Perceived realism of haptic rendering methods for bimanual high force tasks: original and replication study.

Realistic haptic feedback is a key for virtual reality applications in order to transition from solely procedural training to motor-skill training. Currently, haptic feedback is mostly used in low-force medical procedures in dentistry, laparoscopy, arthroscopy and alike. However, joint replacement procedures at hip, knee or shoulder, require the simulation of high-forces in order to enable motor-skill training. In this work a prototype of a haptic device capable of delivering double the force (35 N to 70 N) of state-of-the-art devices is used to examine the four most common haptic rendering methods (penalty-, impulse-, constraint-, rigid body-based haptic rendering) in three bimanual tasks (contact, rotation, uniaxial transition with increasing forces from 30 to 60 N) regarding their capabilities to provide a realistic haptic feedback. In order to provide baseline data, a worst-case scenario of a steel/steel interaction was chosen. The participants needed to compare a real steel/steel interaction with a simulated one. In order to substantiate our results, we replicated the study using the same study protocol and experimental setup at another laboratory. The results of the original study and the replication study deliver almost identical results. We found that certain investigated haptic rendering method are likely able to deliver a realistic sensation for bone-cartilage/steel contact but not for steel/steel contact. Whilst no clear best haptic rendering method emerged, penalty-based haptic rendering performed worst. For simulating high force bimanual tasks, we recommend a mixed implementation approach of using impulse-based haptic rendering for simulating contacts and combine it with constraint or rigid body-based haptic rendering for rotational and translational movements.

Age and gender effects on presence, user experience and usability in virtual environments-first insights.

Virtual Reality (VR) is applied in various areas were a high User Experience is essential. The sense of Presence while being in VR and its relation to User Experience therefore form crucial aspects, which are yet to be understood. This study aims at quantifying age and gender effects on this connection, involving 57 participants in VR, and performing a geocaching game using a mobile phone as experimental task to answer questionnaires measuring Presence (ITC-SOPI), User Experience (UEQ) and Usability (SUS). A higher Presence was found for the older participants, but there was no gender difference nor any interaction effects of age and gender. These findings are contractionary to preexisting limited work which has shown higher Presence for males and decreases of Presence with age. Four aspects discriminating this study from literature are discussed as explanations and as a starting point for future investigations into the topic. The results further showed higher ratings in favor of User Experience and lower ratings towards Usability for the older participants.

Serum Starvation Accelerates Intracellular Metabolism in Endothelial Cells.

Periods of low energy supply are challenging conditions for organisms and cells during fasting or famine. Although changes in nutrient levels in the blood are first sensed by endothelial cells, studies on their metabolic adaptations to diminished energy supply are lacking. We analyzed the dynamic metabolic activity of human umbilical vein endothelial cells (HUVECs) in basal conditions and after serum starvation. Metabolites of glycolysis, the tricarboxylic acid (TCA) cycle, and the glycerol pathway showed lower levels after serum starvation, whereas amino acids had increased levels. A metabolic flux analysis with 13C-glucose or 13C-glutamine labeling for different time points reached a plateau phase of incorporation after 30 h for 13C-glucose and after 8 h for 13C-glutamine under both experimental conditions. Notably, we observed a faster label incorporation for both 13C-glucose and 13C-glutamine after serum starvation. In the linear range of label incorporation after 3 h, we found a significantly faster incorporation of central carbon metabolites after serum starvation compared to the basal state. These findings may indicate that endothelial cells develop increased metabolic activity to cope with energy deficiency. Physiologically, it can be a prerequisite for endothelial cells to form new blood vessels under unfavorable conditions during the process of angiogenesis in vivo.

Serum starvation induces sexual dimorphisms in secreted proteins of human umbilical vein endothelial cells (HUVECs) from twin pairs.

