Autophagy is emerging as a key regulatory process during skeletal muscle development, regeneration and homeostasis, and deregulated autophagy has been implicated in muscular disorders and age-related ...muscle decline. We have monitored autophagy in muscles of mdx mice and human Duchenne muscular dystrophy (DMD) patients at different stages of disease. Our data show that autophagy is activated during the early, compensatory regenerative stages of DMD. A progressive reduction was observed during mdx disease progression, in coincidence with the functional exhaustion of satellite cell-mediated regeneration and accumulation of fibrosis. Moreover, pharmacological manipulation of autophagy can influence disease progression in mdx mice. Of note, studies performed in regenerating muscles of wild-type mice revealed an essential role of autophagy in the activation of satellite cells upon muscle injury. These results support the notion that regeneration-associated autophagy contributes to the early compensatory stage of DMD progression, and interventions that extend activation of autophagy might be beneficial in the treatment of DMD. Thus, autophagy could be a 'disease modifier' targeted by interventions aimed to promote regeneration and delay disease progression in DMD.
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Staked-in-needle prefilled syringes (SIN-PFS) are widely used for the parenteral administration of drug product solutions. During stability studies, clogging of the injection needle ...was observed in syringes filled with concentrated antibody solution. A prerequisite for this phenomenon is that liquid has entered the needle. In this study, we characterized the mechanism causing the entry and movement of liquid in the needle using neutron imaging without manipulating the container closure integrity of the syringe. The gas pressure difference between inside and outside of the syringe was identified as the major cause of liquid movement. The influence of external factors, such as temperature fluctuation and physical pressure on the stopper, were tested and were confirmed to have a relevant impact on the processes of liquid entering and moving inside the injection needle. In a second step, the solidification process of the liquid segments inside the needle via solvent evaporation was further investigated, and the process was found to be dependent on storage time, environmental climate and interaction between the drug product solution and the needle surface. The presence of air/liquid segments was identified as a further factor for the stochastic behavior of needle clogging. For the first time, this fundamental mechanism behind the needle clogging issue was investigated in depth and the results will help to reduce the defect rate for clogged SIN-PFS products.
Functionally distinct T-helper (Th) subsets orchestrate immune responses. Maintenance of homeostasis through the tight control of inflammatory Th cells is crucial to avoid autoimmune inflammation. ...Activation-Induced Cell Death (AICD) regulates homeostasis of T cells, and it has never been investigated in human Th cells. We generated stable clones of inflammatory Th subsets involved in autoimmune diseases, such as Th1, Th17 and Th1/17 cells, from healthy donors (HD) and multiple sclerosis (MS) patients and we measured AICD. We find that human Th1 cells are sensitive, whereas Th17 and Th1/17 are resistant, to AICD. In particular, Th1 cells express high level of FAS-ligand (FASL), which interacts with FAS and leads to caspases' cleavage and ultimately to cell death. In contrast, low FASL expression in Th17 and Th1/17 cells blunts caspase 8 activation and thus reduces cell death. Interestingly, Th cells obtained from healthy individuals and MS patients behave similarly, suggesting that this mechanism could explain the persistence of inflammatory IL-17-producing cells in autoimmune diseases, such as MS, where their generation is particularly substantial.
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Staked-in needle pre-fillable syringes (SIN-PFS) are a convenient delivery system widely established in the growing pharmaceutical market. Under specific storage conditions, the ...needle of PFS containing high concentration drug product (DP) solution is prone to clogging, which prevents administration of the liquid. The purpose of this study is to clarify the clogging phenomenon of SIN-PFS and to elucidate the role of water vapor transmission via the needle shield.
The presence of liquid within needles is a prerequisite condition for clogging and was investigated non-invasively by neutron imaging (NI) to confirm that liquid can migrate into the needle under certain processing conditions. The water vapor transmission rate (WVTR) of different needle shields was measured and the impact of temperature and relative humidity (rH) on the WVTR was investigated on sheets with the same composition as used in commercial needle shields. Our study clearly showed that the partial vapor pressure difference (ΔPP) across the needle shield is the dominant driving factor for water vapor transmission. A linear correlation between ΔPP and WVTR was found and a model to predict the water vapor transmission for PFS under specific storage conditions was developed. The impact of the WVTR on needle clogging was confirmed by clogging tests performed on SIN-PFS stored under different conditions. Thereby, we clearly show that high water loss induced by higher WVTR can be correlated to an increased occurrence of needle clogging. In conclusion, the WVTR of the needle shield plays a key role in needle clogging and the established WVTR model can be employed to assess the clogging risk for product development.
Photobiomodulation (PBM) has ergogenic effects on aerobic and anaerobic efforts and may improve sports performance. As Brazilian jiu-jitsu (BJJ) fighting requires both aerobic and anaerobic ...metabolism, so PBM may be effective in increasing the physical performance of BJJ athletes. Thus, this study aimed to verify the effects of PBM with different energy doses (6 or 12 J per point) on high-intensity intermittent anaerobic performance in BJJ athletes.
Eleven male athletes performed three lower limb Wingate testing sessions. At the beginning of each session, in a randomized, crossover, double-blind fashion, the athletes received PBM with a dose of 6 J (4.5 J/cm
) or 12 J (9.1 J/cm
), or placebo (PLA) at 17 points in each lower limb. In each session, the squat jump (SJ) and three Wingate test series were performed, with a 3-minute interval between series. Heart rate (HR) was collected immediately before, after each Wingate test, and at 1, 3, and 5 minutes after the last test. The rate of perceived exertion (RPE) was reported after each Wingate test. Differences between Wingate tests and treatment sessions were set at p<0.05.
No differences were observed between treatments in SJ height, Wingate performance, HR, and RPE (p>0.05; for all comparisons). The Wingate test session promoted a reduction in anaerobic capacity in the second and third sets in all conditions, indicating fatigue (p<0.05).
Treatment with PBM did not produce a dose-dependent ergogenic response in high-intensity intermittent performance in BJJ athletes.
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