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Abstract: Pulmonary arterial hypertension forms the first and most severe of the 5 categories of pulmonary hypertension. Disease pathogenesis is driven by progressive remodeling of peripheral pulmonary arteries, caused by the excessive proliferation of vascular wall cells, including endothelial cells, smooth muscle cells and fibroblasts, and perivascular inflammation. Compelling evidence from animal models suggests endothelial cell dysfunction is a key initial trigger of pulmonary vascular remodeling, which is characterised by hyperproliferation and early apoptosis followed by enrichment of apoptosis-resistant populations. Dysfunctional pulmonary arterial endothelial cells lose their ability to produce vasodilatory mediators, together leading to augmented pulmonary arterial smooth muscle cell responses, increased pulmonary vascular pressures and right ventricular afterload, and progressive right ventricular hypertrophy and heart failure. It is recognized that a range of abnormal cellular molecular signatures underpin the pathophysiology of pulmonary arterial hypertension and are enhanced by loss-of-function mutations in the BMPR2 gene, the most common genetic cause of pulmonary arterial hypertension and associated with worse disease prognosis. Widespread metabolic abnormalities are observed in the heart, pulmonary vasculature, and systemic tissues, and may underpin heterogeneity in responsivity to treatment. Metabolic abnormalities include hyperglycolytic reprogramming, mitochondrial dysfunction, aberrant polyamine and sphingosine metabolism, reduced insulin sensitivity, and defective iron handling. This review critically discusses published mechanisms linking metabolic abnormalities with dysfunctional BMPR2 (bone morphogenetic protein receptor 2) signaling; hypothesized mechanistic links requiring further validation; and their relevance to pulmonary arterial hypertension pathogenesis and the development of potential therapeutic strategies.

Context Endothelial progenitor cells (EPCs), which are involved in the mechanisms of vascular repair and sexual function, are decreased in diabetic women compared with general population. Objective This work aimed to investigate the circulating levels of EPCs and the change in sexual function during the menstrual cycle in women with type 1 diabetes (T1DM) compared with healthy women. Methods This case-control observational study was conducted at the Unit of Endocrinology and Metabolic Diseases at University Hospital “Luigi Vanvitelli’’ of Naples. Participants included 36 women with T1DM and 64 age-matched healthy controls. EPCs were quantified by flow cytometry and sexual function was assessed using the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale. All assessments were made at the follicular, ovulatory, and luteal phases of the same menstrual cycle. Main outcome measures included differences in EPCs levels and sexual function between patients and controls. Results Compared with controls, women with T1DM showed significantly lower levels of both CD34 + (P Conclusion Women with T1DM show lower levels of EPCs during the menstrual cycle compared with controls. EPCs count predicts sexual function in this selected population.

Olive knot disease (OKD) induced by the bacterium Pseudomonas savastanoi pv. savastanoi seriously affects olive production in the Mediterranean basin. Nowadays, the only strategies to control the disease are pruning and the application of cupric products. An essential strategy to enhance protection is represented by the identification of resistant cultivars, which represents a crucial opportunity for future investments and breeding. We undertook a three-year-long survey at the International Olive Germplasm Collection of “Villa Zagaria” (Sicily, Italy) on thirty-six Sicilian cultivars that were monitored for symptom development. Cultivars with different levels of susceptibility were divided into five clusters. Moreover, in order to investigate possible interactions with endophytic microbial communities, two cultivars with contrasting susceptibilities, Zaituna (highly resistant) and Giarraffa (highly susceptible), were selected for an amplicon-based metagenomic analysis. Distinct endophytic communities colonized the two cultivars, suggesting an interaction between the resident bacterial community and the pathogen. Significantly higher bacterial richness was detected in the shoots of the susceptible cv. Giarraffa, although it had lower diversity. The opposite trend was observed for fungal communities. Among the microbes resulted to be enriched in cv. Giarraffa, it is important to underline the presence of Pseudomonas among the bacterial genera, and Alternaria, Neofusicoccum, Epicoccum, Ascochyta, and Elsinoe among the fungal genera, which include many species often described as plant pathogens and biocontrol agents. Starting from this basic information, new strategies of control, which include breeding for resistance and integrated disease management, can be envisaged.

The aims of this study were to evaluate parathormone (PTH) levels in people with diabetic foot ulcers (DFU) and investigate the relationship between PTH levels and osteomyelitis (OM) in this population.Eighty-eight patients were admitted for DFU in a tertiary-care centre from October 2021 to May 2022. OM was diagnosed by clinical, laboratory, and radiological evaluations. Laboratory measurements and clinical parameters were collected from medical records. Participants in the study were divided into two groups according to the diagnosis of OM (patients with OM, group 1 [n = 54] and patients without OM, group 2 [n = 34]).Compared with group 2, patients in group 1 were younger and had a longer duration of diabetes. Erythrocyte sedimentation rate and fibrinogen were significantly higher in group 1 compared with group 2. PTH levels were significantly lower (group 1 vs. group 2, median [interquartile range] 16.2 (11.6, 31.0) vs. 23.7 (17.0, 38.1), p = 0.008) and alkaline phosphatase was significantly higher (97.0 (79.0, 112.0) vs. 88.0 (63.0, 107.0), p = 0.031) in group 1. In multiple linear regression analysis, the only independent predictors of PTH concentrations were alkaline phosphatase levels (β-coefficient 0.441, p 0.001) and the presence of OM (β-coefficient -0.290, p = 0.038).In a population of patients with diabetes and OM admitted to a tertiary university centre, PTH levels were lower as compared with diabetic individuals without OM. The OM and alkaline phosphatase levels were independent predictors of PTH levels in this selected population.