There is growing evidence for sex and gender differences in the clinical manifestation and outcomes of human diseases. Human primary endothelial cells represent a useful cardiovascular model to study sexual dimorphisms at the cellular level. Here, we analyzed sexual dimorphisms of the secretome after serum starvation using human umbilical vein endothelial cells (HUVECs) from twin pairs of the opposite sex to minimize the impact of varying genetic background. HUVECs were starved for 5 and 16 h, respectively, and proteins of the cell culture supernatants were analyzed by tandem mass spectrometry. Altogether, 960 extracellular proteins were identified of which 683 were amendable to stringent quantification. Significant alterations were observed for 455 proteins between long-term and short-term starvation and the majority were similar in both sexes. Only 5 proteins showed significant sex-specific regulation between long-versus short-term starvation. Furthermore, 19 unique proteins with significant sexual dimorphisms at the same time points of serum starvation were observed. A larger number of proteins, for example tissue factor inhibitor 2 (TFPI2), displayed higher levels in the supernatants of females compared to male cells after long term serum starvation that might point to higher adaptation capacity of female cells. The overall results demonstrate that male and female cells differ in their secretome.

Pazopanib with 5-FU and oxaliplatin as first line therapy in advanced gastric cancer: A randomized phase-II study-The PaFLO trial. A study of the Arbeitsgemeinschaft Internistische Onkologie AIO-STO-0510.

VEGF inhibition in gastric cancer has a proven benefit in the second line setting. Pazopanib, an oral tyrosine kinase inhibitor, selectively inhibits VEGFR-1, -2 and -3, c-kit and PDGF-R resulting in inhibition of angiogenesis. This open-label randomized phase II trial (2:1) investigated the efficacy of combining pazopanib with FLO (5-fluorouracil, oxaliplatin) vs FLO alone (internal control arm) as first-line treatment in patients with advanced adenocarcinoma of the stomach and gastroesophageal junction (GEJ). Eighty-seven patients were randomized and 78 patients were eligible and evaluable (PaFLO arm 51 patients, FLO arm 27 patients). The PFS rate at 6 months (primary endpoint) was 34% in the PaFLO arm vs 30% in the FLO arm. Comparing PaFLO with FLO median PFS was 4.66 months (95% confidence interval [CI] 2.87-6.46) vs 4.47 months (95% CI 1.79-7.14) (95% CI, hazard ratio [HR] 0.96 (0.60-1.55), P = .882 [exploratory]); median OS was 10.19 months (95% CI 5.46-14.92) vs 7.33 months (95% CI 4.93-9.73), (95% CI HR 1.01 [0.62-1.65], P = .953, exploratory), disease control rate was 72% vs 59%. PaFLO was well tolerable, toxicities were slightly higher in the PaFLO arm. Major adverse events were loss of appetite, nausea, fatigue, diarrhea, neutropenia and thrombocytopenia. Adding pazopanib to chemotherapy shows signs of efficacy but no major improvement in this randomized phase 2 trial. The PFS at 6 months in both arms was lower than expected from the literature. Biomarkers identifying subgroups who benefit and novel combinations are needed. ClinicalTrials.gov: NCT01503372.

Epigallocatechin Gallate in Relapsing-Remitting Multiple Sclerosis: A Randomized, Placebo-Controlled Trial.

OBJECTIVE: To assess the safety and efficacy of epigallocatechin-3-gallate (EGCG) add-on to glatiramer acetate (GA) in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We enrolled patients with RRMS (aged 18-60 years, Expanded Disability Status Scale [EDSS] score 0-6.5), receiving stable GA treatment in a multicenter, prospective, double-blind, phase II, randomized controlled trial. Participants received up to 800 mg oral EGCG daily over a period of 18 months. The primary outcome was the proportion of patients without new hyperintense lesions on T2-weighted (T2w) brain MRI within 18 months. Secondary end points included additional MRI and clinical parameters. Immunologic effects of EGCG were investigated in exploratory experiments. RESULTS: A total of 122 patients on GA were randomly assigned to EGCG treatment (n = 62) or placebo (n = 60). We could not demonstrate a difference between groups after 18 months for the primary outcome or other radiologic (T2w lesion volume, T1w hypointense lesion number or volume, number of cumulative contrast-enhancing lesions, percent brain volume change), or clinical (EDSS, MS functional composite, and annualized relapse rate) parameter. EGCG treatment did not affect immune response to GA. Pharmacologic analysis revealed wide ranging EGCG plasma levels. The treatment was well tolerated with a similar incidence of mostly mild adverse events similar in both groups. CONCLUSION: In RRMS, oral EGCG add-on to GA was not superior to placebo in influencing MRI and clinical disease activity over 18 months. The treatment was safe at a daily dosage up to 800 mg EGCG. It did not influence immune parameters, despite indication of EGCG being bioavailable in patients. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS, EGCG added to GA did not significantly affect the development of new hyperintense lesions on T2-weighted brain MRI. TRIAL REGISTRATION INFORMATION: Clinical trial registration number: NCT00525668.

