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The potential of precision population health lies in its capacity to utilize robust patient data for customized prevention and care targeted at specific groups. Machine learning has the potential to automatically identify clinically relevant subgroups of individuals, considering heterogeneous data sources. This study aimed to assess whether unsupervised machine learning (UML) techniques could interpret different clinical data to uncover clinically significant subgroups of patients suspected of coronary artery disease and identify different ranges of aorta dimensions in the different identified subgroups. We employed a random forest-based cluster analysis, utilizing 14 variables from 1170 (717 men/453 women) participants. The unsupervised clustering approach successfully identified four distinct subgroups of individuals with specific clinical characteristics, and this allows us to interpret and assess different ranges of aorta dimensions for each cluster. By employing flexible UML algorithms, we can effectively process heterogeneous patient data and gain deeper insights into clinical interpretation and risk assessment.

The long-established utility of multiwindow interrogation in echocardiography (suprasternal notch, right and left sternal border, apex, and subxiphoid) is sometimes not systematically implemented in routine practice. This case series emphasizes the pivotal importance of such practice for the systematic assessment of aortic valve stenosis and in the evaluation of left ventricular outflow tract and the aorta.

The evaluation of the left atrial (LA) size using the LA volume index (LAVI) is clinically relevant due to its prognostic significance in various conditions. Nonetheless, adding a LA function assessment to the LAVI provides further clinical and prognostic information in different cardiovascular (CV) diseases. The assessment of LA function by echocardiography primarily includes volumetric measurements (LA ejection fraction [LAEF]), tissue Doppler imaging (TDI) (mitral annular late diastolic velocity [a’]), and speckle-tracking methods, such as LA longitudinal reservoir strain (LA strain). This review analyzes and discusses the current medical evidence and potential clinical usefulness of these different methods to analyze LA function.

(1) Background: Although MRI is a well-established tool in Multiple Sclerosis (MS) diagnosis and management, neuroradiological reports often lack standardization and/or quantitative information, with possible consequences in clinical care. The aim of this study was to evaluate the impact of information provided by neuroradiological reports and different reporting systems on the clinical management of MS patients. (2) Methods: An online questionnaire was proposed to neurologists working in Italian tertiary care level MS centers. Questions assessed the impact of different MRI-derived biomarkers on clinical choices, the preferred way of receiving radiological information, and the neurologists’ opinions about different reporting systems and the use of automated software in clinical practice. (3) Results: The online survey was completed by 62 neurologists. New/enlarging (100%) lesions, the global T2w/FLAIR lesion load (96.8%), and contrast-enhancing (95.2%) lesions were considered the most important biomarkers for therapeutic decision, while new/enlarging lesions (98.4%), global T2w/FLAIR lesion load (96.8%), and cerebral atrophy (90.3%) were relevant to prognostic evaluations. Almost all participants (98.4%) considered software for medical imaging quantification helpful in clinical management, mostly in relation to prognostic evaluations. (4) Conclusions: These data highlight the impact of providing accurate and reliable data in neuroradiological reports. The use of software for medical imaging quantification in MS can be helpful to standardize radiological reports and to provide useful clinical information to neurologists.

Brain and spinal cord imaging plays a pivotal role in aiding clinicians with the diagnosis and monitoring of multiple sclerosis. Nevertheless, the significance of magnetic resonance imaging in MS extends beyond its clinical utility. Advanced imaging modalities have facilitated the in vivo detection of various components of MS pathogenesis, and, in recent years, MRI biomarkers have been utilized to assess the response of patients with relapsing–remitting MS to the available treatments. Similarly, MRI indicators of neurodegeneration demonstrate potential as primary and secondary endpoints in clinical trials targeting progressive phenotypes. This review aims to provide an overview of the latest advancements in brain and spinal cord neuroimaging in MS.

Acoustic noise production during Magnetic Resonance Imaging is an important source of patient discomfort and leads to verbal communication problems, difficulties in sedation, and hearing impairment. To address these issues, in this paper we present a systematic characterization of the acoustic field distribution in a MRI cavity in a last generation 7 T scanner, in different spatial locations, with and without a phantom head. Analysis and comparison of various MRI sequences like Echo-planar imaging”, “Gradient echo”, “Spin echo” are carried out. Sound pressure levels are measured using standard statistical descriptors (Leq,Lmean, L90, and Lmode) using two prepolarized free-field microphones measuring pressure levels generated inside scanner cavities in a 50 Hz to 10 kHz range. Acoustic eigenmodes of the cavity are derived numerically in finite element simulations and compared to measurements. Equivalent sound pressure levels exceed 85 dB in the range between 500 and 3,000 Hz, and peak levels are consistently above 100 dB, i.e., the noise levels of 7 T scanners are higher than 3T and 1.5 T counterparts. The presence of the phantom head in the MRI scanner leads to increased noise levels (by 5–10 dB) in its vicinity, as a result of reflections occurring between the head and the bore reflective walls. Numerical finite element simulations allow to extrapolate the noise distribution in the entire cavity and to interpret experimental results and indicate that the frequencies at which the highest noise levels occur correspond to azimuthal or radial resonant modes of the MRI cavity, i.e., with a radially and azimuthally varying pressure field. These results can be useful for the design of future acoustic noise mitigation solutions.