OBJECTIVE BEYOND trial evaluated the feasibility of either basal insulin plus glucagon-like peptide 1 receptor agonist (GLP-1RA) or basal insulin plus sodium–glucose cotransporter 2 inhibitor (SGLT2i) to replace a full basal-bolus insulin (BBI) regimen in participants with type 2 diabetes and inadequate glycemic control. RESEARCH DESIGN AND METHODS Participants were randomized (1:1:1) to: 1) intensification of the BBI regimen (n = 101), 2) fixed ratio of basal insulin plus GLP-1RA (fixed-combo group; n = 102), and 3) combination of basal insulin plus SGLT2i (gliflo-combo group; n = 102). The primary efficacy outcome was change from baseline in HbA1c at 6 months. RESULTS Baseline characteristics were similar among the three groups (mean HbA1c was 8.6% [70 mmol/mol]). At 6 months, patients experienced similar reduction in HbA1c level (−0.6 ± 0.8, −0.6 ± 0.8, and −0.7 ± 0.9%, mean ± SD, respectively; noninferiority P < 0.001 vs. BBI), and the proportion of patients with HbA1c ≤7.5% was also similar (34%, 28%, and 27%, respectively; P = 0.489). Total insulin dose increased in the BBI group (62 units/day) and decreased both in the fixed-combo and gliflo-combo groups (27 units/day and 21 units/day, respectively; P < 0.01). The proportion of patients with hypoglycemia was 17.8%, 7.8%, and 5.9%, respectively (P = 0.015). There were 12 dropouts in the fixed-combo group, 9 in the gliflo-combo group, and none in the BBI group. CONCLUSIONS BEYOND provides evidence that it is possible and safe to switch from a BBI regimen to either a once-daily fixed-combo injection or once-daily gliflozin added to basal insulin, with similar glucose control, fewer insulin doses, fewer injections daily, and less hypoglycemia.

There is a growing research interest in wireless non-invasive solutions for core temperature estimation and their application in clinical settings. This study aimed to investigate the use of a novel wireless non-invasive heat flux-based thermometer in acute stroke patients admitted to a stroke unit and compare the measurements with the currently used infrared (IR) tympanic temperature readings. The study encompassed 30 acute ischemic stroke patients who underwent continuous measurement (Tcore) with the novel wearable non-invasive CORE device. Paired measurements of Tcore and tympanic temperature (Ttym) by using a standard IR-device were performed 3–5 times/day, yielding a total of 305 measurements. The predicted core temperatures (Tcore) were significantly correlated with Ttym (r = 0.89, p < 0.001). The comparison of the Tcore and Ttym measurements by Bland–Altman analysis showed a good agreement between them, with a low mean difference of 0.11 ± 0.34 °C, and no proportional bias was observed (B = −0.003, p = 0.923). The Tcore measurements correctly predicted the presence or absence of Ttym hyperthermia or fever in 94.1% and 97.4% of cases, respectively. Temperature monitoring with a novel wireless non-invasive heat flux-based thermometer could be a reliable alternative to the Ttym method for assessing core temperature in acute ischemic stroke patients.

Anthracnose caused by Colletotrichum spp. is the most damaging olive fruit disease in many countries, including Italy. This disease has been sporadically detected in Sicily, but new agronomic practices can increase risk of olive anthracnose in this region. An etiological study of the disease focused on local olive cultivars growing at the International Olive Germplasm Collection (IOGC) in Villa Zagaria, Enna, Sicily has been undertaken. During 2018 and 2019, 137 Colletotrichum strains were isolated from olives. Colony morphology, conidium characteristics, and multilocus sequence analyses aided identification of three species: C. acutatum (affecting 70% of symptomatic olives), C. gloeosporioides, and C. cigarro. Three C. acutatum strains (B13-16, P77, and P185), and one strain of each C. gloeosporioides (C2.1) and C. cigarro (Perg6B) were evaluated for pathogenicity on olive fruits from 11 Sicilian cultivars, known for their high-quality oil. Differences in virulence were detected among strains and their pathogenicity to the cultivars. The C. acutatum isolates were more virulent than those of C. gloeosporioides or C. cigarro. The Sicilian olive cultivars Cavaliera, Carolea, Calatina, and Nocellara del Belice were the most susceptible to the pathogen, while the cultivars Biancolilla and Nocellara Etnea were the most tolerant. Cultivar response under field conditions showed that anthracnose severity and fruit-rot incidence were positively correlated. This is the first report of C. acutatum and C. cigarro affecting olive trees in Sicily. Control measures for anthracnose depend on accurate characterization of the etiological agents and host cultivar resistance.

Owing to the large inter-subject variability, early post-stroke prognosis is challenging, and objective biomarkers that can provide further prognostic information are still needed. The relation between quantitative EEG parameters in pre-thrombolysis hyper-acute phase and outcomes has still to be investigated. Hence, possible correlations between early EEG biomarkers, measured on bedside wireless EEG, and short-term/long-term functional and morphological outcomes were investigated in thrombolysis-treated strokes. EEG with a wireless device was performed in 20 patients with hyper-acute (

The demand for care services in the healthcare system has changed and is triggering a smooth transition from in-hospital to primary care. In this regard, patient-centered-care models of care delivery might provide a framework to follow patients’ journeys throughout their transition between different levels of care. Accordingly, an Italian research group at a cardiac hospital in Northern Italy implemented the Synergy Model in a Cardiac Surgery Unit, a patient-centered-care model, and is using the framework of the model to guide a smooth transition of patients towards rehabilitation and primary care after their hospitalization. This discursive paper is focused on the experience, perspectives, and future implications of adopting the Synergy Model to facilitate the transition from in-hospital to primary care. The presented experience and discussion might be helpful to the international debate regarding the strategies to boost a smooth transition from in-hospital to primary care.

Highly stressful situations, such as the current COVID-19 pandemic, induce constant changes in the mental state of people who experience them. In the present study, we analyzed the prevalence of some psychological symptoms and their determinants in four different categories of healthcare workers during the second year of the pandemic. A total of 265 physicians, 176 nurses, 184 other healthcare professionals, and 48 administrative employees, working in different Italian healthcare contexts, answered a questionnaire including variables about their mental status and experience with the pandemic. The mean scores for anxiety and depressive symptoms measured more than one year after the onset of the pandemic did not reach the pathological threshold. In contrast, post-traumatic and burnout symptoms tended toward the critical threshold, especially in physicians. The main determinant of psychological distress was perceived stress, followed by job satisfaction, the impact of COVID-19 on daily work, and a lack of recreational activities. These results increase the knowledge of which determinants of mental distress would be important to act on when particularly stressful conditions exist in the workplace that persist over time. If well-implemented, specific interventions focused on these determinants could lead to an improvement in employee well-being and in the quality of care provided.

Infection is a common complication in patients with diabetic foot ulcer, leading to lower extremities amputation and healing failure. In this article, we report the case of a 39‐year‐old man with diabetes who developed a severe soft tissue infection and osteomyelitis after experiencing a major amputation for wet gangrene of both the foot and the ankle.

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Outcome prediction in wake-up ischemic stroke (WUS) is important for guiding treatment strategies, in order to improve recovery and minimize disability. We aimed at producing an interpretable model to predict a good outcome (NIHSS 7-day

CRISPR/Cas9 genome editing is a modern biotechnological approach used to improve plant varieties, modifying only one or a few traits of a specific variety. However, this technology cannot be easily used to improve fruit quality traits in citrus, due to the lack of knowledge of key genes, long juvenile stage, and the difficulty regenerating whole plants of specific varieties. Here, we introduce a genome editing approach with the aim of producing citrus plantlets whose fruits contain both lycopene and anthocyanins. Our method employs a dual single guide RNA (sgRNA)-directed genome editing approach to knockout the fruit-specific β-cyclase 2 gene, responsible for the conversion of lycopene to beta-carotene. The gene is targeted by two sgRNAs simultaneously to create a large deletion, as well as to induce point mutations in both sgRNA targets. The EHA105 strain of Agrobacterium tumefaciens was used to transform five different anthocyanin-pigmented sweet oranges, belonging to the Tarocco and Sanguigno varietal groups, and ‘Carrizo’ citrange, a citrus rootstock as a model for citrus transformation. Among 58 plantlets sequenced in the target region, 86% of them were successfully edited. The most frequent mutations were deletions (from -1 to -74 nucleotides) and insertions (+1 nucleotide). Moreover, a novel event was identified in six plantlets, consisting of the inversion of the region between the two sgRNAs. For 20 plantlets in which a single mutation occurred, we excluded chimeric events. Plantlets did not show an altered phenotype in vegetative tissues. To the best of our knowledge, this work represents the first example of the use of a genome editing approach to potentially improve qualitative traits of citrus fruit.

The use of hyperacute therapies, such as thrombolysis and mechanical thrombectomy, has revolutionized the care of adult patients with arterial ischemic stroke. In this context, one of the most effective Diagnostic Therapeutic Assistance Pathways (PDTAs) in Italy, and particularly in the Friuli Venezia Giulia Region, describes the care received by the patient with cerebral stroke, who for epidemiological reasons is an adult patient. Drawn up in 2015 and operational in Trieste and Udine, it represented a fundamental step forward in medicine as it dramatically reduced mortality and disability in stroke patients. The effectiveness reported in the literature of the use of hyperacute therapies in children with ischemic stroke requires reflection on the management of such children so that they can take advantage of these therapeutic possibilities. The paper presents 3 cases with a brief comment each that suggests some reflections on stroke treatment in paediatrics and on the possibilities of treatment similar to that of adults.

Accurate nutritional assessment based on dietary intake, physical activity, genetic makeup, and metabolites is required to prevent from developing and/or to treat people suffering from malnutrition as well as other nutrition related health issues. Nutritional screening ought to be considered as an essential part of clinical assessment for every patient on admission to healthcare setups, as well as on change in clinical conditions. Therefore, a detailed nutritional assessment must be performed every time nutritional imbalances are observed or suspected. In this review we have explored different techniques used for nutritional and physical activity assessment. Dietary Intake (DI) assessment is a multidimensional and complex process. Traditionally, dietary intake is assessed through self-report techniques, but due to limitations like biases, random errors, misestimations, and nutrient databases-linked errors, questions arise about the adequacy of self-reporting dietary intake procedures. Despite the limitations in assessing dietary intake (DI) and physical activity (PA), new methods and improved technologies such as biomarkers analysis, blood tests, genetic assessments, metabolomic analysis, DEXA (Dual-energy X-ray absorptiometry), MRI (Magnetic resonance imaging), and CT (computed tomography) scanning procedures have made much progress in the improvement of these measures. Genes also plays a crucial role in dietary intake and physical activity. Similarly, metabolites are also involved in different nutritional pathways. This is why integrating knowledge about the genetic and metabolic markers along with the latest technologies for dietary intake (DI) and physical activity (PA) assessment holds the key for accurately assessing one’s nutritional status and prevent malnutrition and its related complications., Journal of Preventive Medicine and Hygiene, Vol. 63 No. 2S3 (2022): The secret of Mediterranean food: How “omic” sciences, biochemistry and human physiology can be applied to exploit the secrets of Mediterranean foods

Small vessel disease (SVD) is one of the most frequent pathological conditions which lead to dementia. Biochemical and neuroimaging might help correctly identify the clinical diagnosis of this relevant brain disease. The microvascular alterations which underlie SVD have common origins, similar cognitive outcomes, and common vascular risk factors. Nevertheless, the arteriolosclerosis process, which underlines SVD development, is based on different mechanisms, not all completely understood, which start from a chronic hypoperfusion state and pass through a chronic brain inflammatory condition, inducing a significant endothelium activation and a consequent tissue remodeling action. In a recent review, we focused on the pathophysiology of SVD, which is complex, involving genetic conditions and different co-morbidities (i.e., diabetes, chronic hypoxia condition, and obesity). Currently, many points still remain unclear and discordant. In this paper, we wanted to focus on new biomarkers, which can be the expression of the endothelial dysfunction, or of the oxidative damage, which could be employed as markers of disease progression or for future targets of therapies. Therefore, we described the altered response to the endothelium-derived nitric oxide-vasodilators (ENOV), prostacyclin, C-reactive proteins, and endothelium-derived hyperpolarizing factors (EDHF). At the same time, due to the concomitant endothelial activation and chronic neuroinflammatory status, we described hypoxia-endothelial-related markers, such as HIF 1 alpha, VEGFR2, and neuroglobin, and MMPs. We also described blood–brain barrier disruption biomarkers and imaging techniques, which can also describe perivascular spaces enlargement and dysfunction. More studies should be necessary, in order to implement these results and give them a clinical benefit.