Epigallocatechin Gallate in Progressive MS: A Randomized, Placebo-Controlled Trial.

OBJECTIVE: To examine whether treatment with epigallocatechin gallate (EGCG) influences progression of brain atrophy, reduces clinical and further radiologic disease activity markers, and is safe in patients with progressive multiple sclerosis (PMS). METHODS: We enrolled 61 patients with primary or secondary PMS in a randomized double-blind, parallel-group, phase II trial on oral EGCG (up to 1,200 mg daily) or placebo for 36 months with an optional open-label EGCG treatment extension (OE) of 12-month duration. The primary end point was the rate of brain atrophy, quantified as brain parenchymal fraction (BPF). The secondary end points were radiologic and clinical disease parameters and safety assessments. RESULTS: In our cohort, 30 patients were randomized to EGCG treatment and 31 to placebo. Thirty-eight patients (19 from each group) completed the study. The primary endpoint was not met, as in 36 months the rate of decrease in BPF was 0.0092 ± 0.0152 in the treatment group and -0.0078 ± 0.0159 in placebo-treated patients. None of the secondary MRI and clinical end points revealed group differences. Adverse events of EGCG were mostly mild and occurred with a similar incidence in the placebo group. One patient in the EGCG group had to stop treatment due to elevated aminotransferases (>3.5 times above normal limit). CONCLUSIONS: In a phase II trial including patients with multiple sclerosis (MS) with progressive disease course, we were unable to demonstrate a treatment effect of EGCG on the primary and secondary radiologic and clinical disease parameters while confirming on overall beneficial safety profile. CLINICALTRIALGOV IDENTIFIER: NCT00799890. CLASSIFICATION OF EVIDENCE: This phase II trial provides Class II evidence that for patients with PMS, EGCG was safe, well tolerated, and did not significantly reduce the rate of brain atrophy.

Wrist at risk? - Considerations derived from a novel experimental setup to assess torques during hip reaming with potential implications on the orthopedic surgeons' health.

Orthopedic surgeons endure high physical stresses when performing surgery, as large forces and torques are applied commonly. Occupational risks are consequently higher when compared to other surgical disciplines. One example is the reaming of the acetabula during total hip arthroplasty, using customized instruments. This surgery may predispose the surgeon to overuse-related wrist pathology. In this study, torques acting along the reaming tool were measured, and the resulting forces applied to the orthopedic surgeons' wrists were estimated based on the measured torque data from hip reaming. Different reamer sizes and tool velocities were analyzed to determine how both parameters may influence the torques applied at the surgeon's wrist. Using a highly standardized setup, torques were measured while the reamer was pushed into the acetabula to remove cartilage. Maximum torques and stoppage torques at blocking of the reamer were compared between feed rates and reamer sizes. Peak values of the maximum torques along the reamer axis averaged 1.5-1.8 Nm. No significant difference between maximum torques and reamer sizes was found. A significant difference in maximum torques was noted between feed rates with a large effect (p = 0.010; η2 = 0.214) and a large interaction effect (p = 0.017; η2 = 0.186). Based on this experimental setup, it can be hypothesized that the impulsive behavior of the torque when the milling tool reaches the subchondral lamella could potentially contribute to wrist pathology. These preliminary data warrant further study. Consequently, torque limiters should be implemented in reamers to minimize the risk of occupation-related pathology to the wrist.

A cadaver-based biomechanical model of acetabulum reaming for surgical virtual reality training simulators.

Total hip arthroplasty (THA) is a highly successful surgical procedure, but complications remain, including aseptic loosening, early dislocation and misalignment. These may partly be related to lacking training opportunities for novices or those performing THA less frequently. A standardized training setting with realistic haptic feedback for THA does not exist to date. Virtual Reality (VR) may help establish THA training scenarios under standardized settings, morphology and material properties. This work summarizes the development and acquisition of mechanical properties on hip reaming, resulting in a tissue-based material model of the acetabulum for force feedback VR hip reaming simulators. With the given forces and torques occurring during the reaming, Cubic Hermite Spline interpolation seemed the most suitable approach to represent the nonlinear force-displacement behavior of the acetabular tissues over Cubic Splines. Further, Cubic Hermite Splines allowed for a rapid force feedback computation below the 1 ms hallmark. The Cubic Hermite Spline material model was implemented using a three-dimensional-sphere packing model. The resulting forces were delivered via a human-machine-interaction certified KUKA iiwa robotic arm used as a force feedback device. Consequently, this novel approach presents a concept to obtain mechanical data from high-force surgical interventions as baseline data for material models and biomechanical considerations; this will allow THA surgeons to train with a variety of machining hardness levels of acetabula for haptic VR acetabulum reaming.

Vasodilation of Tea Polyphenols Ex Vivo Is Mediated by Hydrogen Peroxide Under Rapid Compound Decay.

Improvement of endothelial function represents a major health effect of tea in humans. Ex vivo, tea and tea polyphenols stimulate nitric oxide (NO)-dependent vasodilation in isolated blood vessels. However, it was reported that polyphenols can generate reactive oxygen species (ROS) in vitro. We therefore aimed to elucidate the role of ROS production in tea polyphenol-induced vasodilation in explanted aortic rings. Vasorelaxation of rat aortic rings was assessed in an organ chamber model with low concentrations of epigallocatechin-3-gallate (EGCG), theaflavin-3,3'-digallate (TF3), and with green and black tea, with or without pretreatment with catalase or superoxide dismutase (SOD). The stability of EGCG and TF3 was measured by HPLC, and the levels of hydrogen peroxide (H2O2) were determined. EGCG and green tea-induced vasorelaxation was completely prevented by catalase and slightly increased by SOD. TF3 and black tea yielded similar results. Both EGCG and TF3 were rapidly degraded. This was associated with increasing H2O2 levels over time. Hydrogen peroxide concentrations produced in a time range compatible with tea polyphenol decay induced NO-dependent vasodilation in aortic rings. In conclusion, tea polyphenol-induced vasodilation in vitro is mediated by low levels of H2O2 generated during compound decay. The results could explain the apparent lack of vasodilatory effects of isolated tea polyphenols in humans.

Modified Protocol of Harvesting, Extraction, and Normalization Approaches for Gas Chromatography Mass Spectrometry-Based Metabolomics Analysis of Adherent Cells Grown Under High Fetal Calf Serum Conditions.

A gas chromatography mass spectrometry (GC-MS) metabolomics protocol was modified for quenching, harvesting, and extraction of metabolites from adherent cells grown under high (20%) fetal calf serum conditions. The reproducibility of using either 50% or 80% methanol for quenching of cells was compared for sample harvest. To investigate the efficiency and reproducibility of intracellular metabolite extraction, different volumes and ratios of chloroform were tested. Additionally, we compared the use of total protein amount versus cell mass as normalization parameters. We demonstrate that the method involving 50% methanol as quenching buffer followed by an extraction step using an equal ratio of methanol:chloroform:water (1:1:1, v/v/v) followed by the collection of 6 mL polar phase for GC-MS measurement was superior to the other methods tested. Especially for large sample sets, its comparative ease of measurement leads us to recommend normalization to protein amount for the investigation of intracellular metabolites of adherent human cells grown under high (or standard) fetal calf serum conditions. To avoid bias, care should be taken beforehand to ensure that the ratio of total protein to cell number are consistent among the groups tested. For this reason, it may not be suitable where culture conditions or cell types have very different protein outputs (e.g., hypoxia vs. normoxia). The full modified protocol is available in the Supplementary Materials.

