• Larsson Silverman posted an update 6 months, 1 week ago

    This molecule, netrin-1, guides the growth of the corticospinal tract (CST) during the development of the central nervous system. To assess the potential of this molecule, we used a model of complete spinal cord transection in rats, at thoracic level 10-11. We show that in situ delivery of netrin-1 at the epicenter of the lesion (1) promotes regrowth of CST through the lesion and prevents CST dieback, (2) promotes synaptic reconnection of regenerated motor and sensory axons, and (3) preserves the polymerization of the neurofilaments in the sciatic nerve axons. These anatomical findings correlate with a significant recovery of locomotor function. Our work identifies netrin-1 as a biological agent with the capacity to promote the functional repair and recovery of locomotor function after SCI. These findings support the use of netrin-1 as a therapeutic intervention to be tested in humans.Cells metabolize nutrients for biosynthetic and bioenergetic needs to fuel growth and proliferation. The uptake of nutrients from the environment and their intracellular metabolism is a highly controlled process that involves cross talk between growth signaling and metabolic pathways. Despite constant fluctuations in nutrient availability and environmental signals, normal cells restore metabolic homeostasis to maintain cellular functions and prevent disease. A central signaling molecule that integrates growth with metabolism is the mechanistic target of rapamycin (mTOR). mTOR is a protein kinase that responds to levels of nutrients and growth signals. mTOR forms two protein complexes, mTORC1, which is sensitive to rapamycin, and mTORC2, which is not directly inhibited by this drug. Rapamycin has facilitated the discovery of the various functions of mTORC1 in metabolism. Genetic models that disrupt either mTORC1 or mTORC2 have expanded our knowledge of their cellular, tissue, as well as systemic functions in metabolism. Nevertheless, our knowledge of the regulation and functions of mTORC2, particularly in metabolism, has lagged behind. Since mTOR is an important target for cancer, aging, and other metabolism-related pathologies, understanding the distinct and overlapping regulation and functions of the two mTOR complexes is vital for the development of more effective therapeutic strategies. This review discusses the key discoveries and recent findings on the regulation and metabolic functions of the mTOR complexes. We highlight findings from cancer models but also discuss other examples of the mTOR-mediated metabolic reprogramming occurring in stem and immune cells, type 2 diabetes/obesity, neurodegenerative disorders, and aging.Background This study compared left ventricular (LV) characteristics between patients with type-A and type-B aortic dissection (AD) and evaluated the ability of LV remodeling phenotypes (hypertrophy, concentricity, or geometric patterns) to predict mortality in both AD types. Methods and Results We evaluated 236 patients with type A and 120 patients with type B who had echocardiograms within 60 days before or after AD diagnosis (median time difference between echocardiogram and AD diagnosis=1 days) from 3 centers. Patients were stratified according to LV phenotypes, and early (90-day) and late (1-year) mortality after AD diagnosis were assessed. In adjusted logistic regression analysis, patients with type A had higher and lower odds of concentric and eccentric hypertrophy (odds ratio , 2.56; 95% CI, 1.50-4.36; P less then 0.001; and OR, 0.55; 95% CI, 0.31-0.97; P=0.039, respectively) than those with type B. Results of multivariable Cox-regression analysis showed that LV remed with greater mortality among patients with type A and may be markers of adverse prognosis in this population.Background Current postresuscitative care after cardiac arrest (CA) does not address the cause of CA. We previously reported that asphyxial CA (ACA) and ventricular fibrillation CA (VFCA) elicit unique injury signatures. We hypothesized that the early cytokine profiles of the serum, heart, and brain differ in response to ACA versus VFCA. Methods and Results Adult male rats were subjected to 10 minutes of either ACA or VFCA. Naives and shams (anesthesia and surgery without CA) served as controls (n=12/group). Asphyxiation produced an ≈4-minute period of progressive hypoxemia followed by a no-flow duration of ≈6±1 minute. Ventricular fibrillation immediately induced no flow. Return of spontaneous circulation was achieved earlier after ACA compared with VFCA (42±18 versus 105±22 seconds; P less then 0.001). Brain cytokines in naives were, in general, low or undetectable. Shams exhibited a modest effect on select cytokines. Both ACA and VFCA resulted in robust cytokine responses in serum, heart, and brain at 3 hours. Significant regional differences pinpointed the striatum as a key location of neuroinflammation. No significant differences in cytokines, neuron-specific enolase, S100b, and troponin T were observed across CA models. Conclusions Both models of CA resulted in marked systemic, heart, and brain cytokine responses, with similar degrees of change across the 2 CA insults. Changes in cytokine levels after CA were most pronounced in the striatum compared with other brain regions. These collective observations suggest that the amplitude of the changes in cytokine levels after ACA versus VFCA may not mediate the differences in secondary injuries between these 2 CA phenotypes.

    Enzyme replacement therapy in Fabry disease has been available in Japan since 2004. Two post-authorization safety studies were conducted to evaluate agalsidase beta in Japanese patients with Fabry disease in real-world practice.

    The Special Drug Use Investigation monitored the long-term safety and efficacy of agalsidase beta, and the Drug Use Investigation monitored safety in patients not participating in the Special Drug Use Investigation. Safety and efficacy evaluations included adverse drug reactions (ADRs), infusion-associated reactions and hypersensitivity reactions, and change in blood GL-3 level over time.

    Of 396 patients in the aggregated data set, safety and efficacy analysis sets comprised 307 and 196 patients, respectively. ADRs occurred in 93 (30.3%) patients and serious ADRs occurred in 25 (8.1%) patients, with general disorders and administration site conditions (n=55, 17.9%), nervous system disorders (n=30, 9.8%) and skin and subcutaneous tissue disorders (n=23, 7.5%) the most common. Zavondemstat Reductions in blood GL-3 levels occurred over the study, irrespective of age or disease phenotype.

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