The Mediterranean diet, recognized as being cultural heritage by UNESCO, is mostly plant-based and includes a high consumption of whole-grain, fruit, and vegetables with a moderate consumption of alcohol during meals. Thus, it provides a small amount of saturated fatty acids and a high quantity of antioxidants and fiber. For this reason, it has been considered to have an important role in preventing cardiovascular diseases, chronic kidney diseases, type 2 diabetes mellitus, and cancer, but its relationship with thyroid function and diseases is still under debate. The aim of this review was to search for the possible correlation between the Mediterranean diet and thyroid function, and to critically evaluate the pathophysiological link between selected food intake and thyroid disorders.

Background A meta-analysis is presented of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RA) versus placebo on cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM). Methods We did an electronic search up to June 30, 2021, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals). We included data from 8 CVOTs and 60,080 patients (72.4% with established cardiovascular disease). Results GLP-1RA reduced major cardiovascular events (MACE) by 14% (HR = 0.86, 95% CI 0.79–0.94, P = 0.006) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (P = 0.127). GLP-1RA also reduced the risk of cardiovascular death by 13% (P = 0.016), nonfatal stroke by 16% (P = 0.007), hospitalization for heart failure by 10% (P = 0.023), all-cause mortality by 12% (P = 0.012), and the broad composite kidney outcome by 17% (P = 0.012), which was driven by a reduction in macroalbuminuria only (HR = 0.74, 0.67–0.82, P Conclusions GLP-1RA have moderate benefits on MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also have robust benefits on reducing the incidence of macroalbuminuria.

Background: Extensive studies have suggested epithelial-mesenchymal transition (EMT) and fibroblast-myofibroblast transformation (FMT) as major drivers of fibrosis. Both EMT and FMT are strongly regulated by TGFβ1. Objectives. The aim of this study was to assess a specific transcriptional analysis of a selected panel of genes involved in fibrogenesis by profiling TGFβ-stimulated human lung fibroblasts (HLFs) and human bronchial epithelial cells (HBECs) derived from IPF patients and healthy donors. Moreover, the effects of Nintedanib and the ALK5 inhibitor, SB525334, were evaluated. Methods: Cultured primary HLFs and HBECs were stimulated with TGF-β1 (1.25 and 5 ng/ml, respectively). IPF-derived cells were exposed to Nintedanib (3 µM) and SB525334 (1 µM). RNA was extracted and subsequently reverse transcribed and amplified. RT2 Profiler™ PCR Arrays Human Fibrosis (Qiagen) were used to gene expression analysis. Results: Approximately half of the assessed genes were endowed with a differential expression (≥1.5 fold) between non-stimulated IPF and control HLFs (e.g. GREM1, HGF) and HBECs (e.g. ITGB3, ENG). The above expression pattern was further modified when TGF-β1 was applied to IPF and control cells. Both Nintedanib and SB525334 mainly induced a significant effect on TGFβ1-induced differential expression of genes related to extracellular matrix remodelling (e.g. COL1A1 and COL3A1). Conclusions: Our study revealed a basal differential expression of a selected panel of genes among control and IPF cells. Furthermore, the subsequent validation step with Nintedanib may provide insights on new targets endowed with a potential anti-fibrotic effect.

SARS-COV-2 is a severe medical condition. Old patients are very vulnerable, but they have been studied only as institutionalized patients. During the lock-down, little attention is dedicated to old, demented patients who lived at home. This study wants to examine their behavioral reactions by video-phone follow-up. We conducted a longitudinal study in subcortical vascular dementia (sVAD) patients. We enrolled 221 sVAD, not institutionalized patients. We divided sVAD patients into low-medium grade sVAD (A) and severe sVAD (B), based on neuroimaging severity degree and executive alterations. At baseline, at the end of lock-down, and two months later, global behavioral symptoms were recorded for each patient. We found significantly higher scores of general behavioral deterioration, anxiety, delusions, hallucinations and apathy after controlling for sVAD severity. The direct consequence was a drastic increment of psychotropic drugs prescribed and employed during the lock-down. Moreover, caregivers’ stress has been evaluated, together with their anxiety and depression levels. During the lock-down, their scores increased and reflected a severe worsening of their behavior. Our data demonstrate that social isolation induces a severe perception of loneliness and abandonment, these fears can exacerbate behavior disturbances in old-aged frail persons. Thus, these can be considered as indirect victims of SARS-COV-2.

Lower extremity amputations (LEA) are associated with a high mortality and medical expenditure. Diabetes accounts for 45% to 70% of LEA and is one of the most potent risk factors for peripheral artery diseases (PAD). The existence of a link between the recent relaxation of glycemic targets and the resurgence of LEA is suggested from the analysis of adult participants in the National Health and Nutrition Examination Survey (NHANES) between 2010 and 2015, when diabetes-related LEA increased by more than 25% associated with a decline in glycemic control. Indeed, in “the perfect wave” of NHANES, including the years 2007–2010, there was the highest number of diabetic people with hemoglobin A1c (HbA1c), non-high-density lipoprotein (HDL) cholesterol and blood pressure levels at their respective targets, associated with the lowest number of LEA. Until now, the ACCORD study, testing the role of aggressive vs conventional glucose control, and the LEADER trial, evaluating the effects of liraglutide versus placebo, have shown a reduced incidence of LEA in people with type 2 diabetes. The results of ongoing clinical trials involving glucagon-like peptide-1 receptor agonists (GLP-1RA, liraglutide or semaglutide) hopefully will tell us whether the wider use of these drugs may provide additional vascular benefits for diabetic people affected by PAD to decrease their risk of LEA.

Background Small vessels have the pivotal role for the brain's autoregulation. The arteriosclerosis-dependent alteration of the brain perfusion is one of the major determinants in small vessel disease. Endothelium distress can potentiate the flow dysregulation and lead to subcortical vascular dementia (sVAD). sVAD increases morbidity and disability. Epidemiological studies have shown that sVAD shares with cerebrovascular disease most of the common risk factors. The molecular basis of this pathology remains controversial. Purpose To detect the possible mechanisms between small vessel disease and sVAD, giving a broad vision on the topic, including pathological aspects, clinical and laboratory findings, metabolic process and cholinergic dysfunction. Methods We searched MEDLINE using different search terms ("vascular dementia", "subcortical vascular dementia", "small vessel disease", "cholinergic afferents", etc). Publications were selected from the past 20 years. Searches were extended to Embase, Cochrane Library, and LILIACS databases. All searches were done from January 1, 1998 up to January 31, 2018. Results A total of 560 studies showed up, and appropriate studies were included. Associations between traditional vascular risk factors have been isolated. We remarked that SVD and white matter abnormalities are seen frequently with aging and also that vascular and endothelium changes are related with age; the changes can be accelerated by different vascular risk factors. Vascular function changes can be heavily influenced by genetic and epigenetic factors. Conclusion Small vessel disease and the related dementia are two pathologies that deserve attention for their relevance and impact in clinical practice. Hypertension might be a historical problem for SVD and SVAD, but low pressure might be even more dangerous; CBF regional selective decrease seems to be a critical factor for small vessel disease-related dementia. In those patients, endothelium damage is a super-imposed condition. Several issues are still debatable, and more research is needed.

Introduction and Objectives Nonalcoholic fatty liver disease (NAFLD) can be considered one of the most common causes of liver disease in our days and is regarded as one of the newest vascular risk factors for cerebrovascular and other neurological diseases. Materials and methods We studied a group of neurological outpatients, divided into two homogenous groups based on the presence or absence of NAFLD. Results and conclusions We testified an independent relationship between NAFLD and common vascular risk factors (age, sex, educational level, BMI, cholesterol and lipid assessment, Hb1ac). At the same time, we ascertained an independent relationship between NAFLD and more recently recognized vascular risk factors, such as lack of folate, vitamin B12 and vitamin D-OH25, and increased levels of homocysteine. Finally, we have documented that NAFLD showed worse executive and frontal functions, and behavioral changes, such as depressive mood and anxiety, and apathy.

14 Pág. (This article belongs to the Special Issue Integrating Science on Xanthomonas and Xylella for Integrated Plant Disease Management), Xanthomonas citri pv. citri (Xcc) and X. citri pv. aurantifolii (Xca) are causal agents of Citrus Bacterial Canker (CBC), a devastating disease that severely affects citrus plants. They are harmful organisms not reported in Europe or the Mediterranean Basin. Host plants are in the Rutaceae family, including the genera Citrus, Poncirus, and Fortunella, and their hybrids. In addition, other genera of ornamental interest are reported as susceptible, but results are not uniform and sometimes incongruent. We evaluated the susceptibility of 32 ornamental accessions of the Rutaceae family belonging to the genera Citrus, Fortunella, Atalantia, Clausena, Eremocitrus, Glycosmis, Microcitrus, Murraya, Casimiroa, Calodendrum, and Aegle, and three hybrids to seven strains of Xcc and Xca. Pathotyping evaluation was assessed by scoring the symptomatic reactions on detached leaves. High variability in symptoms and bacterial population was shown among the different strains in the different hosts, indicative of complex host–pathogen interactions. The results are mostly consistent with past findings, with the few discrepancies probably due to our more complete experimental approach using multiple strains of the pathogen and multiple hosts. Our work supports the need to regulate non-citrus Rutaceae plant introductions into areas, like the EU and Mediterranean, that are currently free of this economically important pathogen., This research was funded ORPRAMed Project on “Risk assessment of introduction of Xanthomonas citri subsp. citri through commercial trade of ornamental rutaceous plants in the Mediterranean basin”, ERA-NET ARIMNET 2-Call 2015.C.B., V.C. acknowledge the University of Catania for support under the projects “Investigation of phytopathological problems of the main Sicilian productive contexts and eco-sustainable defense strategies” (PIA.CE.RI. 2020–2022 Linea 2-Research Project MEDIT-ECO.); “Emergent Pests and Pathogens and Relative Sustainable Strategies” (Progetto di ricerca di Ateneo 2018-2020). O.P. and I.R. acknowledge the European Union (ERDF, EAFRD) and Réunion regional council for support

Homocysteine (Hcy) is a sulfur-containing amino acid generated during methionine metabolism, accumulation of which may be caused by genetic defects or the deficit of vitamin B12 and folate. A serum level greater than 15 micro-mols/L is defined as hyperhomocysteinemia (HHcy). Hcy has many roles, the most important being the active participation in the transmethylation reactions, fundamental for the brain. Many studies focused on the role of homocysteine accumulation in vascular or degenerative neurological diseases, but the results are still undefined. More is known in cardiovascular disease. HHcy is a determinant for the development and progression of inflammation, atherosclerotic plaque formation, endothelium, arteriolar damage, smooth muscle cell proliferation, and altered-oxidative stress response. Conversely, few studies focused on the relationship between HHcy and small vessel disease (SVD), despite the evidence that mice with HHcy showed a significant end-feet disruption of astrocytes with a diffuse SVD. A severe reduction of vascular aquaporin-4-water channels, lower levels of high-functioning potassium channels, and higher metalloproteinases are also observed. HHcy modulates the N-homocysteinylation process, promoting a pro-coagulative state and damage of the cellular protein integrity. This altered process could be directly involved in the altered endothelium activation, typical of SVD and protein quality, inhibiting the ubiquitin-proteasome system control. HHcy also promotes a constant enhancement of microglia activation, inducing the sustained pro-inflammatory status observed in SVD. This review article addresses the possible role of HHcy in small-vessel disease and understands its pathogenic impact.

Purpose The diagnosis of vitamin D deficiency is based on the determination of total plasma 25-hydroxyvitamin D (25-OHD) concentrations, but the regulation of vitamin D 25-hydroxylation is not a major consideration and very little information is available on this activity. To check what factors could interfere with the activity of vitamin D-25-hydroxylase and thus alter the 25-OHD concentrations, we looked for potential correlations between 25-OHD and results of liver function tests in healthy adults. Methods This single-centre study was retrospective and consisted of evaluating the correlations between 25-OHD and the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), and bone alkaline phosphatase (BALP) in 349 healthy subjects aged from 18 to 65 years. In particular, in Group 1 (n = 119), we looked for correlations between 25OHD and all liver function tests and in Group 2 (n = 230) the correlation between 25OHD and BALP. Results In Group 1, we found no correlation between 25OHD and AST (r = − 0.03; p = 0.8), ALT (r = − 0.02; p = 0.91), GGT (r = − 0.08; p = 0.68), direct bilirubin (r = − 0.02; p = 0.89), indirect bilirubin (r = − 0.24; p = 0.21), and total bilirubin (r = − 0.24; p = 0.21) but one between 25OHD and ALP (r = − 0.2; p = 0.007); in Group 2, we found a significant negative correlation between 25-OHD and BALP (r = − 0.2; p = 0.0008). Conclusions The correlations that we found suggest that ALP and BALP might be involved in the regulation of vitamin D-25-hydroxylase activity, but further studies are mandatory to confirm our assumptions.

Hospitalization for major diabetes complications, including myocardial infarction, stroke, lower-extremity amputation, and end-stage kidney disease, is on the rise and represents a great health burden for patients with type 2 diabetes (T2D), in particular for older people. Newer glucose-lowering medications have generated some optimism on the possibility to influence the natural history of cardiorenal complications of T2D. This review summarizes work in the area of sodium–glucose cotransporter 2 inhibitors (SGLT-2i) treatment and prevention of cardiorenal complications in patients with T2D (major adverse cardiovascular events, hospitalization for heart failure, kidney outcomes), with a particular emphasis on the effect of age, the role of primary versus secondary prevention and the possible extension of their cardiorenal benefits to the entire class of SGLT-2i.

Background:Advanced neuroimaging can identify patients who can most benefit from reperfusion treatment, discriminating between ischemic core and penumbra area in a quick and accurate manner. Despite core-penumbra mismatch being an independent prognostic factor, computed tomography perfusion (CTP) assessment is still debated in hyperacute decision-making. The authors aimed to study a novel CTP mismatch score in emergency settings and to investigate its relation with clinical outcome in acute ischemic stroke patients treated with intravenous thrombolysis (IVT).Methods:Neuroimaging and clinical data of 226 consecutive acute ischemic stroke patients were analyzed. The study population was divided into 5 different CTP scores: (0) without perfusion deficit, (1) only penumbra, (2) penumbra > core, (3) core >= penumbra, (4) only core. For differences in outcome between treated and nontreated patients, and among CTP core-penumbra groups to be assessed, the authors have evaluated the outcome in terms of National Institutes of Health Stroke Scale (NIHSS) and modified Rankin scale (mRS) at discharge and symptomatic intracerebral hemorrhage.Results:A decrease in NIHSS was statistically greater in IVT-treated patients compared to nontreated patients showing only penumbra (Delta NIHSS%: 80.0% vs. 50.0%; P=0.0023) or no perfusion deficit (Delta NIHSS%: 89.4% vs. 61.5%; P=0.027) on CTP maps. The same trend was found in other groups without significant difference. A significant correlation was found in IVT patients between core/penumbra score and outcome in terms of Delta NIHSS (Kendall tau=-0.19; P=0.004).Conclusions:The authors proposed a novel immediate CTP assessment to score perfusion mismatch in emergency settings to guide clinicians' decision-making for aggressive treatment and to prevent stroke-related disability.

A meta-analysis of cardiorenal outcomes of sodium-glucose co-transporter-2 inhibitors (SGLT-2is) available in Europe or the United States in patients with type 2 diabetes (T2D) is presented. An electronic search up to 6 January 2021 was conducted to determine eligible trials. A total of eight cardiorenal outcomes trials of SGLT-2is (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin and sotagliflozin) were identified, with 65,587 patients. Data were analysed using a random effects model. Overall, SGLT-2is were associated with a 12% reduced risk of major adverse cardiovascular events (MACE; HR = 0.88; 95% CI, 0.83-0.93; Q statistic, p = .19), with no significant heterogeneity (p for interaction = .465) between subgroups of patients with or without cardiovascular disease (CVD). The risk of the composite renal outcome was significantly reduced by treatment with SGLT-2is (HR = 0.61, 95% CI, 0.54-0.70), with no significant heterogeneity of associations with outcome (I2 = 37%, p = .11), and no difference in the risk between patients with or without CVD (p for interaction = .665). SGLT-2is have moderate benefits on MACE and major benefits on the progression of diabetic kidney disease.

It is not known whether the current territorial organization for acute revascularization treatments in ischemic stroke patients guarantees similar time to treatment and functional outcomes among different levels of institutional stroke care. We aimed to assess the impact of time to treatment on functional outcomes in ischemic stroke patients who received intravenous thrombolysis (IVT) alone, bridging (IVT plus thrombectomy), or primary thrombectomy in level 1 and level 2 Stroke Units (SUs) in Triveneto, a geographical macroarea in Northeast of Italy. We conducted an analysis of data prospectively collected from 512 consecutive ischemic stroke patients who received IVT and/or mechanical thrombectomy in 25 SUs from September 17th to December 9th 2018. The favorable outcome measures were mRS score 0–1 and 0–2 at 3months. The unfavorable outcome measures were mRS score 3–5 and death at 3months. We estimated separately the possible association of each variable for time to treatment (onset-to-door, door-to-needle, onset-to-needle, door-to-groin puncture, needle-to-groin puncture, and onset-to-groin puncture) with 3-month outcome measures by calculating the odds ratios (ORs) with two-sided 95% confidence intervals (CI) after adjustment for pre-defined variables and variables with a probability value ≤ 0.10 in the univariate analysis for each outcome measure. Distribution of acute revascularization treatments was different between level 1 and level 2 SUs (p < 0.001). Among 182 patients admitted to level 1 SUs (n = 16), treatments were IVT alone in 164 (90.1%), bridging in 12 (6.6%), and primary thrombectomy in 6 (3.3%) patients. Among 330 patients admitted to level 2 SUs (n = 9), treatments were IVT alone in 219 (66.4%), bridging in 74 (22.4%), and primary thrombectomy in 37 (11.2%) patients. Rates of excellent outcome (51.4% vs 45.9%), favorable outcome (60.1% vs 58.7%), unfavorable outcome (33.3% vs 33.8%), and death (9.8% vs 11.3%) at 3months were similar between level 1 and 2 SUs. No significant association was found between time to IVT alone (onset-to-door, door-to-needle, and onset-to-needle) and functional outcomes. After adjustment, door-to-needle time ≤ 60min (OR 4.005, 95% CI 1.232–13.016), shorter door-to-groin time (OR 0.991, 95% CI 0.983–0.999), shorter needle-to-groin time (OR 0.986, 95% CI 0.975–0.997), and shorter onset-to-groin time (OR 0.994, 95% CI 0.988–1.000) were associated with mRS 0–1. Shorter door-to-groin time (OR 0.991, 95% CI 0.984–0.998), door-to-groin time ≤ 90min (OR 12.146, 95% CI 2.193–67.280), shorter needle-to-groin time (OR 0.983, 95% CI 0.972–0.995), and shorter onset-to-groin time (OR 0.993, 95% CI 0.987–0.999) were associated with mRS 0–2. Longer door-to-groin time (OR 1.007, 95% CI 1.001–1.014) and longer needle-to-groin time (OR 1.019, 95% CI 1.005–1.034) were associated with mRS 3–5, while door-to-groin time ≤ 90min (OR 0.229, 95% CI 0.065–0.808) was inversely associated with mRS 3–5. Longer onset-to-needle time (OR 1.025, 95% CI 1.002–1.048) was associated with death. Times to treatment influenced the 3-month outcomes in patients treated with thrombectomy (bridging or primary). A revision of the current territorial organization for acute stroke treatments in Triveneto is needed to reduce transfer time and to increase the proportion of patients transferred from a level 1 SU to a level 2 SU to perform thrombectomy.

Background Female sexual dysfunctions (FSDs) are frequent concerns in women with type 1 diabetes (T1D), which is frequently associated with other autoimmune diseases (ADs). Aim To assess sexual function in young type 1 diabetic women with or without additional ADs. Methods Women with T1D aged 18–35 years with a stable couple relationship and no oral contraceptive use were enrolled. Diabetic women with concomitant ADs were also identified. All women completed the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale. Outcomes The main outcome was the prevalence of FSD. The FSFI-single domain scores were also evaluated in diabetic women with or without additional ADs. Results The global population included 154 diabetic women, of whom 66 (42%) had at least one additional AD. The prevalence of FSD was similar among diabetic women with and those without (30% vs 32%, P = .980) additional ADs. The FSFI-desire score was significantly lower among diabetic women with concomitant ADs than those without ADs [median (interquartile range), 4.1 (3.6, 4.8) vs 4.6 (4.0, 5.0), P = .042]. Clinical Implications An early evaluation of sexual function in women with T1D and concomitant ADs should be encouraged. Strengths & Limitations Major strengths are the use of 2 validated tools to diagnose FSD and the relatively large number of subjects investigated. The limitations include the cross-sectional nature of the study, which does not allow to make inference regarding the cause and effect. Conclusion Diabetic women with additional ADs show an impairment in sexual desire as compared with those suffering only from diabetes. Longo M, Cirillo P, Scappaticcio L, et al. Female Sexual Function in Young Women With Type 1 Diabetes and Additional Autoimmune Diseases. J Sex Med 2021;18:219–223.

Background Dietary regimens have so far been studied as possible determinants of semen quality and fertility. The aim of this study was to evaluate the effects of a Mediterranean diet, as compared with a low-fat diet, on seminal parameters of young healthy adults from southern Italy. Methods In a randomized controlled trial, 160 young adults aged 18-30 years were assigned to Mediterranean diet (N.=80) or a low-fat diet (N.=80). The primary outcome measures were changes in semen parameters after six months. Results Mean age of participants in the study was 24.7 years. There was no difference in baseline semen parameters of men randomized to Mediterranean diet or low-fat diet. After the entire follow-up, participants in both groups showed a significant increase in sperm concentration and sperm total count, with significant differences favoring the Mediterranean diet group (sperm concentration, 1.93 M/mL 95% CI [1.22 to 3.64], P=0.027; total sperm count 8.02 M 95% CI [1.51 to 15.45], P=0.035). No differences in other semen parameters were found between groups. Conclusions In healthy young adults, the consumption of Mediterranean diet was associated with an improvement of both sperm concentration and total count, as compared with a low-fat diet.

Brain electrical activity in acute ischemic stroke is related to the hypoperfusion of cerebral tissue as manifestation of neurovascular coupling. EEG could be applicable for bedside functional monitoring in emergency settings. We aimed to investigate the relation between hyper-acute ischemic stroke EEG changes, measured with bedside wireless-EEG, and hypoperfused core-penumbra CT-perfusion (CTP) volumes. In addition, we investigated the association of EEG and CTP parameters with neurological deficit measured by NIHSS. We analyzed and processed EEG, CTP and clinical data of 31 anterior acute ischemic stroke patients registered within 4.5 h from symptom onset. Delta/alpha ratio (DAR), (delta + theta)/(alpha + beta) ratio (DTABR) and relative delta power correlated directly (ρ = 0.72; 0.63; 0.65, respectively), while alpha correlated inversely (ρ = − 0.66) with total hypoperfused volume. DAR, DTBAR and relative delta and alpha parameters also correlated with ischemic core volume (ρ = 0.55; 0.50; 0.59; − 0.51, respectively). The same EEG parameters and CTP volumes showed significant relation with NIHSS at admission. The multivariate stepwise regression showed that DAR was the strongest predictor of NIHSS at admission (p < 0.001). The results of this study showed that hyper-acute alterations of EEG parameters are highly related to the extent of hypoperfused tissue highlighting the value of quantitative EEG as a possible complementary tool in the evaluation of stroke severity and its potential role in acute ischemic stroke monitoring.

Purpose The fear of COVID-19 infection may discourage patients from going to the hospital even in case of sudden onset of disabling symptoms. There is growing evidence of the reduction of stroke admissions and higher prevalence of severe clinical presentation. Yet, no studies have investigated the perfusion pattern of acute strokes admitted during the lockdown. We aimed to evaluate the effects of the COVID-19 pandemic on hyper-acute stroke CT perfusion (CTP) pattern during the first months of the pandemic in Italy. Methods In this retrospective observational study, we analyzed CTP images and clinical data of ischemic stroke patients admitted between 9 March and 2 June 2020 that underwent CTP (n = 30), to compare ischemic volumes and clinical features with stroke patients admitted during the same period in 2019 (n = 51). In particular, CTP images were processed to calculate total hypoperfused volumes, core volumes, and mismatch. The final infarct volumes were calculated on follow-up CT. Results Significantly higher total CTP hypoperfused volume (83.3 vs 18.5 ml, p = 0.003), core volume (27.8 vs 1.0 ml, p < 0.001), and unfavorable mismatch (0.51 vs 0.91, p < 0.001) were found during the COVID-19 period compared to no-COVID-19 one. The more unfavorable perfusion pattern at admission resulted in higher infarct volume on follow-up CT during COVID-19 (35.5 vs 3.0 ml, p < 0.001). During lockdown, a reduction of stroke admissions (− 37%) and a higher prevalence of severe clinical presentation (NIHSS ≥ 10; 53% vs 36%, p = 0.029) were observed. Conclusion The results of CTP analysis provided a better insight in the higher prevalence of major severity stroke patients during the COVID-19 period.