Sex-specific metabolic and functional differences in human umbilical vein endothelial cells from twin pairs.

BACKGROUND AND AIMS: Gonadal hormones are mainly thought to account for sex and gender differences in the incidence, clinical manifestation and therapy of many cardiovascular diseases. However, intrinsic sex differences at the cellular level are mostly overlooked. Here, we assessed sex-specific metabolic and functional differences between male and female human umbilical vein endothelial cells (HUVECs). METHODS: Cellular metabolism was investigated by bioenergetic studies (Seahorse Analyser) and a metabolomic approach. Protein levels were determined by Western blots and proteome analysis. Vascular endothelial growth factor (VEGF)-stimulated cellular migration was assessed by gap closure. HUVECs from dizygotic twin pairs were used for most experiments. RESULTS: No sex differences were observed in untreated cells. However, sexual dimorphisms appeared after stressing the cells by serum starvation and treatment with VEGF. Under both conditions, female cells had higher intracellular ATP and metabolite levels. A significant decline in ATP levels was observed in male cells after serum starvation. After VEGF, the ratio of glycolysis/mitochondrial respiration was higher in female cells and migration was more pronounced. CONCLUSIONS: These results point to an increased stress tolerance of female cells. We therefore propose that female cells have an energetic advantage over male cells under conditions of diminished nutrient supply. A more favourable energy balance of female HUVECs after serum starvation and VEGF could potentially explain their stronger migratory capacity.

Sex-specific differences in the intracellular proteome of human endothelial cells from dizygotic twins.

Differences between men and women are being continuously identified in many human diseases. The underlying reasons are not yet fully understood. Beside the influence of endogenous hormones and life style, intrinsic sex-specific dimorphisms at the cellular level may also play a role. HUVECs from twin pairs of opposite sex provide an excellent tool to address the question of sex-specific differences at the molecular level. We compared for the first time protein levels of male and female HUVECs from dizygotic twins using a proteomic approach. To investigate differences under basal and stress conditions, cells were either left untreated or wounded and serum starved for different time points. Approximately 10% of all proteins monitored showed significant sexual dimorphisms in their level under the different conditions tested. The majority of the proteins displayed a higher abundance in female cells. The magnitude of the difference in protein levels between male and female cells was rather small. The most prominent differences throughout all conditions were observed for several X-chromosome encoded proteins with higher levels in female (UBA1, HDHD1) or in male cells (G6PD). Proteins involved in basic cellular processes, such as gene expression and translation (e.g. HMGN1, SRP54) displayed sex-specific levels in particular conditions only. SIGNIFICANCE: This study provides novel insights into sexual dimorphic protein levels in HUVECs from twin pairs of the opposite sex. The findings identify proteins with sex-specific differences in their levels under different cell culture conditions. The study also highlights the presence of X-chromosome encoded proteins escaping X-chromosomal inactivation. The results emphasize the need to consider the cellular sex of male and female HUVECs in in vitro experiments.

Pyrrolizidine alkaloid-induced alterations of prostanoid synthesis in human endothelial cells.

Pyrrolizidine alkaloids (PA) are a group of secondary plant metabolites belonging to the most widely distributed natural toxins. PA intoxication of humans leads to severe liver damage, such as hepatomegaly, hepatic necrosis, fibrosis and cirrhosis. An acute consequence observed after ingestion of high amounts of PA is veno-occlusive disease (VOD) where the hepatic sinusoidal endothelial cells are affected. However, the mechanisms leading to VOD after PA intoxication remain predominantly unknown. Thus, we investigated PA-induced molecular effects on human umbilical vein endothelial cells (HUVEC). We compared the effects of PA with the effects of PA metabolites obtained by in vitro metabolism using liver homogenate (S9 fraction). In vitro-metabolized lasiocarpine and senecionine resulted in significant cytotoxic effects in HUVEC starting at 300 µM. Initial molecular effect screening using a PCR array with genes associated with endothelial cell biology showed PA-induced upregulation of the Fas receptor, which is involved in extrinsic apoptosis, and regulation of a number of interleukins, as well as of different enzymes relevant for prostanoid synthesis. Modulation of prostanoid synthesis was subsequently studied at the mRNA and protein levels and verified by increased release of prostaglandin I2 as the main prostanoid of endothelial cells. All effects occurred only with in vitro-metabolically activated PA lasiocarpine and senecionine. By contrast, no effect was observed for the PA echimidine, heliotrine, lasiocarpine, senecionine, senkirkine and platyphylline in the absence of an external metabolizing system up to the highest tested concentration of 500 µM. Overall, our results confirm the metabolism-dependent toxification of PA and elucidate the involved pathways. These include induction of inflammatory cytokines and deregulation of the prostanoid synthesis pathway in endothelial cells, linking for the first time PA-dependent changes in prostanoid release to distinct alterations at the mRNA and protein levels of enzymes of prostanoid synthesis.

Presence and User Experience in a Virtual Environment under the Influence of Ethanol: An Explorative Study.

Virtual Reality (VR) is used for a variety of applications ranging from entertainment to psychological medicine. VR has been demonstrated to influence higher order cognitive functions and cortical plasticity, with implications on phobia and stroke treatment. An integral part for successful VR is a high sense of presence - a feeling of 'being there' in the virtual scenario. The underlying cognitive and perceptive functions causing presence in VR scenarios are however not completely known. It is evident that the brain function is influenced by drugs, such as ethanol, potentially confounding cortical plasticity, also in VR. As ethanol is ubiquitous and forms part of daily life, understanding the effects of ethanol on presence and user experience, the attitudes and emotions about using VR applications, is important. This exploratory study aims at contributing towards an understanding of how low-dose ethanol intake influences presence, user experience and their relationship in a validated VR context. It was found that low-level ethanol consumption did influence presence and user experience, but on a minimal level. In contrast, correlations between presence and user experience were strongly influenced by low-dose ethanol. Ethanol consumption may consequently alter cognitive and perceptive functions related to the connections between presence and user experience.

A Possible Indicator of Oxidative Damage in Smokers: (13Z)-Lycopene?

In vitro, the gaseous phase of cigarette smoke is known to induce both isomerization and degradation of dietary carotenoids, such as ß-carotene and lycopene. However, the effects of cigarette smoke on the composition of circulating lycopene in vivo are not well understood. In this study, we examined the lycopene profiles of plasma from non-smokers and smokers. No oxidative intermediates of lycopene that have been observed previously in vitro were detected in the plasma, but evidence of isomerization of the carotenoid was seen. Four geometric forms of lycopene were detected in the plasma of both smokers and non-smokers, namely the (5Z), (9Z), (13Z) and (all-E) forms. The relative amounts of these isomers differed between the two cohorts and there was a significant difference (p < 0.05) between smokers and non-smokers for the ratio of total-Z:all-E lycopene, and in the relative amounts of (13Z) and (all-E)-lycopene. The ratio of (all-E):(13Z)-lycopene was 0.84:1.00 in smokers compared to 1.04:1.00 in non-smokers. In smokers, the (13Z)-isomer was generated in preference to the more thermodynamically stable (5Z) and (9Z)-isomers. This mirrors the scenario seen in vitro, in which the formation of (13Z)-lycopene was the main isomer that accompanied the depletion of (all-E) lycopene, when exposed to cigarette smoke. The results suggest that the relative amount of (13Z)-lycopene could be used as an indicator of oxidative damage to lycopene in vivo.

Tea-induced improvement of endothelial function in humans: No role for epigallocatechin gallate (EGCG).

