In monozygotic twins discordant for multiple sclerosis, the influence of genetic predisposition and environmental factors is determined using matched-pair analyses. Multiple sclerosis (MS) is a ...chronic inflammatory disorder of the central nervous system underpinned by partially understood genetic risk factors and environmental triggers and their undefined interactions(1,2). Here we investigated the peripheral immune signatures of 61 monozygotic twin pairs discordant for MS to dissect the influence of genetic predisposition and environmental factors. Using complementary multimodal high-throughput and high-dimensional single-cell technologies in conjunction with data-driven computational tools, we identified an inflammatory shift in a monocyte cluster of twins with MS, coupled with the emergence of a population of IL-2 hyper-responsive transitional naive helper T cells as MS-related immune alterations. By integrating data on the immune profiles of healthy monozygotic and dizygotic twin pairs, we estimated the variance in CD25 expression by helper T cells displaying a naive phenotype to be largely driven by genetic and shared early environmental influences. Nonetheless, the expanding helper T cells of twins with MS, which were also elevated in non-twin patients with MS, emerged independent of the individual genetic makeup. These cells expressed central nervous system-homing receptors, exhibited a dysregulated CD25-IL-2 axis, and their proliferative capacity positively correlated with MS severity. Together, our matched-pair analysis of the extended twin approach allowed us to discern genetically and environmentally determined features of an MS-associated immune signature.
Regenerative processes occurring under physiological and pathological (reparative) conditions are a fundamental part of life, and they vary greatly among different species, individuals and tissues. ...Physiological regeneration occurs naturally as a consequence of normal cell turnover, or as an inevitable outcome of any biological process requiring the restoration of homeostasis. Reparative regeneration occurs as a consequence of tissue damage. Although the central nervous system (CNS) has been considered for years as a ‘perennial’ tissue, it is now becoming clear that both physiological and reparative regeneration occur within the CNS to sustain tissue homeostasis and repair. Neural progenitor cells (NPCs) residing within the healthy CNS are emerging as crucial actors in both physiological as well as pathological conditions. Thus, a large number of experimental stem cell–based transplantation systems for CNS repair have recently been established, suggesting that transplanted NPCs might promote tissue repair not only via cell replacement but also via bystander (paracrine) mechanisms favourably influencing the diseased tissue milieu.
Abstract
Aims
Cardiac myxomas usually develop in the atria and consist of an acid-mucopolysaccharide-rich myxoid matrix with polygonal stromal cells scattered throughout. These human benign tumours ...are a valuable research model because of the rarity of cardiac tumours, their clinical presentation and uncertain origin. Here, we assessed whether multipotent cardiac stem/progenitor cells (CSCs) give rise to atrial myxoma tissue.
Methods and results
Twenty-three myxomas were collected and analysed for the presence of multipotent CSCs. We detected myxoma cells positive for c-kit (c-kitpos) but very rare Isl-1 positive cells. Most of the c-kitpos cells were blood lineage-committed CD45pos/CD31pos cells. However, c-kitpos/CD45neg/CD31neg cardiac myxoma cells expressed stemness and cardiac progenitor cell transcription factors. Approximately ≤10% of the c-kitpos/CD45neg/CD31neg myxoma cells also expressed calretinin, a characteristic of myxoma stromal cells. In vitro, the c-kitpos/CD45neg/CD31neg myxoma cells secrete chondroitin-6-sulfate and hyaluronic acid, which are the main components of gelatinous myxoma matrix in vivo. In vitro, c-kitpos/CD45neg/CD31neg myxoma cells have stem cell properties being clonogenic, self-renewing, and sphere forming while exhibiting an abortive cardiac differentiation potential. Myxoma-derived CSCs possess a mRNA and microRNA transcriptome overall similar to normal myocardium-derived c-kitpos/CD45neg/CD31negCSCs , yet showing a relatively small and relevant fraction of dysregulated mRNA/miRNAs (miR-126-3p and miR-335-5p, in particular). Importantly, myxoma-derived CSCs but not normal myocardium-derived CSCs, seed human myxoma tumours in xenograft’s in immunodeficient NOD/SCID mice.
Conclusion
Myxoma-derived c-kitpos/CD45neg/CD31neg CSCs fulfill the criteria expected of atrial myxoma-initiating stem cells. The transcriptome of these cells indicates that they belong to or are derived from the same lineage as the atrial multipotent c-kitpos/CD45neg/CD31neg CSCs. Taken together the data presented here suggest that human myxomas could be the first-described CSC-related human heart disease.
Background
Several reports demonstrated a strong association between the level of adherence to the protocol and improved clinical outcomes after surgery. However, it is difficult to obtain full ...adherence to the protocol into clinical practice and has still not been identified the threshold beyond which improved functional results can be reached.
Methods
The ERCOLE (ERas and COLorectal Endoscopic surgery) study was as a cohort, prospective, multi-centre national study evaluating the association between adherence to ERAS items and clinical outcomes after minimally invasive colorectal surgery. The primary endpoint was to associate the percentage of ERAS adherence to functional recovery after minimally invasive colorectal cancer surgery. The secondary endpoints of the study was to validate safety of the ERAS programme evaluating complications’ occurrence according to Clavien-Dindo classification and to evaluate the compliance of the Italian surgeons to each ERAS item.
Results
1138 patients were included. Adherence to the ERAS protocol was full only in 101 patients (8.9%), > 75% of the ERAS items in 736 (64.7%) and > 50% in 1127 (99%). Adherence to > 75% was associated with a better functional recovery with 90.2 ± 98.8 vs 95.9 ± 33.4 h (
p
= 0.003). At difference, full adherence to the ERAS components 91.7 ± 22.1 vs 92.2 ± 31.6 h (
p
= 0.8) was not associated with better recovery.
