Converging circuits between pain and depression: the ventral tegmental area as a therapeutic hub

Chronic pain and depression are highly prevalent pathologies and cause a major socioeconomic burden to society. Chronic pain affects the emotional state of the individuals suffering from it, while depression worsens the prognosis of chronic pain patients and may diminish the effectiveness of pain treatments. There is a high comorbidity rate between both pathologies, which might share overlapping mechanisms. This review explores the evidence pinpointing a role for the ventral tegmental area (VTA) as a hub where both pain and emotional processing might converge. In addition, the feasibility of using the VTA as a possible therapeutic target is discussed. The role of the VTA, and the dopaminergic system in general, is highly studied in mood disorders, especially in deficits in reward-processing and motivation. Conversely, the VTA is less regarded where it concerns the study of central mechanisms of pain and its mood-associated consequences. Here, we first outline the brain circuits involving central processing of pain and mood disorders, focusing on the often-understudied role of the dopaminergic system and the VTA. Next, we highlight the state-of-the-art findings supporting the emergence of the VTA as a link where both pathways converge. Thus, we envision a promising part for the VTA as a putative target for innovative therapeutic approaches to treat chronic pain and its effects on mood. Finally, we emphasize the urge to develop and use animal models where both pain and depression-like symptoms are considered in conjunction

Long-Term Iron and Vitamin B12 Deficiency Are Present after Bariatric Surgery, Despite the Widespread Use of Supplements

There are few long-term nutritional studies in subjects undergoing bariatric surgery that have assessed weight regain and nutritional deficiencies. In this study, we report data 8 years after surgery on weight loss, use of dietary supplements and deficit of micronutrients in a cohort of patients from five centres in central and northern Italy. The study group consisted of 52 subjects (age: 38.1 +/- 10.6 y, 42 females): 16 patients had Roux-en-Y gastric bypass (RYGB), 25 patients had sleeve gastrectomy (SG) and 11 subjects had adjustable gastric banding (AGB). All three bariatric procedures led to sustained weight loss: the average percentage excess weight loss, defined as weight loss divided by excess weight based on ideal body weight, was 60.6% +/- 32.3. Despite good adherence to prescribed supplements, 80.7% of subjects (72.7%, AGB; 76.7%, SG; 93.8 %, RYGB) reported at least one nutritional deficiency: iron (F 64.3% vs. M 30%), vitamin B12 (F 16.6% vs. M 10%), calcium (F 33.3% vs. M 0%) and vitamin D (F 38.1% vs. M 60%). Long-term nutritional deficiencies were greater than the general population among men for iron and among women for vitamin B12

La lutte des ouvriers de GKN Florence, entre auto-organisation ouvrière et mobilisation sociale

Cette chronique décrit la lutte des travailleurs de l’usine GKN de Florence contre sa fermeture et sa délocalisation. Après avoir rendu compte des principales étapes du conflit, l’article se penche sur trois aspects fondamentaux : l’organisation syndicale interne à l’usine et sa capacité à renforcer les ressources militantes autonomes des travailleurs, l’habileté de ces derniers à mobiliser le tissu social environnant et à nouer des alliances avec d’autres mouvements sociaux et, enfin, la contribution apportée par le monde de l’université et de la recherche dans l’élaboration d’un plan de reconversion du site

Escherichia coli Is Overtaking Group B Streptococcus in Early-Onset Neonatal Sepsis

The widespread use of intrapartum antibiotic prophylaxis (IAP) to prevent group B streptococcus (GBS) early-onset sepsis (EOS) is changing the epidemiology of EOS. Italian prospective area-based surveillance data (from 1 January 2016 to 31 December 2020) were used, from which we identified 64 cases of culture-proven EOS (E. coli, n = 39; GBS, n = 25) among 159,898 live births (annual incidence rates of 0.24 and 0.16 per 1000, respectively). Approximately 10% of E. coli isolates were resistant to both gentamicin and ampicillin. Five neonates died; among them, four were born very pre-term (E. coli, n = 3; GBS, n = 1) and one was born full-term (E. coli, n = 1). After adjustment for gestational age, IAP-exposed neonates had ≥95% lower risk of death, as compared to IAP-unexposed neonates, both in the whole cohort (OR 0.04, 95% CI 0.00-0.70; p = 0.03) and in the E. coli EOS cohort (OR 0.05, 95% CI 0.00-0.88; p = 0.04). In multi-variable logistic regression analysis, IAP was inversely associated with severe disease (OR = 0.12, 95% CI 0.02-0.76; p = 0.03). E. coli is now the leading pathogen in neonatal EOS, and its incidence is close to that of GBS in full-term neonates. IAP reduces the risk of severe disease and death. Importantly, approximately 10% of E. coli isolates causing EOS were found to be resistant to typical first-line antibiotics