Consumption of tea is inversely associated with cardiovascular diseases. However, the active compound(s) responsible for the protective effects of tea are unknown. Although many favorable cardiovascular effects in vitro are mediated by epigallocatechin gallate (EGCG), its contribution to the beneficial effects of tea in vivo remains unresolved. In a randomised crossover study, a single dose of 200 mg EGCG was applied in three different formulas (as green tea beverage, green tea extract (GTE), and isolated EGCG) to 50 healthy men. Flow-mediated dilation (FMD) and endothelial-independent nitro-mediated dilation (NMD) was measured before and two hours after ingestion. Plasma levels of tea compounds were determined after each intervention and correlated with FMD. FMD significantly improved after consumption of green tea containing 200 mg EGCG (p < 0.01). However, GTE and EGCG had no significant effect on FMD. NMD did not significantly differ between interventions. EGCG plasma levels were highest after administration of EGCG and lowest after consumption of green tea. Plasma levels of caffeine increased after green tea consumption. The results show that EGCG is most likely not involved in improvement of flow-mediated dilation by green tea. Instead, other tea compounds, metabolites or combinations thereof may play a role.

Human Umbilical Vein Endothelial Cells foster conversion of CD4+CD25-Foxp3- T cells into CD4+Foxp3+ Regulatory T Cells via Transforming Growth Factor-ß.

Trans-placental cell trafficking is a naturally occurring process during pregnancy that results in the direct recognition of foreign maternal antigens by fetal tissue and vice versa. Immigration of potentially harmful allo-reactive maternal T cells into fetal circulation may provoke anti-fetal immune responses. However, the contact with fetal tissue may favor differentiation of maternal immune cells into cells with a regulatory phenotype. Human Umbilical Vein Endothelial Cells (HUVECs) possess immune-regulating properties and are one of the first fetal cells to get in contact with foreign maternal immune cells. Therefore, here we studied whether HUVECs induce the conversion of maternal T cells into regulatory T (Treg) cells. Moreover, we assessed whether this response is changing according to the sex of the HUVECs. Both female and male HUVECs induced the conversion of maternal T cells into Treg cells which is partially mediated via TGF-ß. Female HUVECs showed a stronger capacity to induce Treg cells compared to male HUVECs. Our findings propose that HUVECs contribute to fetal-maternal tolerance by the increase of the Treg cell population. Sex-specific differences in Treg cell induction may partly account for the disparities on the incidence of infectious and autoimmune diseases between both sexes during early childhood.

Metabolic response to epigallocatechin-3-gallate in relapsing-remitting multiple sclerosis: a randomized clinical trial.

BACKGROUND: Muscle weakness and fatigue are common symptoms in multiple sclerosis (MS). Green tea catechins such as (-)epigallocatechin-3-gallate (EGCG) are known to improve energy metabolism at rest and during exercise. OBJECTIVE: We tested the hypothesis that EGCG improves energy metabolism and substrate utilization in patients with MS. DESIGN: Eighteen patients (8 men) with relapsing-remitting MS (expanded disability status scale score <4.5, all receiving glatiramer acetate) participated in this randomized, double-blind, placebo-controlled, crossover trial at a clinical research center. All patients received EGCG (600 mg/d) and placebo over 12 wk (4-wk washout in between). After each intervention, fasting and postprandial energy expenditure (EE), as well as fat oxidation (FAOx) and carbohydrate oxidation (CHOx) rates, were measured either at rest or during 40 min of exercise (0.5 W/kg). At rest, blood samples and microdialysates from adipose tissue and skeletal muscle were also taken. RESULTS: At rest, postprandial EE and CHOx, as well as adipose tissue perfusion and glucose supply, were significantly lower in men but higher in women receiving EGCG compared with placebo. During exercise, postprandial EE was lower after EGCG than after placebo, indicating an increased working efficiency (men > women). After placebo, exercise EE was mainly fueled by FAOx in both men and women. After EGCG, there was a shift to a higher and more stable CHOx during exercise in men but not in women. CONCLUSIONS: Our data indicate that EGCG given to patients with MS over 12 wk improves muscle metabolism during moderate exercise to a greater extent in men than in women, possibly because of sex-specific effects on autonomic and endocrine control.