Conclusions
Our results were encouraging to affirm that adherence to the ERAS program up to 75% could be considered satisfactory to get the goal. Our study could be considered a call to simplify the ERAS protocol facilitating its penetrance into clinical practice.
Summary
Objective
Combined pituitary hormonal deficiency (CPHD) can result from mutations within genes that encode transcription factors. This study evaluated the frequency of mutations in these ...genes in a cohort of 144 unrelated Italian patients with CPHD and estimated the overall prevalence of mutations across different populations using a systematic literature review.
Material and methods
A multicentre study of adult and paediatric patients with CPHD was performed. The PROP1, POU1F1, HESX1, LHX3 and LHX4 genes were analysed for the presence of mutations using direct sequencing. We systematically searched PubMed with no date restrictions for studies that reported genetic screening of CPHD cohorts. We only considered genetic screenings with at least 10 individuals. Data extraction was conducted in accordance with the guidelines set by the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA).
Results
Global mutation frequency in Italian patients with CPHD was 2·9% (4/136) in sporadic cases and 12·5% (1/8) in familial cases. The worldwide mutation frequency for the five genes calculated from 21 studies was 12·4%, which ranged from 11·2% in sporadic to 63% in familial cases. PROP1 was the most frequently mutated gene in sporadic (6·7%) and familial cases (48·5%).
Conclusion
The frequency of defects in genes encoding pituitary transcription factors is quite low in Italian patients with CPHD and other western European countries, especially in sporadic patients. The decision of which genes should be tested and in which order should be guided by hormonal and imaging phenotype, the presence of extrapituitary abnormalities and the frequency of mutation for each gene in the patient‐referring population.
Background
Hypertension management in older patients represents a challenge, particularly when hospitalized.
Objective
The objective of this study is to investigate the determinants and related ...outcomes of antihypertensive drug prescription in a cohort of older hospitalized patients.
Methods
A total of 5671 patients from REPOSI (a prospective multicentre observational register of older Italian in‐patients from internal medicine or geriatric wards) were considered; 4377 (77.2%) were hypertensive. Minimum treatment (MT) for hypertension was defined according to the 2018 ESC guidelines an angiotensin‐converting‐enzyme‐inhibitor (ACE‐I) or an angiotensin‐receptor‐blocker (ARB) with a calcium‐channel‐blocker (CCB) and/or a thiazide diuretic; if >80 years old, an ACE‐I or ARB or CCB or thiazide diuretic. Determinants of MT discontinuation at discharge were assessed. Study outcomes were any cause rehospitalization/all cause death, all‐cause death, cardiovascular (CV) hospitalization/death, CV death, non‐CV death, evaluated according to the presence of MT at discharge.
Results
Hypertensive patients were older than normotensives, with a more impaired functional status, higher burden of comorbidity and polypharmacy. A total of 2233 patients were on MT at admission, 1766 were on MT at discharge. Discontinuation of MT was associated with the presence of comorbidities (lower odds for diabetes, higher odds for chronic kidney disease and dementia). An adjusted multivariable logistic regression analysis showed that MT for hypertension at discharge was associated with lower risk of all‐cause death, all‐cause death/hospitalization, CV death, CV death/hospitalization and non‐CV death.
Conclusions
Guidelines‐suggested MT for hypertension at discharge is associated with a lower risk of adverse clinical outcomes. Nevertheless, changes in antihypertensive treatment still occur in a significant proportion of older hospitalized patients.
In this observational cohort study, we investigated the impact of hospitalization on changes in antihypertensive therapy in 5671 hypertensive older inpatients from the REPOSI register. Fifty‐one percent of patients were on minimum treatment (MT, defined according to the 2018 ESC guidelines) at admission. This percentage reduced to 40% at discharge, mostly due to specific clinical impairment and comorbidities such as chronic kidney disease and dementia. Maintaining a MT at discharge was associated with a lower risk of major clinical outcomes.
Exercise intervention improves macrovascular function in metabolic syndrome (MeS) patients, but few studies have evaluated the effect of exercise on microcirculatory dysfunction, which plays a key ...role in the development of MeS and its correlated organ damage. We carried out this intervention study to evaluate the influence of an aerobic and resistance training on skin microvascular reactivity in MeS patients.
Postocclusive reactive hyperemia (PORH) of the forearm skin was evaluated, by laser-Doppler flowmetry, before and after a 12-week program of aerobic and resistance training in 15 MeS patients referring to our Lipid Metabolism Outpatients Clinic, together with anthropometric, fitness and metabolic parameters; 15 matched MeS patients who did not exercise, served as a control group. The exercise training consisted of 2 sessions/week of aerobic and resistant exercise.
Following exercise program, we observed a significant reduction in body weight, fat mass, fasting blood glucose, serum HbA1c and triglycerides, while HDL-cholesterol significantly increased. The exercise-treated group experienced a significant improvement in the area of hyperemia (AH) after PORH, and in all fitness parameters: VO2max, strength on the pulldown lat machine, chest press, leg press and leg extension. A significant correlation emerged between the increase in AH and the reduction in HbA1c and between increase in AH and strength at the chest press, and at the leg extension.
Our study showed that a short-term combined aerobic-resistance training positively affects microvascular reactivity in MeS patients. This improvement is correlated with the reduction of HbA1c and fitness parameters, and particularly with increased muscle strength at the upper and lower limbs.
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