There is growing evidence about the ability of cyclic adenosine monophosphate (cAMP) signaling and nonselective phosphodiesterase (PDE) inhibitors on mitigate muscle atrophy. PDE4 accounts for the ...major cAMP hydrolyzing activity in skeletal muscles, therefore advances are necessary about the consequences of treatment with PDE4 inhibitors on protein breakdown in atrophied muscles. We postulated that rolipram (selective PDE4 inhibitor) may activate cAMP downstream effectors, inhibiting proteolytic systems in skeletal muscles of diabetic rats.
Streptozotocin-induced diabetic rats were treated with 2 mg/kg rolipram for 3 days. Changes in the levels of components belonging to the proteolytic machineries in soleus and extensor digitorum longus (EDL) muscles were investigated, as well as cAMP effectors.
Treatment of diabetic rats with rolipram decreased the levels of atrogin-1 and MuRF-1 in soleus and EDL, and reduced the activities of calpains and caspase-3; these findings partially explains the low ubiquitin conjugates levels and the decreased proteasome activity. The inhibition of muscle proteolysis may be occurring due to phosphorylation and inhibition of forkhead box O (FoxO) factors, probably as a consequence of the increased cAMP levels, followed by the activation of PKA and Akt effectors. Akt activation may be associated with the increased levels of exchange protein directly activated by cAMP (EPAC). As a result, rolipram treatment spared muscle mass in diabetic rats.
The antiproteolytic responses associated with PDE4 inhibition may be helpful to motivate future investigations about the repositioning of PDE4 inhibitors for the treatment of muscle wasting conditions.
•PDE4 inhibition decreased the atrogenes levels in muscles of diabetic rats.•PDE4 inhibition reduced the activities of proteasome, calpain and caspase-3.•PDE4 inhibition increased cAMP levels, activating PKA and EPAC in muscles.•PDE4 inhibition increased Akt activation and inhibited FoxO1/3 factors in muscles.•PDE4 inhibition decreased the loss of skeletal muscle mass in diabetic rats.
Gas embolism is a potentially fatal occurrence in which bubbles are introduced into the arterial/venous circulation. A multifocal ischemia could be the life-threatening scenario of that and occurring ...after diving-related activities, or pulmonary barotrauma, or even iatrogenic procedure capable to cause an accidental introduction of gas into the vasculature. The case here reported concerns the good outcome of one of these rare occurrences thanks to a prompt diagnosis and proper management of the ongoing gaseous lesion. Unfortunately, it remains ethically and technically complex to consider feasible Randomized Clinical Trials (RCTs) in hyperbaric medicine in general, and even more so in this type of eventuality. We are happy to share this further favorable result as we believe it is just thanks to growing documented clinical evidence that now anyone, if ever had to be suffering from gas embolism, in presence of a RCT would widely prefer to be included in the arm that can take advantage of oxygen hyperbaric (HBO) therapy.
Lithium-oxygen batteries, with their very high energy density (3500 Wh kg
), could represent a real breakthrough in the envisioned strategies towards more efficient energy storage solutions for a ...less and less carbonated energy mix. However, the problems associated with this technology are numerous. A first one is linked to the high reactivity of the lithium metal anode, while a second one is linked to the highly oxidative environment created by the cell's O
saturation. Keeping in mind the necessity for greener materials in future energy storage solutions, in this work an innovative lithium protective membrane is prepared based on chitosan, a polysaccharide obtained from the deacetylation reaction of chitin. Chitosan was methacrylated through a simple, one-step reaction in water and then cross-linked by UV-induced radical polymerization. The obtained membranes were successively activated in liquid electrolyte and used as a lithium protection layer. The cells prepared with protected lithium were able to reach a higher full discharge capacity, and the chitosan's ability to slow down degradation processes was verified by post-mortem analyses. Moreover, in long cycling conditions, the protected lithium cell performed more than 40 cycles at 0.1 mA cm
, at a fixed capacity of 0.5 mAh cm
, retaining 100% coulombic efficiency, which is more than twice the lifespan of the bare lithium cell.
Background
Maintaining healthy mitochondria is mandatory for muscle viability and function. An essential surveillance mechanism targeting defective and harmful mitochondria to degradation is the ...selective form of autophagy called mitophagy. Ambra1 is a multifaceted protein with well‐known autophagic and mitophagic functions. However, the study of its role in adult tissues has been extremely limited due to the embryonic lethality caused by full‐body Ambra1 deficiency.
Methods
To establish the role of Ambra1 as a positive regulator of mitophagy, we exploited in vivo overexpression of a mitochondria‐targeted form of Ambra1 in skeletal muscle. To dissect the consequence of Ambra1 inactivation in skeletal muscle, we generated muscle‐specific Ambra1 knockout (Ambra1fl/fl:Mlc1f‐Cre) mice. Mitochondria‐enriched fractions were obtained from muscles of fed and starved animals to investigate the dynamics of the mitophagic flux.
Results
Our data show that Ambra1 has a critical role in the mitophagic flux of adult murine skeletal muscle and that its genetic inactivation leads to mitochondria alterations and myofibre remodelling. Ambra1 overexpression in wild‐type muscles is sufficient to enhance mitochondria clearance through the autophagy‐lysosome system. Consistently with this, Ambra1‐deficient muscles display an abnormal accumulation of the mitochondrial marker TOMM20 by +76% (n = 6–7; P < 0.05), a higher presence of myofibres with swollen mitochondria by +173% (n = 4; P < 0.05), and an alteration in the maintenance of the mitochondrial membrane potential and a 34% reduction in the mitochondrial respiratory complex I activity (n = 4; P < 0.05). Lack of Ambra1 in skeletal muscle leads to impaired mitophagic flux, without affecting the bulk autophagic process. This is due to a significantly decreased recruitment of DRP1 (n = 6–7 mice; P < 0.01) and Parkin (n = 6–7 mice; P < 0.05) to the mitochondrial compartment, when compared with controls. Ambra1‐deficient muscles also show a marked dysregulation of the endolysosome compartment, as the incidence of myofibres with lysosomal accumulation is 20 times higher than wild‐type muscles (n = 4; P < 0.05). Histologically, Ambra1‐deficient muscles of both 3‐ and 6‐month‐old animals display a significant decrease of myofibre cross‐sectional area and a 52% reduction in oxidative fibres (n = 6–7; P < 0.05), thus highlighting a role for Ambra1 in the proper structure and activity of skeletal muscle.
Conclusions
Our study indicates that Ambra1 is critical for skeletal muscle mitophagy and for the proper maintenance of functional mitochondria.
Emerging evidence suggests a role of the posterior cortices in regulating alpha oscillatory activity and organizing low-level processing in non-alpha frequency bands. Therefore, posterior brain ...lesions, which damage the neural circuits of the visual system, might affect functional connectivity patterns of brain rhythms. To test this hypothesis, eyes-closed resting state EEG signal was acquired from patients with hemianopia with left and right posterior lesions, patients without hemianopia with more anterior lesions and healthy controls. Left-lesioned hemianopics showed reduced intrahemispheric connectivity in the range of upper alpha only in the lesioned hemisphere, whereas right-lesioned hemianopics exhibited reduced intrahemispheric alpha connectivity in both hemispheres. In terms of network topology, these impairments were characterized by reduced local functional segregation, with no associated change in global functional integration. This suggests a crucial role of posterior cortices in promoting functional connectivity in the range of alpha. Right-lesioned hemianopics revealed also additional impairments in the theta range, with increased connectivity in this frequency band, characterized by both increased local segregated activity and decreased global integration. This indicates that lesions to right posterior cortices lead to stronger impairments in alpha connectivity and induce additional alterations in local and global low-level processing, suggesting a specialization of the right hemisphere in generating alpha oscillations and in coordinating complex interplays with lower frequency bands. Importantly, hemianopic patient’s visual performance in the blind field was linked to alpha functional connectivity, corroborating the notion that alpha oscillatory patterns represent a biomarker of the integrity and the functioning of the underlying visual system.
Although it is well known that administration of the selective β(2)-adrenergic agonist clenbuterol (CB) protects muscle following denervation (DEN), the underlying molecular mechanism remains ...unclear. We report that in vivo treatment with CB (3 mg/kg sc) for 3 days induces antiproteolytic effects in normal and denervated rat soleus muscle via distinct mechanisms. In normal soleus muscle, CB treatment stimulates protein synthesis, inhibits Ca(2+)-dependent proteolysis, and increases the levels of calpastatin protein. On the other hand, the administration of CB to DEN rats ameliorates the loss of muscle mass, enhances the rate of protein synthesis, attenuates hyperactivation of proteasomal and lysosomal proteolysis, and suppresses the transcription of the lysosomal protease cathepsin L and of atrogin-1/MAFbx and MuRF1, two ubiquitin (Ub) ligases involved in muscle atrophy. These effects were not associated with alterations in either IGF-I content or Akt phosphorylation levels. In isolated muscles, CB (10(-6) M) treatment significantly attenuated DEN-induced overall proteolysis and upregulation in the mRNA levels of the Ub ligases. Similar responses were observed in denervated muscles exposed to 6-BNZ-cAMP (500 μM), a PKA activator. The in vitro addition of triciribine (10 μM), a selective Akt inhibitor, did not block the inhibitory effects of CB on proteolysis and Ub ligase mRNA levels. These data indicate that short-term treatment with CB mitigates DEN-induced atrophy of the soleus muscle through the stimulation of protein synthesis, downregulation of cathepsin L and Ub ligases, and consequent inhibition of lysosomal and proteasomal activities and that these effects are independent of Akt and possibly mediated by the cAMP/PKA signaling pathway.
Background: Alternative Disputes Resolution (ADR) systems are becoming increasingly important tools in recent years for the management and resolution of health responsibility cases, but their ...dissemination and efficiency are still poorly described. The purpose of this paper is to present an ADR system in the autonomous province of Bolzano: the Conciliation Commission. Methods: systematic collection of all claims of the South Tyrol Sanitary Service that were dealt with in the Conciliation Commission from 1 January 2012 to 31 December 2022. Results: closing times of the applications received turn out to be less than a year in 63.8% of the cases, with a number of cases managed rather stably in the time, even if minimal if compared to the number of complaints received to the South Tirol Health Service. Only 5.3% of the application continued the legal process before a civil court. Conclusions: the Conciliation Commission of South Tirol appears to be an excellent instrument for the resolution of disputes in the healthcare field, with rapid resolution times and little to zero costs for the healthcare company, a public health institution. Despite its effectiveness, it seems to be a tool that is still little-known in South Tyrol.
Electrical storm is a medical emergency characterized by ventricular arrythmia recurrence that can lead to hemodynamic instability. The incidence of this clinical condition is rising, mainly in ...implantable cardioverter defibrillator patients, and its prognosis is often poor. Early acknowledgment, management and treatment have a key role in reducing mortality in the acute phase and improving the quality of life of these patients. In an emergency setting, several measures can be employed. Anti-arrhythmic drugs, based on the underlying disease, are often the first step to control the arrhythmic burden; besides that, new therapeutic strategies have been developed with high efficacy, such as deep sedation, early catheter ablation, neuraxial modulation and mechanical hemodynamic support. The aim of this review is to provide practical indications for the management of electrical storm in acute settings.