Abstract Migraine is a major health burden worldwide with complex pathophysiology and multifarious underlying mechanisms. One poorly understood issue concerns the early steps in the generation of migraine pain. To elucidate the basic process of migraine pain further, it seems useful to consider key molecular players that may operate synergistically to evoke headache. While the neuropeptide CGRP is an important contributor, we propose that extracellular ATP (that generally plays a powerful nociceptive role) is also a major component of migraine headache, acting in concert with CGRP to stimulate trigeminal nociceptive neurons. The aim of the present focused review is to highlight the role of ATP activating its P2X3 membrane receptors selectively expressed by sensory neurons including their nerve fiber terminals in the meninges. Specifically, we present data on the homeostasis of ATP and related purines in the trigeminovascular system and in the CNS; the basic properties of ATP signalling at peripheral and central nerve terminals; the characteristics of P2X3 and related receptors in trigeminal neurons; the critical speed and persistence of P2X3 receptor activity; their cohabitation at the so-called meningeal neuro-immune synapse; the identity of certain endogenous agents cooperating with ATP to induce neuronal sensitization in the trigeminal sensory system; the role of P2X3 receptors in familial type migraine; the current state of P2X3 receptor antagonists and their pharmacological perspectives in migraine. It is proposed that the unique kinetic properties of P2X3 receptors activated by ATP offer an interesting translational value to stimulate future studies for innovative treatments of migraine pain.

Serelaxin (RLX), namely the human recombinant Relaxin-2 hormone, protects the heart from ischemia/reperfusion (I/R)-induced damage due to its anti-inflammatory, anti-apoptotic and antioxidant properties. RLX acts by binding to its specific RXFP1 receptor whereby it regulates multiple transduction pathways. In this in vitro study, we offer the first evidence for the involvement of the AMP kinase/Sirtuin1 (AMPK/SIRT1) pathway in the protection by RLX against hypoxia/reoxygenation (H/R)-induced damage in H9c2 cells. The treatment of the H/R-exposed cells with RLX (17 nmol L−1) enhanced SIRT1 expression and activity. The inhibition of SIRT1 signaling with EX527 (10 µmol L−1) reduced the beneficial effect of the hormone on mitochondrial efficiency and cell apoptosis. Moreover, RLX upregulated the AMPK pathway, as shown by the increase in the expression of phospho-AMPK-activated protein. Finally, AMPK pathway inhibition by Compound C (10 and 20 μmol L−1) abrogated the increase in SIRT1 expression induced by RLX, thus suggesting the involvement of the AMPK pathway in this effect of RLX. These results strengthen the concept that RLX exerts its cardioprotective effects against H/R-induced injury through multiple pathways which also include AMPK/SIRT1. These new findings support the use of RLX or RLX-derived molecules as a promising therapeutic for those diseases in which I/R and oxidative stress play a pathogenic role.

BackgroundRadiologically isolated syndrome (RIS) describes asymptomatic individuals with incidental radiologic abnormalities suggestive of multiple sclerosis (MS). Much of RIS literature is about adult-onset cases. Treatment of RIS is controversial, especially in pediatric age, but early treatment in selected patients might improve long-term outcomes.Case presentationWe report a single RIS patient who followed up for 18 years in our MS center. At first, she was only monitored with follow-up MRIs. Then, as the lesion load increased, she was treated with a first-line disease-modifying treatment (DMT) reaching MRI stability.ConclusionThis report highlights how treatment can be an appropriate choice in pediatric forms of RIS.

ABSTRACT: The recovery, safeguarding, and valorization of autochthonous poultry breeds may contribute toward the preservation of animal biodiversity and utilization of marginal lands that otherwise offer little agricultural or industrial value. A key strategy in promoting local breeds involves the characterization of morphological traits and productive performances, which are influenced by the breed's genetic make-up as well as its environment. The Mugellese breed is an Italian local poultry breed originating in the Mugello area of north-east Tuscany. It is characterized by frugality, resilience and resistance to disease, cold, and heat stress. Moreover, these birds are particularly suitable for free-range farming. The Mugellese chicken is described as a dwarf breed with a medium neck, broad shoulders, fairly long and horizontal wings, wide, and well-developed breast (especially in the hen). Over the course of a 1-yr observation and data collection period, involving 23 breeders and 405 adult chickens, the Mugellese breed showed the following performances: 1) a hen-day egg production characterized by 2 major peaks: the first in the spring time (March–April, 65.75%), and the second in the late summer period (August–September, 51.86%); 2) high true fertility values (94.35%) throughout the entire breeding season; 3) a weight gain of 732.44 ± 117.06 g and a feed conversion ratio of 3.94 ± 2.42 at an age of 140 d; 4) a slaughter yield of 77.80% (± 3.91); v) a respective protein, fat, and mineral content in the yolk and albumen were: 27.21 ± 4.21 g, 57.77 ± 1.03 g and 3.47 ± 0.40 g per 100 g of yolk; and 82.50 ± 0.57 g, 0.12 ± 0.01 g and 5.43 ± 0.34 g per 100 g of albumen. More data are needed to validate the data obtained in this trial.

Abstract Cardiovascular (CV) engagement in coronavirus disease 2019 (COVID‐19) is a huge determinant of prognosis during the acute phase of the disease. However, little is known about the potential chronic implications of the late phase of COVID‐19 and about the appropriate approach to these patients. Heart failure, type 1 and type 2 myocardial infarction, arrhythmias, myocarditis, pulmonary fibrosis, and thrombosis have been shown to be related to severe acute respiratory syndrome coronavirus 2 infection, and a ‘long COVID‐19’ illness has been recognized with fatigue, chest pain, and dyspnoea among the most frequent symptoms reported after discharge from hospital. This paper focuses on some open questions that cardiologists are going to face during the next months in a general cardiology outpatient clinic, in particular how to evaluate a ‘post‐COVID’ patient during follow‐up of CV complications of the acute phase and how to manage new CV symptoms that could be the consequence, at least in part, of heart/vessels and/or lung involvement of the previous virus infection. Present symptoms and signs, history of previous CV disease (both preceding COVID‐19 and occurring during viral infection), and specific laboratory and imaging measurements during the acute phase may be of interest in focusing on how to approach the clinical evaluation of a post‐COVID patient and how to integrate in our standard of care the new information on COVID‐19, possibly in a multidisciplinary view. Dealing with the increased COVID‐associated CV risk burden and becoming acquainted with potential new e‐cardiology approaches aimed at integrating the cardiology practice are relevant new challenges brought by severe acute respiratory syndrome coronavirus 2 infection and its sequelae.

BackgroundVaccinations provided the most effective tool to fight the SARS-CoV-2 pandemic. It is now well established that COVID-19 vaccines are safe for the general population; however, some cases of rare adverse events following immunization have been described, including CNS Inflammatory Demyelinating Events (CIDEs). Although observational studies are showing that these events are rare and vaccines' benefits highly outweigh the risks, collecting and characterizing post-COVID-19 vaccine CIDEs might be relevant to single out potential risk factors and suggest possible underlying mechanisms.MethodsHere we describe six CIDEs, including two acute transverse myelitis (ATM), three multiple sclerosis (MS), and one neuromyelitis optica spectrum disorder (NMOSD), occurring between 8 and 35 days from a COVID-19 vaccine. Moreover, we performed a systematic literature search of post-COVID-19 vaccines CIDEs, including ATM, ADEM, MS, and NMOSD/MOGAD, published worldwide between December 2020 and December 2021, during 1 year of the vaccination campaign. Clinical/MRI and CSF/serum characteristics were extracted from reviewed studies and pooled-analyzed.ResultsForty-nine studies were included in the systematic review, reporting a total amount of 85 CIDEs. Considering our additional six cases, 91 CIDEs were summarized, including 24 ATM, 11 ADEM, 47 MS, and nine NMOSD/MOGAD. Overall, CIDEs occurred after both mRNA (n = 46), adenoviral-vectored (n = 37), and inactivated vaccines (n = 8). Adenoviral-vectored vaccines accounted for the majority of ADEM (55%) and NMOSD/MOGAD (56%), while mRNA vaccines were more frequent in MS new diagnoses (87%) and relapses (56%). Age was heterogeneous (19–88) and the female sex was prevalent. Time from vaccine to symptoms onset was notably variable: ADEM and NMOSD/MOGAD had a longer median time of onset (12.5 and 10 days) compared to ATM and MS (6 and 7 days) and further timing differences were observed between events following different vaccine types, with ATM and MS after mRNA-vaccines occurring earlier than those following adenoviral-vectored ones.ConclusionBoth the prevalence of vaccine types for certain CIDEs and the heterogeneity in time of onset suggest that different mechanisms—with distinct dynamic/kinetic—might underly these events. While epidemiological studies have assessed the safety of COVID-19 vaccines, descriptions and pooled analyses of sporadic cases may still be valuable to gain insights into CIDE's pathophysiology.

The peptide hormone relaxin (RLX), also available as clinical-grade recombinant protein (serelaxin), holds great promise as a cardiovascular and anti-fibrotic agent but is limited by the pharmacokinetic issues common to all peptide drugs. In this study, by a computational modelling chemistry approach, we have synthesized and tested a set of low molecular weight peptides based on the putative receptor-binding domain of the B chain of human H1 RLX isoform, with the objective to obtain RLX analogues with improved pharmacokinetic features. Some of them were stabilized to induce the appropriate 3-D conformation by intra-chain tri-azolic staples, which should theoretically enhance their resistance to digestive enzymes making them suited for oral administration. Despite these favourable premises, none of these H1 peptides, either linear or stapled, revealed a sufficient affinity to the specific RLX receptor RXFP1. Moreover, none of them was endowed with any RLX-like biological effects in RXFP1-expressing THP-1 human monocytic cells and mouse NIH-3T3-derived myofibroblasts in in vitro culture, in terms of significantly relevant cAMP elevation and ERK1/2 phosphorylation, which represent two major signal transduction events downstream RXFP1 activation. This was at variance with authentic serelaxin, which induced a clear-cut, significant activation of both these classical RLX signaling pathways. Albeit negative, the results of this study offer additional information about the structural requirements that new peptide therapeutics shall possess to effectively behave as RXFP1 agonists and RLX analogues.

Resistin, among its several actions, has been reported to exert central anorexigenic effects in rodents. Some adipokines which centrally modulate food intake have also been reported to affect the activity of gastric smooth muscle, whose motor responses represent a source of peripheral signals implicated in the control of the hunger-satiety cycle through the gut-brain axis. On this basis, in the present experiments, we investigated whether resistin too could affect the mechanical responses in the mouse longitudinal gastric fundal strips. Electrical field stimulation (EFS) elicited tetrodotoxin- and atropine-sensitive contractile responses. Resistin reduced the amplitude of the EFS-induced contractile responses. This effect was no longer detected in the presence of L-NNA, a nitric oxide (NO) synthesis inhibitor. Resistin did not influence the direct muscular response to methacholine. In the presence of carbachol and guanethidine, EFS elicited inhibitory responses whose amplitude was increased by resistin. L-NNA abolished the inhibitory responses evoked by EFS, indicating their nitrergic nature. In the presence of L-NNA, resistin did not have any effect on the EFS-evoked inhibitory responses. Western blot and immunofluorescence analysis revealed a significant increase in neuronal nitric oxide synthase (nNOS) expression in neurons of the myenteric plexus following resistin exposure. In conclusion, the present results offer the first evidence that resistin acts on the gastric fundus, likely through a modulatory action on the nitrergic neurotransmission.

Background: Aortic dilation (AoD) is commonly reported in patients with bicuspid aortic valve (BAV) and has been related to flow abnormalities and genetic predisposition. AoD-related complications are reported to be extremely rare in children. Conversely, an overestimate of AoD related to body size may lead to excess diagnoses and negatively impact quality of life and an active lifestyle. In the present study, we compared the diagnosis performance of the newly introduced Q-score (based on a machine-learning algorithm) versus the traditional Z-score in a large consecutive pediatric cohort with BAV. Materials and methods: Prevalence and progression of AoD were evaluated in 281 pediatric patients ages > 5 and < 18 years at first observation, 249 of whom had isolated BAV and 32 had BAV associated with aortic coarctation (CoA–BAV). An additional group of 24 pediatric patients with isolated CoA was considered. Measurements were made at the level of the aortic annulus, Valsalva sinuses, sinotubular aorta, and proximal ascending aorta. Both Z-scores using traditional nomograms and the new Q-score were calculated at baseline and at followup (mean 4.5 years). Results: A dilation of the proximal ascending aorta was suggested by traditional nomograms (Z-score > 2) in 31.2% of patients with isolated BAV and 18.5% with CoA–BAV at baseline and in 40.7% and 33.3%, respectively, at followup. No significant dilation was found in patients with isolated CoA. Using the new Q-score calculator, ascending aorta dilation was detected in 15.4% of patients with BAV and 18.5% with CoA–BAV at baseline and in 15.8% and 3.7%, respectively, at followup. AoD was significantly related to the presence and degree of aortic stenosis (AS) but not to aortic regurgitation (AR). No AoD-related complications occurred during the followup. Conclusions: Our data confirm the presence of ascending aorta dilation in a consistent subgroup of pediatric patients with isolated BAV, with progression during followup, while AoD was less common when CoA was associated with BAV. A positive correlation was found with the prevalence and degree of AS, but not with AR. Finally, the nomograms used may significantly influence the prevalence of AoD, especially in children, with a possible overestimation by traditional nomograms. This concept requires prospective validation in long-term followup.

Introduction Attachment style is defined by the American Psychological Association as “the characteristic way people relate to others in the context of intimate relationships”. Four attachment styles have been described: secure, fearful, preoccupied, and dismissing. While the effect of attachment style on psychotherapy was widely investigated, few studies have investigated its role in determining beliefs about medicines in patients with Major Depressive Disorder (MDD). Objectives This study aimed to investigate the relationship between preoccupied attachment style and beliefs about medicines in patients with MDD. Methods 27 patients admitted in the Psychiatric Unit of Careggi with diagnosis of MDD were enrolled. Working Alliance Inventory - patient version (WAI-P), Relationship Style Questionnaire (RSQ) and Beliefs about Medicines Questionnaire (BMQ) were administered. An ANCOVA model having BMQ total score as dependent variable and age, sex, RSQ preoccupied attachment subscale and WAI-P task subscale as predictors was considered. WAI-P task was intended to assess the role of agreement on therapeutic choices. Results The overall model was significant (F(4,22)=9,571, P

Introduction Working Alliance is defined as the emotional bond and the agreement on therapeutic goals and tasks between patients and therapists. Despite the wide use of the construct of working alliance in research on psychotherapy, few studies have investigated the role of working alliance in influencing adherence to pharmacotherapy, and drug attitude. A deeper knowledge of the interplay between working alliance and drug attitude could help to challenge low adherence to psychopharmacological treatments in Major Depressive Disorder. Objectives This study aimed to investigate the relationship between working alliance and drug attitude in patients with Major Depressive Disorder. Methods 27 patients admitted in the Psychiatric Unit of Careggi with diagnosis of Major Depressive Disorders were enrolled. Working Alliance Inventory - patient version (WAI-P), Drug Attitude Inventory (DAI) and Beliefs about Medicines (BMQ) were administered. Pearson’s correlation was used to assess relationships between variables. Results A significant positive correlation was detected between BMQ total scores, DAI total scores and WAI-P task, bond, and goal subscales. Correlations between WAI-P subscales and BMQ and DAI total scores DAI total scores BMQ total scores r p r p WAI-P task 0.551 0.003 0.613 0.001 WAI-P bond 0.430 0.001 0.560 0.004 WAI-P goal 0.621 0.001 0.603 0.002 Conclusions Such preliminary data suggest a relationship between Working Alliance and drug attitude. This could contribute to provide tools to challenge low adherence to psychopharmacological treatments in patients with Major Depressive Disorder. Disclosure No significant relationships.

BackgroundMultiple Sclerosis (MS) is a complex disease in which multiple factors contribute to disability accrual. Mediterranean Diet (MeDi) has shown beneficial effects across neurodegenerative diseases. We hypothesize that specific food habits, rather than global adherence to MeDi, might impact on MS. We aimed to (i) evaluate differences in adherence to MeDi between people living with MS (PwMS) and healthy controls (HC); (ii) characterize eating patterns in PwMS and HC, identifying the most influential MeDi items for each group by the use of network analysis; (iii) explore the relationship between patients' eating habits and disability.Materials and MethodsIn this cross-sectional study, we consecutively recruited 424 PwMS and 165 matched HC. Data were obtained through the administration of self-reported questionnaires. Expanded Disability Status Scale (EDSS) and Fatigue Severity Scale (FSS) were evaluated in the MS population. We performed between-groups comparisons via unpaired two-sample t-test and X2 test as appropriate. We calculated food networks in both MS cases and HC using and tested the association between hub nodes and disability. Finally, we conducted a post-hoc analysis, investigating the relationship between food items, lifestyle factors (smoking, exercise) and clinical outcomes.ResultsMost participants adhered sufficiently to MeDi. Exploring each group separately, fruit, vegetables, cereal, and fish were identified as hubs in PwMS, while meat and alcohol were identified as hubs in HC. Hubs were all inter-correlated, indicating that eating habits of PwMS include a large intake of all the foods identified as hubs. EDSS was predicted by the intake of vegetables (beta = −0.36, p < 0.03) and fish (beta = −0.34, p < 0.02). The model including smoking pack/year, International Physical Activity Questionnaire (IPAQ) score and intake of “negative foods” predicted 6% of the variance in EDSS (p < 0.001), while the model including smoking pack/year and IPAQ score predicted 4% of the variance in FSS (p < 0.001).ConclusionsWe identified a sufficient adherence to MeDi in our population. PwMS showed overall a healthier dietary pattern than HC. Vegetables and fish intake were associated with disability outcomes. Future longitudinal studies applying integrated approaches are needed to understand lifestyle added value to the use of standard pharmacological therapies.

Natural history museums are irreplaceable tools to study and preserve the biological diversity around the globe and among the primary actors in the recognition of species and the logical repositories for their type specimens. In this paper we surveyed the consistency of the preserved specimens of amphibians and reptiles housed in the major Italian scientific collections, and verified the presence of threatened species according to the IUCN Red List, including the Extinct (EX), Extinct in the Wild (EW), Critically Endangered (CR), Endangered (EN), and Vulnerable (VU) categories. Altogether, we analyzed 39 Italian zoological collections. We confirmed the presence of one extinct reptile (Chioninia coctei) and five extinct or extinct in the wild amphibian species (Atelopus longirostris, Nectophrynoides asperginis, Pseudophilautus leucorhinus, P. nasutus, and P. variabilis). Seven CR amphibians, fourteen CR reptile species and the extinct skink C. coctei are shared by more than one institution. Museums which host the highest number of threatened and extinct amphibian species are respectively Turin (17 CR and 1 EX), Florence (13 CR and 1 EX), and Trento (15 CR and 1 EW), while for reptiles the richest museums are those from Genoa (15 CR and 1 EX), Florence (11 CR and 1 EX), and Pisa (7 CR). Finally, we discussed the utility of natural history museums and the strategies to follow for the implementation of their functionality.

The impact of pregnancy and breastfeeding on the development and outcomes of Multiple sclerosis (MS) has been debated for decades. Since several factors can influence the evolution of the disease, the protective role of multiparity and breastfeeding remains uncertain, as well the role of hormone replacement therapy in the perimenopausal period. We report two cases of relatively late-onset MS in two parous women, who developed their first neurological symptoms after six and nine pregnancies, respectively. Both women breastfed each of their children for 3 to 12 months. One of them underwent surgical menopause and received hormone replacement therapy for 7 years before MS onset. We performed a systematic literature review to highlight the characteristics shared by women who develop the disease in similar conditions, after unique hormonal imbalances, and to collect promising evidence on this controversial issue. Several studies suggest that the beneficial effects of pregnancy and breastfeeding on MS onset and disability accumulation may only be realized when several pregnancies occur. However, these data on pregnancy and breastfeeding and their long-term benefits on MS outcomes suffer from the possibility of reverse causality, as women with milder impairment might choose to become pregnant more readily than those with a higher level of disability. Thus, the hypothesis that multiparity might have a protective role on MS outcomes needs to be tested in larger prospective cohort studies of neo-diagnosed women, evaluating both clinical and radiological features at presentation.

We present a case report of an older patient with aortic stenosis who was managed before and after transcatheter aortic valve implantation by a team of cardiologists but without the support of a geriatrician. We first describe the patient’s post-interventional complications from a geriatric perspective and afterwards, discuss the unique approach that the geriatrician would have provided. This case report was written by a group of geriatricians working in an acute hospital, along with a clinical cardiologist who is an expert in aortic stenosis. We discuss the implications for modifying conventional practice in tandem with existing literature.

Cigarette smoking (CS) is the cause of several organ and apparatus diseases. The effects of smoke in the gut are partially known. Accumulating evidence has shown a relationship between smoking and inflammatory bowel disease, prompting us to investigate the mechanisms of action of smoking in animal models. Despite the role played by neuropeptides in gut inflammation, there are no reports on their role in animal models of smoking exposure. The hormone relaxin has shown anti-inflammatory properties in the intestine, and it might represent a putative therapy to prevent gut damage caused by smoking. Presently, we investigate the effects of chronic smoke exposure on inflammation, mucosal secretion, and vasoactive intestinal peptide (VIP) and substance P (SP) expressions in the ileum and colon of guinea pigs. We also verify the ability of relaxin to counter the smoke-induced effects. Smoke impacted plasma carbon monoxide (CO). In the ileum, it induced inflammatory infiltrates, fibrosis, and acidic mucin production; reduced the blood vessel area; decreased c-kit-positive mast cells and VIP-positive neurons; and increased the SP-positive nerve fibers. In the colon, it reduced the blood vessel area and the goblet cell area and decreased c-kit-positive mast cells, VIP-positive neurons, and SP-positive nerve fibers. Relaxin prevented most of the smoking-induced changes in the ileum, while it was less effective in the colon. This study shows the diverse sensitivity to CS between the ileum and the colon and demonstrates that both VIP and SP are affected by smoking. The efficacy of relaxin proposes this hormone as a potential anti-inflammatory therapeutic to counteract gut damage in humans affected by inflammatory bowel diseases.

Objective: To describe a temporal association between COVID-19 vaccine administration and multiple sclerosis (MS) relapses.Methods: This case series study was collected in four MS Centres in Central Italy, using data from 16 MS patients who received COVID-19 vaccination and presented both clinically and radiologically confirmed relapses between March and June 2021. We collected patients' relevant medical history, including demographics, MS clinical course, disease-modifying treatment (DMT) received (if applicable), and data from MRI scans obtained after the COVID-19 vaccination.Results: Three out of 16 patients received a diagnosis of MS with a first episode occurring after COVID-19 vaccination; 13 had already a diagnosis of MS and, among them, 9 were on treatment with DMTs. Ten patients received BNT162b2/Pfizer-BioNTech, 2 patients mRNA-1273/Moderna, and 4 patients ChAdOx1 nCoV-19/AstraZeneca. All MS relapses occurred from 3 days to 3 weeks after receiving the first dose of the COVID-19 vaccination or the booster. All patients had evidence of radiological activity on MRI.Discussion: Clinical and radiological findings in these cohort of MS patients confirmed disease re/activation and suggested a temporal association between disease activity and COVID-19 vaccination. The nature of this temporal association, whether causative or incidental, remains to be established.

It has been reported that adiponectin (ADPN) and resistin are co-secreted by white mouse adipocytes and exert similar inhibitory effects in the mouse gastric fundus, in which resistin was observed to increase neuronal nitric oxide synthase (nNOS) expression. On these grounds, the present work aimed to investigate whether the effects of the two adipokines on the neurally-induced relaxant responses potentiate each other and whether there is a possible correlation with changes in nNOS expression in preparations from the mouse gastric fundus. In carbachol (CCh)-precontracted strips, electrical field stimulation elicited nitrergic relaxant responses, whose amplitude was increased by ADPN or resistin, but no additional enhancements were observed in their concomitant presence. Western blot and immunofluorescence analyses revealed that ADPN, like resistin, was able to up-regulate nNOS expression and to increase the percentage of nNOS-positive neurons in the myenteric plexus: co-treatment with the two adipokines did not induce additional changes. The results indicate that the two adipokines modulate nitrergic neurotransmission, and both do so by up-regulating nNOS expression. Therefore, nNOS appears to be a shared target for the two adipokines’ effects, which, rather than mutually reinforcing each other, may represent a dual physiological control mechanism to guarantee gastric fundus relaxation.

Despite human recombinant H2 relaxin or serelaxin holding promise as a cardiovascular drug, its actual efficacy in chronic treatment of heart failure patients was hampered by the need to be administered by multiple daily IV injections for a long time, with obvious drawbacks in terms of patients’ compliance. This in vitro study aimed at exploring the molecular background for a possible administration of the peptide hormone relaxin by the oral route. Serelaxin and purified porcine relaxin (pRLX) were subjected to simulated intestinal fluid (SIF) enzymatic digestion in vitro to mimic the behavior of gastroprotective formulations. The digestion time course was studied by HPLC, and the relative bio-potency of the intact molecules and their proteolytic fragments was assessed by second messenger (cAMP) response in RXFP1 relaxin receptor-bearing THP-1 human monocytic cells. Both intact proteins (100 ng/mL) induced a significant cAMP rise in THP-1 cells. Conversely, SIF-treated serelaxin showed a brisk (30 s) bioactivity decay, dropping down to the levels of the unstimulated controls at 120 s, whereas SIF-treated pRLX retained significant bioactivity for up to 120 s. After that, it progressively declined to the levels of the unstimulated controls. HPLC analysis indicates that this bioactivity could be ascribed to a minor component of the pRLX sample more resistant to proteolysis. When identified and better characterized, this peptide could be exploited for the development of synthetic relaxin agonists suitable for oral formulations.

The main challenge in diagnosing and managing thoracic aortic aneurysm and dissection (TAA/D) is represented by the early detection of a disease that is both deadly and “elusive”, as it generally grows asymptomatically prior to rupture, leading to death in the majority of cases. Gender differences exist in aortic dissection in terms of incidence and treatment options. Efforts have been made to identify biomarkers that may help in early diagnosis and in detecting those patients at a higher risk of developing life-threatening complications. As soon as the hereditability of the TAA/D was demonstrated, several genetic factors were found to be associated with both the syndromic and non-syndromic forms of the disease, and they currently play a role in patient diagnosis/prognosis and management-guidance purposes. Likewise, circulating biomarker could represent a valuable resource in assisting the diagnosis, and several studies have attempted to identify specific molecules that may help with risk stratification outside the emergency department. Even if promising, those data lack specificity/sensitivity, and, in most cases, they need more testing before entering the “clinical arena”. This review summarizes the state of the art of the laboratory in TAA/D diagnostics, with particular reference to the current and future role of molecular-genetic testing.

