-based relational interpretation of our study is limited due to the uncontrolled study design. However, molecular profiling of biofluids (saliva, serum) represents a novel and experimental field in applied neuromodulation, which warrant further investigations to unveil mechanisms of neuroimmune modulation.

Systemic High-Mobility Group Box-1: A Novel Predictive Biomarker for Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVES: To investigate the release of proinflammatory damage-associated molecular pattern molecule "high-mobility group box-1" in the serum of patients after aneurysmal subarachnoid hemorrhage and its association with cerebral vasospasm. DESIGN: Retrospective observational study. SETTING: University hospital. PATIENTS: Aneurysmal subarachnoid hemorrhage patients admitted within 24 hours of ictus. INTERVENTIONS: Standard subarachnoid hemorrhage treatment after clipping or coiling of aneurysm. MEASUREMENTS AND MAIN RESULTS: We enrolled 53 aneurysmal subarachnoid hemorrhage patients from which peripheral venous blood was withdrawn on days 1, 3, 5, 7, 9, 11, and 13 and once from the controls to obtain the serum. Serum high-mobility group box-1 concentration was quantified by enzyme-linked immunosorbent assay. Serum interleukin-6 and peripheral blood leukocytes were also determined over the first 2 weeks after subarachnoid hemorrhage. Patients' data were recorded prospectively. Serum high-mobility group box-1 was significantly elevated in subarachnoid hemorrhage patients from day 1 to day 13 when compared with nonsubarachnoid hemorrhage patients (p < 0.05). Patients with cerebral vasospasm showed significantly higher high-mobility group box-1 starting from day 1 to day 13 when compared with patients without cerebral vasospasm. Cumulative levels of high-mobility group box-1 showed significant correlation with peripheral blood leukocytes and interleukin-6 levels (p < 0.05). Receiver operating characteristic curve analysis showed that serum high-mobility group box-1 level at admission may be a predictive biomarker for cerebral vasospasm with a sensitivity of 59% and a specificity of 82% at a cutoff value of 5.6 ng/mL. CONCLUSIONS: Serum high-mobility group box-1 is differentially elevated after subarachnoid hemorrhage. Serum high-mobility group box-1 levels were elevated early after subarachnoid hemorrhage (day 1) and remained significantly high until day 13 in patients who developed cerebral vasospasm. Our data suggest that serum high-mobility group box-1 may be a predictive biomarker for the detection of CVS.

Combining GFR estimates from cystatin C and creatinine-what is the optimal mix?

BACKGROUND: Combining estimated glomerular filtration rate (eGFR) equations based on creatinine and cystatin C has been shown to improve the accuracy of GFR estimation. This study aims to optimize this strategy for height-independent GFR estimation in children. METHODS: Retrospective study of 408 inulin clearance tests with simultaneous International Federation of Clinical Chemistry-calibrated measurements of creatinine, cystatin C, and urea in children (mean age 12.5 years, GFR 91.2 ml/min/1.73m2) comparing the arithmetic (meanarith) and geometric means (meangeom) of a height-independent creatinine-based (full age spectrum, based on age (FASage)) and a cystatin C-based equation (FAScys), with the complex height-dependent CKiD3 equation incorporating gender, height, cystatin C, creatinine, and urea. RESULTS: Meangeom had a P30 accuracy of 89.2% compared to meanarith 87.7% (p = 0.030) as well as lower bias and %precision error and performed almost as well as CKiD3 (P30 accuracy 90.9%). Modifying the weight of FASage and FAScys when calculating the means showed that an equal contribution was most accurate in most patients. In spina bifida patients, FAScys alone outperformed any combination. Malignancy or nephritis patients had slightly higher accuracy with weighted means favoring cystatin C or creatinine, respectively. Disagreement between FAScys and FASage was inversely correlated with the accuracy of meangeom. When disagreement exceeded 40%, application of weighted means based on diagnosis improved the performance of eGFR. CONCLUSIONS: In the absence of height data, the optimal strategy for estimating GFR in children is by using the geometric mean of FASage and FAScys. When there is large disagreement between the two, weighted means based on diagnosis improve accuracy.

How the brain codes intimacy: The neurobiological substrates of romantic touch.

Humans belong to a minority of mammalian species that exhibit monogamous pair-bonds, thereby enabling biparental care of offspring. The high reward value of interpersonal closeness and touch in couples is a key proximate mechanism facilitating the maintenance of enduring romantic bonds. However, surprisingly, the neurobiological underpinnings mediating the unique experience of a romantic partner's touch remain unknown. In this randomized placebo (PLC)-controlled, between-group, pharmacofunctional magnetic resonance imaging (fMRI) study involving 192 healthy volunteers (96 heterosexual couples), we intranasally administered 24 IU of the hypothalamic peptide oxytocin (OXT) to either the man or the woman. Subsequently, we scanned the subjects while they assumed that they were being touched by their romantic partners or by an unfamiliar person of the opposite sex, although in reality an identical pattern of touch was always given by the same experimenter. Our results show that intranasal OXT compared to PLC selectively enhanced the subjective pleasantness of the partner's touch. Importantly, intranasal OXT selectively increased responses to partner touch in the nucleus accumbens (NAcc) and anterior cingulate cortex. Under OXT, NAcc activations to partner touch positively correlated with the subjects' evaluation of their relationship quality. Collectively, our results suggest that OXT may contribute to the maintenance of monogamous relationships in humans by concomitantly increasing the reward value of partner touch and diminishing the hedonic quality of stranger touch. Hum Brain Mapp 38:4525-4534, 2017. © 2017 Wiley Periodicals, Inc.

Clinical performance of LOCI™-based tumor marker assays for tumor markers CA 15-3, CA 125, CEA, CA 19-9 and AFP in gynecological cancers.

Evidence is sparse regarding the clinical performance of luminescent oxygen channeling immunoassays-based tumor marker assays in gynecological cancer. Analyzing serum samples of 336 patients with Dimension™Vista1500, we investigated the diagnostic power of carbohydrate antigen 15-3, carbohydrate antigen 125, carcinoembryonic antigen, carbohydrate antigen 19-9, and alpha-fetoprotein in patients suffering from different types of gynecological cancer and precancerous gynecological diseases and compared findings to appropriate control groups. The cohort comprised 177 female patients with gynecological cancers (73 breast, 22 cervical, 16 endometrial, 17 vulva, and 49 ovarian cancers), 26 patients with precancerous gynecological diseases (11 vulva, 4 cervical, and 10 breast), 109 patients with benign gynecological diseases, and 24 healthy controls. Discriminative power was assessed by areas under the curve in receiver operating characteristic curves, and sensitivities were determined at a fixed specificity of 95%. Levels of biomarkers in healthy controls were in the expected ranges and a discriminative power between gynecological cancers and healthy controls was observed for several tumor markers. Established tumor type-associated markers were elevated in specific gynecological cancers and benign controls as well as within precancerous gynecological diseases and healthy control group. In ovarian cancer, carbohydrate antigen 125 and carbohydrate antigen 15-3 were significantly elevated compared to the respective benign diseases. Carbohydrate antigen 125 was the most conclusive marker (area under the curve = 0.86% and 77.6% sensitivity at 95% specificity). In breast cancer, carcinoembryonic antigen and carbohydrate antigen 15-3 were significantly higher than in the respective benign diseases. Carcinoembryonic antigen achieved the most conclusive area under the curve (0.65) with 31.5% sensitivity at 95% specificity. None of the investigated markers was found to be of value in discriminating benign and malignant cervical diseases. Carcinoembryonic antigen and alpha-fetoprotein distinguished precancerous breast and vulva diseases from healthy controls. These findings show that luminescent oxygen channeling immunoassays-based tumor marker assays provide reliable results in routine diagnostics.