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Background Propionic acidemia is a rare autosomal recessive inherited metabolic disorder that can inhibit the synthesis of N -acetylglutamate, the obligatory activator in urea synthesis, leading to hyperammonemia. N -carbamylglutamate ameliorates hyperammonemia in decompensated propionic acidemia. The effects of long-term continuous N -acetylglutamate administration in such patients are unknown. We report our clinical experience with continuous administration of N -acetylglutamate for 6 years in a patient with propionic acidemia frequently presenting with hyperammonemia. Case presentation A male Caucasian patient with frequently decompensated propionic acidemia and hyperammonemia was admitted 78 times for acute attacks during the first 9 years of his life. Continuous daily treatment with oral N -carbamylglutamate 100 mg/kg (50 mg/kg after 6 months) was initiated. During 6 years of treatment, he had a significant decrease in his mean plasma ammonia levels (75.7 μmol/L vs. 140.3 μmol/L before N -carbamylglutamate therapy, p < 0.005 [normal range 50–80 μmol/L]) and fewer acute episodes (two in 6 years). Conclusion Our results suggest a benefit of N -acetylglutamate administration outside the emergency setting. If this observation is confirmed, future studies should aim to optimize the dosage and explore effects of the dosage requirements on other drugs and on protein tolerance.

Abstract Context and Objective COVID-19 has become the most relevant medical issue globally. Despite several studies that have investigated clinical characteristics of COVID-19 patients, no data have been reported on the prevalence of vertebral fractures (VFs). Since VFs may influence cardiorespiratory function and disease outcomes, the aim of this study was to assess VFs prevalence and clinical impact in COVID-19. Design and Patients This was a retrospective cohort study performed at San Raffaele Hospital, a tertiary health care hospital in Italy. We included COVID-19 patients for whom lateral chest x-rays at emergency department were available. VFs were detected using a semiquantitative evaluation of vertebral shape on chest x-rays. Results A total of 114 patients were included in this study and thoracic VFs were detected in 41 patients (36%). Patients with VFs were older and more frequently affected by hypertension and coronary artery disease (P < 0.001, P = 0.007, P = 0.034; respectively). Thirty-six (88%) patients in VFs+ group compared to 54 (74%) in VFs− group were hospitalized (P = 0.08). Patients with VFs more frequently required noninvasive mechanical ventilation compared with those without VFs (P = 0.02). Mortality was 22% in VFs+ group and 10% in VFs− group (P = 0.07). In particular, mortality was higher in patients with severe VFs compared with those with moderate and mild VFs (P = 0.04). Conclusions VFs may integrate the cardiorespiratory risk of COVID-19 patients, being a useful and easy to measure clinical marker of fragility and poor prognosis. We suggest that morphometric thoracic vertebral evaluation should be performed in all suspected COVID-19 patients undergoing chest x-rays.

Background New evidence is emerging on the importance of lean body mass during periods of illness and recovery. The preservation of lean body mass during such periods of intense stress impacts both patient and treatment outcomes. However, data concerning the incidence of sarcopenia among older people during hospitalization are scarce. The objective of this study was to evaluate the development of sarcopenia in a sample of hospitalized older subjects. Methods We used data of 394 participants from the multicentre Italian Study conducted by the Gruppo Lavoro Italiano Sarcopenia—Trattamento e Nutrizione (GLISTEN) in 12 Acute Care Wards (Internal Medicine and Geriatrics) of University Hospitals across Italy. This study was designed to determine the prevalence of sarcopenia at hospital admission and the change in muscle mass and strength during hospitalization. Sarcopenia was defined as low skeletal mass index (kg/m2) along with either low handgrip strength or slow walking speed [European Working Groups on Sarcopenia in Older People (EWGSOP) criteria]. Estimation of skeletal muscle mass was performed by bioelectrical impedance analysis (BIA). Results The mean age of the 394 enrolled patients (including 211 females who accounted for 53% of the sample) was 79.6 ± 6.4 years. Among those without sarcopenia at hospital admission, 14.7% of the study sample met the EWGSOP sarcopenia diagnostic criteria at discharge. The incidence of sarcopenia during hospitalization was significantly associated with the number of days spent in bed but was not correlated with the total length of hospital stay. In particular, patients who developed sarcopenia spent an average of 5.1 days in bed compared with 3.2 days for those with no sarcopenia at discharge (P = 0.02). Patients with sarcopenia showed a significantly lower body mass index compared with non‐sarcopenic peers (25.0 ± 3.8 kg/m2 vs. 27.6 ± 4.9 kg/m2, respectively; P < 0.001). Similarly, the skeletal mass index at admission was significantly lower among patients who developed sarcopenia during hospital stay. Conclusions Incident sarcopenia during hospital stay is relatively common and is associated with nutritional status and the number of days of bed rest.