Cell cycle block by p53 activation reduces SARS-CoV-2 release in infected alveolar basal epithelial A549-hACE2 cells

SARS-CoV viruses have been shown to downregulate cellular events that control antiviral defenses. They adopt several strategies to silence p53, key molecule for cell homeostasis and immune control, indicating that p53 has a central role in controlling their proliferation in the host. Specific actions are the stabilization of its inhibitor, MDM2, and the interference with its transcriptional activity. The aim of our work was to evaluate a new approach against SARS-CoV-2 by using MDM2 inhibitors to raise p53 levels and activate p53-dependent pathways, therefore leading to cell cycle inhibition. Experimental setting was performed in the alveolar basal epithelial cell line A549-hACE2, expressing high level of ACE2 receptor, to allow virus entry, as well as p53 wild-type. Cells were treated with several concentrations of Nutlin-3 or RG-7112, two known MDM2 inhibitors, for the instauration of a cell cycle block steady-state condition before and during SARS-CoV-2 infection, and for the evaluation of p53 activation and impact on virus release and related innate immune events. The results indicated an efficient cell cycle block with inhibition of the virion release and a significant inhibition of IL-6, NF-kB and IFN-λ expression. These data suggest that p53 is an efficient target for new therapies against the virus and that MDM2 inhibitors deserve to be further investigated in this field

Perinatal outcomes among immigrant mothers over two periods in a region of central Italy

<p>Abstract</p> <p>Background</p> <p>The number of immigrants has increased in Italy in the last twenty years (7.2% of the Italian population), as have infants of foreign-born parents, but scanty evidence on perinatal outcomes is available. The aim of this study was to investigate whether infants of foreign-born mothers living in Italy have different odds of adverse perinatal outcomes compared to those of native-born mothers, and if such measures changed over two periods.</p> <p>Methods</p> <p>The source of this area-based study was the regional hospital discharge database that records perinatal information on all births in the Lazio region. We analysed 296,739 singleton births born between 1996-1998 and 2006-2008. The exposure variable was the mother's region of birth. We considered five outcomes of perinatal health. We estimated crude and adjusted odds ratios and 95% confidence intervals (CIs) to evaluate the association between mother's region of birth and perinatal outcomes.</p> <p>Results</p> <p>Perinatal outcomes were worse among infants of immigrant compared to Italian mothers, especially for sub-Saharan and west Africans, with the following crude ORs (in 1996-1998 and 2006-2008 respectively): 1.80 (95%CI:1.44-2.28) and 1.95 (95%CI:1.72-2.21) for very preterm births, and 1.32 (95%CI:1.16-1.50) and 1.32 (95%CI:1.25-1.39) for preterm births; 1.18 (95%CI:0.99-1.40) and 1.17 (95%CI:1.03-1.34) for a low Apgar score; 1.22 (95%CI:1.15-1.31) and 1.24 (95%CI:1.17-1.32) for the presence of respiratory diseases; 1.47 (95%CI:1.30-1.66) and 1.45 (95%CI:1.34-1.57) for the need for special or intensive neonatal care/in-hospital deaths; and 1.03 (95%CI:0.93-1.15) and 1.07 (95%CI:1.00-1.15) for congenital malformations. Overall, time did not affect the odds of outcomes differently between immigrant and Italian mothers and most outcomes improved over time among all infants. None of the risk factors considered confounded the associations.</p> <p>Conclusion</p> <p>Our findings suggest that migrant status is a risk factor for adverse perinatal health. Moreover, they suggest that perinatal outcomes improved over time in some immigrant women. This could be due to a general improvement in immigrants' health in the past decade, or it may indicate successful application of policies that increase accessibility to mother-child health services during the periconception and prenatal periods for legal and illegal immigrant women in Italy.</p

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage