Archivio Istituzionale della Ricerca - Università degli Studi di Pavia
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Diazepam modulates hippocampal CA1 functional connectivity in people at clinical high-risk for psychosis
No full textBackground Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence. Methods In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals underwent resting-state functional magnetic resonance imaging twice, once following a 5 mg dose of diazepam and once following a placebo. They were compared to 20 healthy controls (HC) who did not receive diazepam/placebo. Functional connectivity (FC) between the hippocampal CA1 subfield and the nucleus accumbens (NAc), amygdala, and ventromedial prefrontal cortex (vmPFC) was calculated. Mixed-effects models investigated the effect of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on CA1-to-region FC. Results In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC (Z = 3.17, P FWE = 0.002) and CA1-NAc (Z = 2.94, P FWE = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased (Z = 4.13, P FWE = 0.008) compared to placebo in CHR-P individuals, and both CA1-vmPFC and CA1-NAc FC were normalised to HC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower contralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam conditions (lower: placebo Z = 3.46, P FWE = 0.002, diazepam Z = 3.33, P FWE = 0.003; higher: placebo Z = 4.48, P FWE < 0.001, diazepam Z = 4.22, P FWE < 0.001). Conclusions This study demonstrates that diazepam can partially restore hippocampal CA1 dysconnectivity in CHR-P individuals, suggesting that modulation of GABAergic function might be useful in the treatment of this clinical group
Running the risk: Immunity and mobility in response to a pandemic
No full textThe relative effectiveness of non-pharmaceutical interventions, such as lockdowns and work-from-home mandates, depends on whether individuals adjust their social behavior in response to infection risk when policy restrictions are absent. Exploiting geographic variation in COVID-19 exposure during the first wave, three key results emerge. First, we find evidence that areas with relatively high excess death rates during the first wave of the pandemic had relatively low excess death rates during the second wave. Second, using granular mobility data from GPS devices, we show that the same areas saw relatively high mobility during the second wave, which may suggest that the first finding is driven by an immunity effect. Finally, the heterogeneity analysis reveals that scarring, behavioral responses, and immunization may operate with varying intensity across municipalities with different age compositions, yielding observable differences in both second-wave mobility and mortality patterns
Genetic and Phenotypic Features of 2 Northern Italy Families with Dowling-Degos Disease Type 4
No full textDowling-Degos disease (DDD) is an autosomal dominant genodermatosis involving the folds with lentiginous hyperpigmentation and reddish–brown papules. Four main types of DDD with variable clinical presentations likely related to the heterogeneity of the gene variant landscape have been implicated. Pathogenic keratin 5 gene K5 gene variants favor a reticular distribution with predominant fold involvement, whereas pathogenic variants in POGLUT1 lead to a widespread form with acantholytic features previously named Galli–Galli disease, now belonging to the disease spectrum of DDD and renamed DDD type 4. This study details the clinical and histopathological features associated with the sequence variant c.205C>T, p.(Arg69∗) in POGLUT1 of 2 families from northern Italy affected by DDD4. Despite sharing the same variant, clinical manifestations varied among the affected members of the 2 families. Environmental factors probably contributed to phenotypic variability and symptoms exacerbation. Histopathology was sustained by digitiform rete ridges, suprabasal acantholysis, and dyskeratosis. Moreover, we detected aberrant keratin 5 gene K5 expression in 2 biopsies. A review of the literature on POGLUT1-related DDD subtypes contextualizes these findings. The fact that several patients have been reported to carry the variant c.205C>T, p.(Arg69∗) might point to a potential mutational hotspot
DuoStim Shows Comparable Efficacy but Better Efficiency than Two Conventional Stimulations in Poor/Suboptimal Responders Undergoing Vitrified Oocyte Accumulation for PGT-A
No full textThis study compared the DuoStim protocol with two conventional follicular phase stimulations for vitrified oocyte accumulation in poor-prognosis patients undergoing PGT-A. A retrospective analysis of 112 IVF cycles was conducted, with 66 cycles among patients undergoing DuoStim (DS-Group) and 46 among patients undergoing conventional follicular phase stimulations (DF-Group). The primary outcome was the time to live birth, while secondary outcomes included clinical pregnancy rate, miscarriage rate, live birth rate, and cumulative live birth rate. The final analysis included 66 patients in the DS-Group and 40 in the DF-Group, as 6 women (13%) in the DF-Group discontinued treatment after the first stimulation. Oocyte yield was similar between groups (8.4 ± 3.9 in DS-Group vs. 8.2 ± 4.0 in DF-Group, p = 0.80), as was the number of euploid blastocysts (0.9 ± 1.2 vs. 1.1 ± 1.1, p = 0.37). The cumulative live birth rate was 22.7% in the DS-Group and 25% in the DF-Group (multivariate odds ratio adjusted for maternal age and male factor: 1.05, p = 0.93). The time to live birth was significantly shorter in the DS-Group (81.5 ± 15.5 days) compared to the DF-Group (153.7 ± 78.2 days, p < 0.001). DuoStim showed similar efficacy but a shorter time to live birth
Visible Light-promoted Esterification of Carboxylic Acids via Photoacid Generation Catalysis
No full textTHERAPEUTIC STRATEGIES TO COMBAT STAPHYLOCOCCUS AUREUS INFECTIONS IN CYSTIC FIBROSIS
No full text: Staphylococcus aureus infections remain a great concern in people with cystic fibrosis also after the introduction of modulator therapy. Here we describe the state of the art of traditional and novel therapeutic strategies to fight both acute and chronic infections caused by sensitive and drug resistant strains
Voghera Sweet Pepper Regulates Cell Death Pathways in an Aging In Vitro Model
No full textBackground/Objectives: Aging and its related disorders are important issues nowadays, and ROS overproduction is one of the primary contributors to this physio-pathological condition. In this regard, ascorbic acid is a strong antioxidant molecule and its anti-aging proprieties are well known. Our previous data demonstrated that Voghera sweet pepper (VP), a peculiar type of pepper cultivated in Italy, is particularly rich in ascorbic acid and displayed a potential anti-aging effect in both young and aged in vitro models, regulating oxidative stress and senescence/proliferation. Based on these data, the anti-aging effect mediated by the extract of the edible part of VP, in terms of regulation of specific cell death mechanisms, was evaluated in an in vitro model of both young and old Normal Human Dermal Fibroblasts (NHDF). Methods: Immunofluorescence analyses were performed to assess the expression levels of specific markers related to autophagy (p62, LC3b) and mitophagy (Pink1, Parkin), as well as the apoptotic marker caspase-3. In addition, transmission electron microscopy (TEM) was used to analyze cellular ultrastructure and to provide further morphological evidence of the extract’s impact. Results: Immunofluorescence analyses revealed that VP extract led to modulated expression levels of p62, LC3b, Pink1, and Parkin, along with a reduction in caspase-3 activity, indicating decreased apoptosis. TEM ultrastructural analysis supported these findings, showing morphological changes consistent with the modulatory effects of VP extract during aging. Conclusions: Based on these results, we may suppose that Voghera pepper (VP) is able to modulate different mechanisms of regulated cell death (RCD) in our in vitro aging model
The BioSUD Biobank as a genomic resource for substance use disorders in Italy
No full textSubstance Use Disorders (SUDs) are a significant public health concern with complex etiologies involving genetic, environmental, and psychological factors. Here, we present BioSUD, a biobank that, by integrating genomic data with comprehensive phenotypic assessments, including sociodemographic, psychosocial, and addiction-related variables, was designed to investigate the etiology of SUDs within the Southern Italian population. We assessed a cohort of 1,806 participants (1,508 controls and 298 individuals with SUD diagnosis). Genomic analyses of the newly generated genotypes showed a predominantly Southern Italian ancestry for the BioSUD cohort. Admixture analysis reveals a complex history of genetic admixture in Southern Italian populations, exhibiting Southern European, African, and other ancestries. This results in significant genetic variation, potentially limiting the applicability of translational studies primarily based on Northern European ancestries. From a social and psychological perspective, individuals with SUDs exhibited lower socioeconomic status, increased exposure to adverse experiences, and compromised familial and peer relationships relative to controls. These results show that the BioSUD cohort is valuable for studying SUD-associated complex behavioral traits
