Deregulation of protein synthesis and ER stress/unfolded protein response (ER stress/UPR) have been reported in astrocytes. However, the relationships between protein synthesis deregulation and ER stress/UPR, as well as their role in the altered homeostatic support of Alzheimer’s disease (AD) astrocytes remain poorly understood. Previously, we reported that in astrocytic cell lines from 3xTg-AD mice (3Tg-iAstro) protein synthesis was impaired and ER-mitochondria distance was reduced. Here we show that impaired protein synthesis in 3Tg-iAstro is associated with an increase of p-eIF2α and downregulation of GADD34. Although mRNA levels of ER stress/UPR markers were increased two-three-fold, we found neither activation of PERK nor downstream induction of ATF4 protein. Strikingly, the overexpression of a synthetic ER-mitochondrial linker (EML) resulted in a reduced protein synthesis and augmented p-eIF2α without any effect on ER stress/UPR marker genes. In vivo, in hippocampi of 3xTg-AD mice, reduced protein synthesis, increased p-eIF2α and downregulated GADD34 protein were found, while no increase of p-PERK or ATF4 proteins was observed, suggesting that in AD astrocytes, both in vitro and in vivo, phosphorylation of eIF2α and impairment of protein synthesis are PERK-independent. Next, we investigated the ability of 3xTg-AD astrocytes to support metabolism and function of other cells of the central nervous system. Astrocyte-conditioned medium (ACM) from 3Tg-iAstro cells significantly reduced protein synthesis rate in primary hippocampal neurons. When added as a part of pericyte/endothelial cell (EC)/astrocyte 3D co-culture, 3Tg-iAstro, but not WT-iAstro, severely impaired formation and ramification of tubules, the effect, replicated by EML overexpression in WT-iAstro cells. Finally, a chemical chaperone 4-phenylbutyric acid (4-PBA) rescued protein synthesis, p-eIF2α levels in 3Tg-iAstro cells and tubulogenesis in pericyte/EC/3Tg-iAstro co-culture. Collectively, our results suggest that a PERK-independent, p-eIF2α-associated impairment of protein synthesis compromises astrocytic homeostatic functions, and this may be caused by the altered ER-mitochondria interaction.

This study aims to evaluate the efficacy of the PECARN Rule (PR) in reducing radiological investigations in children with mild traumatic head injury in comparison with current clinical practice. A retrospective study was performed in our hospital between July 2015 and June 2020. Data of all children < 18 years of age admitted to the emergency department (ED), within 24 h after a head trauma with GCS ≥ 14, were analyzed. PECARN Rule was retrospectively applied to all patients. In total, 3832 patients were enrolled, 2613 patients ≥ 2 years and 1219 < 2 years. In the group of children ≥ 2 years, 10 presented clinically important traumatic brain injury (ciTBI) and were hospitalized, 7/10 underwent neurosurgery, and 3/10 clinical observation in the pediatric ward for more than 48 h. In children < 2 years, only 3 patients presented ciTBI, 2 underwent neurosurgery and 1 hospitalized. Applying the PR, no patient with ciTBI would have been discharged without an accurate diagnosis and we would have avoided 139 CT scans in patients ≥ 2 years, and 23 in those < 2 years of age (29% less).Conclusion: We demonstrated the safety and validity of the PR in our setting with 100% sensitivity in both age groups in identifying patients with ciTBI and theoretically in reducing performed CT scans by 29%. Therefore, in patients classified in the low-risk category, it is a duty not to expose the child to ionizing radiation. What is Known:• CT is the gold standard to identify intracranial pathology in children with head injury but CT imaging of head-injured children expose them to higher carcinogenic risk.• PECARN Rules support doctors in identifying children with ciTBI in order to reduce exposure to ionizing radiation. What is New:• We demonstrate the safety and validity of the PR with 100% sensitivity in both age groups in identifying patients with ciTBI.• In our setting, the application of PECARN Rule would theoretically have allowed us to reduce the CT scan by 29%.

Perinatal stroke is related to possible differences in predisposing factors and outcomes between acutely and retrospectively diagnosed cases. In most cases, there are different risk factors and infections that could play an important role. Thus far, different clinical manifestations have been reported in children presenting with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ranging from asymptomatic status to severe disease sustained by an immune-mediated inflammatory response. SARS-CoV-2 has been associated with severe neurological diseases including seizures and encephalitis in both adults and children. However, there are still few reports regarding the possible relation between SARS-CoV-2 infection of mothers during pregnancy and the neurologic outcome of the newborns. We described the case of a newborn diagnosed with a perinatal stroke, born at 35 weeks of gestation from a mother presenting with SARS- CoV-2 infection during the last months of pregnancy. We also added a brief review of the literature with similar cases. Close monitoring and early intervention in young children born to infected mothers would be highly recommended for the potential neurodevelopmental risk.

Tumour cells modify their cellular metabolism with the aim to sustain uncontrolled proliferation. Cancer cells necessitate adequate amounts of NAD and NADPH to support several enzymes that are usually overexpressed and/or overactivated. Nicotinamide adenine dinucleotide (NAD) is an essential cofactor and substrate of several NAD-consuming enzymes, such as PARPs and sirtuins, while NADPH is important in the regulation of the redox status in cells. The present review explores the rationale for targeting the key enzymes that maintain the cellular NAD/NADPH pool in colorectal cancer and the enzymes that consume or use NADP(H).

Deregulation of protein synthesis and ER stress/unfolded protein response (ER stress/UPR) have been reported in astrocytes. However, the relationships between protein synthesis deregulation and ER stress/UPR, as well as their role in the altered homeostatic support of Alzheimer's disease (AD) astrocytes remain poorly understood. Previously, we reported that in astrocytic cell lines from 3xTg-AD mice (3Tg-iAstro) protein synthesis was impaired and ER-mitochondria distance was reduced. Here we show that impaired protein synthesis in 3Tg-iAstro is associated with an increase of p-eIF2α and downregulation of GADD34. Although mRNA levels of ER stress/UPR markers were increased two-three-fold, we found neither activation of PERK nor downstream induction of ATF4 protein. Strikingly, the overexpression of a synthetic ER-mitochondrial linker resulted in a reduced protein synthesis and augmented p-eIF2α without any effect on ER stress/UPR marker genes. In vivo, in hippocampi of 3xTg-AD mice, reduced protein synthesis, increased p-eIF2α and downregulated GADD34 protein were found, while no increase of p-PERK or ATF4 proteins was observed, suggesting that in AD astrocytes, both in vitro and in vivo, phosphorylation of eIF2α and impairment of protein synthesis are PERK-independent. Next, we investigated the ability of 3xTg-AD astrocytes to support metabolism and function of other cells of the central nervous system. Astrocyte conditioned medium (ACM) from 3Tg-iAstro cells significantly reduced protein synthesis rate in primary hippocampal neurons. When added as a part of pericyte/endothelial cell (EC)/astrocyte 3D co-culture, 3Tg-iAstro, but not WT-iAstro, severely impaired formation and ramification of tubules. Finally, a chemical chaperone 4-phenylbutyric acid (4-PBA) rescued protein synthesis, p-eIF2α levels in 3Tg-iAstro cells and tubulogenesis in pericyte/EC/3Tg-iAstro co-culture. Collectively, our results suggest that a PERK-independent, p-eIF2α-associated impairment of protein synthesis compromises astrocytic homeostatic functions and this may be caused by the altered ER-mitochondria interaction.