Stroke severely affects walking ability, and assessment of gait kinematics is important in defining diagnosis, planning treatment, and evaluating interventions in stroke rehabilitation. Although observational gait analysis is the most common approach to evaluate gait kinematics, tools useful for this purpose have received little attention in the scientific literature and have not been thoroughly reviewed. The aims of this systematic review were to identify tools proposed to conduct observational gait analysis in adults with a stroke, to summarize evidence concerning their quality, and to assess their implementation in rehabilitation research and clinical practice. An extensive search was performed of original articles reporting on visual/observational tools developed to investigate gait kinematics in adults with a stroke. Two reviewers independently selected studies, extracted data, assessed quality of the included studies, and scored the metric properties and clinical utility of each tool. Rigor in reporting metric properties and dissemination of the tools also was evaluated. Five tools were identified, not all of which had been tested adequately for their metric properties. Evaluation of content validity was partially satisfactory. Reliability was poorly investigated in all but one tool. Concurrent validity and sensitivity to change were shown for 3 and 2 tools, respectively. Overall, adequate levels of quality were rarely reached. The dissemination of the tools was poor. Based on critical appraisal, the Gait Assessment and Intervention Tool shows a good level of quality, and its use in stroke rehabilitation is recommended. Rigorous studies are needed for the other tools in order to establish their usefulness.

Objective During rheumatoid arthritis (RA), the angiogenic processes, occurring with pannus-formation, may be a therapeutic target. JAK/STAT-pathway may play a role and the aim of this work was to investigate the inhibiting role of a JAK-inhibitor, tofacitinib, on the angiogenic mechanisms occurring during RA. Methods After ethical approval, JAK-1, JAK-3, STAT-1, STAT-3 and VEGF expression was evaluated on RA-synovial-tissues. In vitro, endothelial cells (ECs), stimulated with 20 ng/ml of VEGF and/or 1 μM of tofacitinib, were assessed for tube formation, migration and proliferation, by Matrigel, Boyden chamber assay and ki67 gene-expression. In vivo, 32 mice received collagen (collagen-induced arthritis (CIA)) and 32 mice PBS (control). At day 19, CIA and controls mice were divided: 16 mice receiving vehicle and 16 mice receiving tofacitinib. At day 35, the arthritis score, the thickness of paw joints and the serum levels of VEGF and Ang-2 were evaluated. Results The expression of JAK-1, JAK-3, STAT-1, STAT-3 and VEGF in synovial tissue of RA-patients were significantly higher than healthy controls. In vitro, tofacitinib inhibited the ECs ability to form vessels, to proliferate and to migrate. In vivo, administration of tofacitinib prevented the increase of the arthritis score, the paw thickness, the synovial vessels and VEGF and Ang-2 serum-accumulation, when compared to CIA without tofacitinib. Conclusions We explored the anti-angiogenic role of tofacitinib, reporting its ability to inhibit in vitro the angiogenic mechanisms of ECs and in vivo the formation of new synovial vessels, occurring in CIA model. These findings suggest that the therapeutic effect of tofacitinib during RA may be also related to its anti-angiogenic activity.

Saffron, branded as Repron®, is effective in slowing the progression of several neurodegenerative diseases. Its production, however, requires specific cultivation techniques and procedures that, together with low yields, make it expensive. To address this challenge, hydroponic cultivation has been adopted. Previous studies have shown that hydroponically cultivated saffron and Repron® share comparable chemical compositions and neuroprotective effects under oxidative stress conditions. In this study, we evaluated the protective properties of extracts derived from Crocus sativus L. waste, compared with those of saffron derived from stigmas. Human retinal pigment epithelium (ARPE-19) cells were pre-treated with extracts of various plant waste fractions before being subjected to three stress conditions: H2O2-induced oxidative stress (500 μM, 3 h), lipopolysaccharide (LPS; 0.25 mg/mL, 24 h), and hyperglycemia (25 mM glucose, 96 h). Saffron Repron® served as a positive control. The results revealed that the extract derived from C. sativus waste had superior protective effects against oxidative stress and inflammation by preserving the state of the mitochondria and tight junctions (ZO-1); conversely, the tepal extract alone was more effective under hyperglycemic conditions by also modulating acrolein levels. These results suggest that different plant fractions contain bioactive compounds with specific protective actions, which together lead to increased cell survival.

The second messenger cyclic AMP regulates many nuclear processes including transcription, pre-mRNA splicing and mitosis. While most functions are attributed to protein kinase A, accumulating evidence suggests that not all nuclear cyclic AMP-dependent effects are mediated by this kinase, implying that other effectors may be involved. Here we explore the nuclear roles of Exchange Protein Activated by cyclic AMP 1. We find that it enters the nucleus where forms reversible biomolecular condensates in response to cyclic AMP. This phenomenon depends on intrinsically disordered regions present at its amino-terminus and is independent of protein kinase A. Finally, we demonstrate that nuclear Exchange Protein Activated by cyclic AMP 1 condensates assemble at genomic loci on chromosome 6 in the proximity of Histone Locus Bodies and promote the transcription of a histone gene cluster. Collectively, our data reveal an unexpected mechanism through which cyclic AMP contributes to nuclear spatial compartmentalization and promotes the transcription of specific genes. Spatial compartmentalization is central to nuclear function. Here, the authors demonstrate that EPAC1 can enter the nucleus and regulate the transcription of a histone cluster by forming biomolecular condensates in its proximity in response to cAMP.

To date, four vaccines have been authorised for emergency use and under conditional approval by the European Medicines Agency to prevent COVID-19: Comirnaty, COVID-19 Vaccine Janssen, Spikevax (previously COVID-19 Vaccine Moderna) and Vaxzevria (previously COVID-19 Vaccine AstraZeneca). Although the benefit–risk profile of these vaccines was proven to be largely favourable in the general population, evidence in special cohorts initially excluded from the pivotal trials, such as pregnant and breastfeeding women, children/adolescents, immunocompromised people and persons with a history of allergy or previous SARS-CoV-2 infection, is still limited. In this narrative review, we critically overview pre- and post-marketing evidence on the potential benefits and risks of marketed COVID-19 vaccines in the above-mentioned special cohorts. In addition, we summarise the recommendations of the scientific societies and regulatory agencies about COVID-19 primary prevention in the same vaccinee categories.

Background Microsatellite instability (MSI) is a well-established predictive biomarker for immune checkpoint inhibitor (ICI) response in metastatic colon cancer. Both high MSI and tumor mutational burden (TMB) are markers of genomic instability. However, the prognostic and predictive value of TMB in patients with microsatellite stable (MSS) tumors remains unclear. Methods We evaluated the prognostic significance of TMB levels in MSS metastatic colon cancer patients undergoing standard treatments. Tumor responses were assessed using RECIST v1.1 criteria. Comprehensive clinical and molecular profiling was conducted, including next-generation sequencing (NGS) for TMB evaluation with the TruSight Oncology® kit. Overall survival (OS) was the primary endpoint. Multivariate Cox regression analysis was utilized to assess the relationship among potential prognostic factors. Results Among 102 MSS metastatic colon cancer patients, high TMB (> 10 mut/mb) was associated with a significantly longer median OS compared to low TMB (70.0 vs 45.0 months, respectively; HR: 0.45; 95% CIs 0.21 to 0.96; P = 0.0396). Multivariate analysis, adjusting for age, gender, number of metastatic sites, response to first-line chemotherapy, RAS mutational status, and liver involvement, identified TMB as an independent prognostic factor, along with response to first-line chemotherapy. Conclusions Our results highlight the prognostic significance of TMB in MSS metastatic colon cancer patients, suggesting its potential role in patient stratification and treatment decision-making.

MRE11 is a component of the MRE11/RAD50/NBS1 (MRN) complex, whose activity is essential to control faithful DNA replication and to prevent accumulation of deleterious DNA double-strand breaks. In humans, hypomorphic mutations in these genes lead to DNA damage response (DDR)-defective and cancer-prone syndromes. Moreover, MRN complex dysfunction dramatically affects the nervous system, where MRE11 is required to restrain MYCN-dependent replication stress, during the rapid expansion of progenitor cells. MYCN activation, often due to genetic amplification, represents the driving oncogenic event for a number of human tumors, conferring bad prognosis and predicting very poor responses even to the most aggressive therapeutic protocols. This is prototypically exemplified by neuroblastoma, where MYCN amplification occurs in about 25% of the cases. Intriguingly, MRE11 is highly expressed and predicts bad prognosis in MYCN-amplified neuroblastoma. Due to the lack of direct means to target MYCN, we explored the possibility to trigger intolerable levels of replication stress-dependent DNA damage, by inhibiting MRE11 in MYCN-amplified preclinical models. Indeed, either MRE11 knockdown or its pharmacological inhibitor mirin induce accumulation of replication stress and DNA damage biomarkers in MYCN-amplified cells. The consequent DDR recruits p53 and promotes a p53-dependent cell death, as indicated by p53 loss- and gain-of-function experiments. Encapsulation of mirin in nanoparticles allowed its use on MYCN-amplified neuroblastoma xenografts in vivo, which resulted in a sharp impairment of tumor growth, associated with DDR activation, p53 accumulation, and cell death. Therefore, we propose that MRE11 inhibition might be an effective strategy to treat MYCN-amplified and p53 wild-type neuroblastoma, and suggest that targeting replication stress with appropriate tools should be further exploited to tackle MYCN-driven tumors.