Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Prolyl carboxypeptidase regulates energy expenditure and the thyroid axis

Hypothalamic α-melanocyte-stimulating hormone (α-MSH) plays a central role in regulating energy uptake and expenditure. Prolyl carboxypeptidase (PRCP), a protease expressed in the hypothalamus, is responsible for the degradation of α-MSH. PRCP null animals (PRCP gt/gt mice) display elevated α-MSH in the hypothalamus, lower body weight, and are protected from diet induced obesity. Here, we report that PRCP gt/gt mice have a significant decrease in fat mass, although an increase in lean mass was also observed. In agreement with low fat accumulation, reduced leptin levels were found. Consistent with the effect of α-MSH on energy metabolism, PRCP gt/gt mice had increased energy expenditure with elevated circulating thyroid hormone levels and brown adipose tissue uncoupling protein 1mRNA levels compared with control mice when exposed to regular diet. TRH mRNA levels in the PVN were significantly higher in fed PRCP gt/gt animals compared with fed wild-type controls. Fasting significantly decreased TRH mRNA levels in both PRCP gt/gt and wild-type (WT) mice. However, TRH mRNA levels in fasted PRCP gt/gt animals were significantly higher than those of fasted WT mice. Refeeding analysis after fasting showed a reduced food intake in PRCP gt/gt compared with WT mice. Finally, TRH mRNA levels in T 3-treated hypothyroid PRCP gt/gt mice showed a non significant reduction compared with those of hypothyroid PRCP gt/gt mice, supporting the impairment of the hypothalamo-pituitary-thyroid axis in PRCP gt/gt mice. All together, these data confirm that PRCP plays a role in the regulation of energy metabolism. Copyright © 2012 by The Endocrine Society

Prolyl carboxypeptidase regulates energy expenditure and the thyroid axis

Hypothalamic α-melanocyte-stimulating hormone (α-MSH) plays a central role in regulating energy uptake and expenditure. Prolyl carboxypeptidase (PRCP), a protease expressed in the hypothalamus, is responsible for the degradation of α-MSH. PRCP null animals (PRCP(gt/gt) mice) display elevated α-MSH in the hypothalamus, lower body weight, and are protected from diet induced obesity. Here, we report that PRCP(gt/gt) mice have a significant decrease in fat mass, although an increase in lean mass was also observed. In agreement with low fat accumulation, reduced leptin levels were found. Consistent with the effect of α-MSH on energy metabolism, PRCP(gt/gt) mice had increased energy expenditure with elevated circulating thyroid hormone levels and brown adipose tissue uncoupling protein 1 mRNA levels compared with control mice when exposed to regular diet. TRH mRNA levels in the PVN were significantly higher in fed PRCP(gt/gt) animals compared with fed wild-type controls. Fasting significantly decreased TRH mRNA levels in both PRCP(gt/gt) and wild-type (WT) mice. However, TRH mRNA levels in fasted PRCP(gt/gt) animals were significantly higher than those of fasted WT mice. Refeeding analysis after fasting showed a reduced food intake in PRCP(gt/gt) compared with WT mice. Finally, TRH mRNA levels in T(3)-treated hypothyroid PRCP(gt/gt) mice showed a non significant reduction compared with those of hypothyroid PRCP(gt/gt) mice, supporting the impairment of the hypothalamo-pituitary-thyroid axis in PRCP(gt/gt) mice. All together, these data confirm that PRCP plays a role in the regulation of energy metabolism

Radio Propagation Digital Twin Aided Multi-Point Transmission With In-Network Dynamic On-Off Switching

GPUs and programmable data planes have gone through an enormous evolution in the past years. GPUs can be used for modeling the real-world environment accurately, while programmable data planes can monitor the network in real-time and implement novel packet processing and decision logic. In this paper, we investigate how these two distant technologies can be combined to implement efficient coordinated multi-point (CoMP) transmission in an indoor environment. The proposed system implements the concept of dynamic on-off switching (DOOS) among various radio transmitters, relying on two information sources: 1) radio propagation digital twin based on real-time simulations of radio channels in the accurate 3D digital representation of the real industrial environment and 2) traffic load collected by the data plane for each transmitter. The proposed DOOS method implemented as a data plane algorithm dynamically selects a set of radio transmitters for each receiver by mixing information provided by the digital twin and the in-network traffic load measurements. The proposed method has low computational complexity and reduces the number of actively used radio transmitters. The proof-of-concept implementation of the proposed system has been validated in simulations as well as with measurements. The method achieves 69% energy saving for the radio compared to the default CoMP transmission and reception

Deletion of prolyl carboxypeptidase attenuates the metabolic effects of diet-induced obesity

α-Melanocyte-stimulating hormone (α-MSH) is a critical regulator of energy metabolism. Prolyl carboxypeptidase (PRCP) is an enzyme responsible for its degradation and inactivation. PRCP-null mice (PRCP gt/gt) showed elevated levels of brain α-MSH, reduced food intake, and a leaner phenotype compared with wild-type controls. In addition, they were protected against diet-induced obesity. Here, we show that PRCP gt/gt animals have improved metabolic parameters compared with wild-type controls under a standard chow diet (SD) as well as on a high-fat diet (HFD). Similarly to when they are exposed to SD, PRCP gt/gt mice exposed to HFD for 13 wk showed a leaner phenotype due to decreased fat mass, increased energy expenditure, and locomotor activity. They also showed improved insulin sensitivity and glucose tolerance compared with WT controls and a significant reduction in fasting glucose levels. These improvements occured before changes in body weight and composition were evident, suggesting that the beneficial effect of PRCP ablation is independent of the adiposity levels. In support of a reduced gluconeogenesis, liver PEPCK and G-6-Pase mRNA levels were reduced significantly in PRCP gt/gt compared with WT mice. A significant decrease in liver weight and hepatic triglycerides were also observed in PRCP gt/gt compared with WT mice. Altogether, our data suggest that PRCP is an important regulator of energy and glucose homeostasis since its deletion significantly improves metabolic parameters in mice exposed to both SD and HFD. © 2012 the American Physiological Society

Deletion of prolyl carboxypeptidase attenuates the metabolic effects of diet-induced obesity

α-Melanocyte-stimulating hormone (α-MSH) is a critical regulator of energy metabolism. Prolyl carboxypeptidase (PRCP) is an enzyme responsible for its degradation and inactivation. PRCP-null mice (PRCP gt/gt) showed elevated levels of brain α-MSH, reduced food intake, and a leaner phenotype compared with wild-type controls. In addition, they were protected against diet-induced obesity. Here, we show that PRCP gt/gt animals have improved metabolic parameters compared with wild-type controls under a standard chow diet (SD) as well as on a high-fat diet (HFD). Similarly to when they are exposed to SD, PRCP gt/gt mice exposed to HFD for 13 wk showed a leaner phenotype due to decreased fat mass, increased energy expenditure, and locomotor activity. They also showed improved insulin sensitivity and glucose tolerance compared with WT controls and a significant reduction in fasting glucose levels. These improvements occured before changes in body weight and composition were evident, suggesting that the beneficial effect of PRCP ablation is independent of the adiposity levels. In support of a reduced gluconeogenesis, liver PEPCK and G-6-Pase mRNA levels were reduced significantly in PRCP gt/gt compared with WT mice. A significant decrease in liver weight and hepatic triglycerides were also observed in PRCP gt/gt compared with WT mice. Altogether, our data suggest that PRCP is an important regulator of energy and glucose homeostasis since its deletion significantly improves metabolic parameters in mice exposed to both SD and HFD. © 2012 the American Physiological Society

Viable protoplast formation of the coral endosymbiont alga Symbiodinium spp. in a microfluidics platform

Symbiodiniaceae is an important dinoflagellate family which lives in endosymbiosis with reef invertebrates, including coral polyps, making them central to the holobiont. With coral reefs currently under extreme threat from climate change, there is a pressing need to improve our understanding on the stress tolerance and stress avoidance mechanisms of Symbiodinium spp. Reactive oxygen species (ROS) such as singlet oxygen are central players in mediating various stress responses; however, the detection of ROS using specific dyes is still far from definitive in intact Symbiodinium cells due to the hindrance of uptake of certain fluorescent dyes because of the presence of the cell wall. Protoplast technology provides a promising platform for studying oxidative stress with the main advantage of removed cell wall, however the preparation of viable protoplasts remains a significant challenge. Previous studies have successfully applied cellulose-based protoplast preparation in Symbiodiniaceae; however, the protoplast formation and regeneration process was found to be suboptimal. Here, we present a microfluidics-based platform which allowed protoplast isolation from individually trapped Symbiodinium cells, by using a precisely adjusted flow of cell wall digestion enzymes (cellulase and macerozyme). Trapped single cells exhibited characteristic changes in their morphology, cessation of cell division and a slight decrease in photosynthetic activity during protoplast formation. Following digestion and transfer to regeneration medium, protoplasts remained photosynthetically active, regrew cell walls, regained motility, and entered exponential growth. Elevated flow rates in the microfluidic chambers resulted in somewhat faster protoplast formation; however, cell wall digestion at higher flow rates partially compromised photosynthetic activity. Physiologically competent protoplasts prepared from trapped cells in microfluidic chambers allowed for the first time the visualization of the intracellular localization of singlet oxygen (using Singlet Oxygen Sensor Green dye) in Symbiodiniaceae, potentially opening new avenues for studying oxidative stress