Trigeminal sensory neurons of transgenic knock-in (KI) mice expressing the R192Q missense mutation in the α1A subunit of neuronal voltage-gated CaV2.1 Ca2+ channels, which leads to familial hemiplegic migraine type 1 (FHM1) in patients, exhibit a hyperexcitability phenotype. Here, we show that the expression of NaV1.7 channels, linked to pain states, is upregulated in KI primary cultures of trigeminal ganglia (TG), as shown by increased expression of its α1 subunit. In the majority of TG neurons, NaV1.7 channels are co-expressed with ATP-gated P2X3 receptors (P2X3R), which are important nociceptive sensors. Reversing the trigeminal phenotype with selective CaV2.1 channel inhibitor ω-agatoxin IVA inhibited NaV1.7 overexpression. Functionally, KI neurons revealed a TTX-sensitive inward current of larger amplitude that was partially inhibited by selective NaV1.7 blocker Tp1a. Under current-clamp condition, Tp1a raised the spike threshold of both wild-type (WT) and KI neurons with decreased firing rate in KI cells. NaV1.7 activator OD1 accelerated firing in WT and KI neurons, a phenomenon blocked by Tp1a. Enhanced expression and function of NaV1.7 channels in KI TG neurons resulted in higher excitability and facilitated nociceptive signaling. Co-expression of NaV1.7 channels and P2X3Rs in TGs may explain how hypersensitivity to local stimuli can be relevant to migraine.

Abstract Oxidative stress due to excess superoxide anion ($${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{\cdot }}{\boldsymbol{-}}}$$ O2⋅− ) produced by dysfunctional mitochondria is a key pathogenic event of aging and ischemia-reperfusion diseases. Here, a new $${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{\cdot }}{\boldsymbol{-}}}$$ O2⋅− -scavenging MnII complex with a new polyamino-polycarboxylate macrocycle (4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetate) containing 2 quinoline units (MnQ2), designed to improve complex stability and cell permeability, was compared to parental MnII complex with methyls replacing quinolines (MnM2). MnQ2 was more stable than MnM2 (log K = 19.56(8) vs. 14.73(2) for the equilibrium Mn2+ + L2−, where L = Q2 and M2) due to the involvement of quinoline in metal binding and to the hydrophobic features of the ligand which improve metal desolvation upon complexation. As oxidative stress model, H9c2 rat cardiomyoblasts were subjected to hypoxia-reoxygenation. MnQ2 and MnM2 (10 μmol L−1) were added at reoxygenation for 1 or 2 h. The more lipophilic MnQ2 showed more rapid cell and mitochondrial penetration than MnM2. Both MnQ2 and MnM2 abated endogenous ROS and mitochondrial $${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{\cdot }}{\boldsymbol{-}}}$$ O2⋅− , decreased cell lipid peroxidation, reduced mitochondrial dysfunction, in terms of efficiency of the respiratory chain and preservation of membrane potential (Δψ) and permeability, decreased the activation of pro-apoptotic caspases 9 and 3, and increased cell viability. Of note, MnQ2 was more effective than MnM2 to exert cytoprotective anti-oxidant effects in the short term. Compounds with redox-inert ZnII replacing the functional MnII were ineffective. This study provides clues which further our understanding of the structure-activity relationships of MnII-chelates and suggests that MnII-polyamino-polycarboxylate macrocycles could be developed as new anti-oxidant drugs.

Questo breve contributo vuole offrire alcune riflessioni emerse a seguito di un'esperienza di ricerca etnografica realizzata, in collaborazione con un altro ricercatore etnografo coordinatore dell’indagine, nell’ambito del progetto “Architettura complessiva degli interventi da parte di una struttura preventiva” dell’ASL 7 di Siena. Si tratta di una ricerca progettata affinché, attraverso l’approccio teorico metodologico proprio delle discipline etno-antropologiche, emergessero elementi utili a svelare la complessità del fenomeno del gioco d’azzardo e del disturbo ad esso correlato.

Cardiac involvement has been described during the course of SARS-CoV-2 disease (COVID-19), with different manifestations. Several series have reported only increased cardiac troponin without ventricular dysfunction, others the acute development of left or right ventricular dysfunction, and others myocarditis. Ventricular dysfunction can be of varying degrees and may recover completely in some cases. Generally, conventional echocardiography is used as a first approach to evaluate cardiac dysfunction in patients with COVID-19, but, in some cases, this approach may be silent and more advanced cardiac imaging techniques, such as myocardial strain imaging or cardiac magnetic resonance, are necessary to document alterations in cardiac structure or function. In this review we sought to discuss the information provided by different cardiac imaging techniques in patients with COVID-19, both in the acute phase of the disease and after discharge from hospital, and their diagnostic and prognostic role. We also aimed at verifying whether a specific form of cardiac disease due to the SARS-CoV-2 can be identified.