There is growing research interest on identification of CT Perfusion (CTP) parameters that predict the outcome in acute ischemic stroke patients. The aim of this study is to produce the model, based on core-penumbra related parameters assessed by CTP processing and commonly used clinical prediction factors, to predict the final infarct volume in thrombolysis-treated anterior circulation wake-up stroke (WUS) patients. The study was conducted on 51 consecutive wake-up ischemic stroke patients. The model for the predictive estimation of final ischemic volume was determined by using the Least Absolute Shrinkage and Selection Operator (LASSO) regularized least-squares regression. The results showed that CTP core volume and CTP total ischemic volume at admission, together with ASPECT score predict the final infarct lesion volume. In particular, the identified model presented 5-fold cross-validation root mean square error RMSE of 8.1 ml and the coefficient of determination (R2=0.94) on our dataset. The results should be confirmed in a lager study. In conclusion, in this study we preliminarily identified a predictive model to estimate final ischemic lesion volume in thrombolysis treated wake-up stroke patients.

Hypohydration may be associated with vascular diseases, poor prognosis and worse outcomes in stroke. The underlying mechanisms have not yet been completely investigated, although some studies suggested potential associations with brain perfusion and collaterals status. Despite the potentially different mechanisms promoting serum or urine biomarkers of hypohydration, few studies have investigated both markers separately. A prospective descriptive study was conducted in stroke patients admitted to a stroke unit 15 and “underhydrated” (UND) if urine osmolality was >500 mOsm/kg. CTP images were processed to calculate core, penumbra, their mismatch and total hypoperfused volume. Forty-six patients were included and were grouped according to hydration status. Despite no different NIHSS at baseline, at CTP HYP was independently associated with core-penumbra mismatch (β: −0.157, 95% CI: −0.305 to −0.009; p =.04), while UND was independently associated with the total hypoperfused volume (β: 31.502, 95% CI: 8.522‒54.481; p =.01). Using CTP imaging, this study proposes a physiological insight of some possible mechanisms associated with the better outcomes observed in acute stroke patients when properly hydrated. These results suggest different associations between hydration status and CTP parameters depending on serum or urine biomarkers in the hyper-acute phase and encourage the association between hydration status and stroke characteristics.

Aim: To investigate the rate of antibiotic resistance and its main risk factors in a population of patients with diabetic foot infection (DFI) during the COVID-19 pandemic, in comparison with the population of 2019. Methods: Two hundred and twenty-five patients with DFI were admitted in a tertiary care center from January 2019 to December 2020. Antibiotic resistance was evaluated by microbiological examination of soft tissues’ or bone's biopsy. Results: Compared with 2019 group (n = 105), 2020 group (n = 120) had a significantly higher prevalence of antibiotic resistance [2019 vs 2020, 36% vs 63%, P

Background: When it comes to critical early post-acute TIA/stroke phase, there is a lack of a comprehensive multi-parametric telemonitoring system. The COVID-19 emergency, its related global mobility restrictions and fear of hospitalization further highlighted the need of a comprehensive solution. Objective: We aimed to design and test a pragmatic e-Health system based on multiparametric telemonitoring to support of TIA/stroke patients in sub-acute phase during the COVID-19 pandemic. Methods: We proposed a telemonitoring system and protocol for TIA/minor stroke patients during COVID-19 pandemic for patients at risk of stroke recurrence. This system involves the use of portable devices for BP/HR/SpO2/temperature sensing, panic-button, gateway, and a dedicated ICT platform. The protocol is a 14-day multiparametric telemonitoring, therapy, and emergency intervention based on vital sign alteration notifications. We conducted a proof-of-concept validation test on 8 TIA/minor stroke patients in the early post-acute phase (< 14 days from ischemic event). Results: The proposed solution allowed to promptly and remotely identify vital sign alterations at home during the early post-acute phase, allowing therapy and behavioral intervention adjustments. Also, we observed a significant improvement of quality of life, as well as a significant reduction of anxiety and depression status. TUQ showed ease of use, good interface quality and high user satisfaction of the proposed solution. The 3-month follow-up showed total adherence of prescribed therapy and no stroke/TIA recurrence or other emergency department admissions. Conclusion: The proposed e-Health solution and telemonitoring protocol may be highly useful for early post-acute remote patient management, thus supporting constant monitoring and patient adherence to the treatment pathway, especially during the COVID-19 emergency.

Sexual health is a fundamental component of human well-being. Any disease threating human well-being may also impair both male and female sexual life. The most common “non-communicable diseases” (NCDs) in the world are strictly associated with sexual dysfunctions as they share most risk factors and pathogenetic mechanisms. Chronic low-grade inflammation, together with oxidative stress and endothelial dysfunction, represents a common predisposing pathological condition for both chronic diseases and sexual dysfunctions. Mediterranean diet, based on high intake of plant-based foods, olive oil as the main source of fat, low-to-moderate intake of fish, dairy products, and poultry, low consumption of red or processed meat, and low to- moderate consumption of wine with meals has showed several beneficial effects on cardio-metabolic and sexual health. The adoption of healthy lifestyles, including Mediterranean dietary pattern and regular physical activity helps reducing inflammation, endothelial dysfunction, and oxidative stress – all of which are desirable target to achieve for a better health and sexual life., Atti della Accademia Peloritana dei Pericolanti - Classe di Scienze Medico-Biologiche, Vol 108, No 2 (2020)

Background: Abnormal liver blood tests (LBTs) in hyperthyroid patients are not uncommonly encountered. One major adverse event of antithyroid drug (ATD) therapy is drug-induced hepatotoxicity. Abnormal LBT in the hyperthyroidism scenario is a main diagnostic and therapeutic dilemma. We aimed to assess the prevalence and the response to ATD therapy of LBT abnormalities in newly diagnosed and uncomplicated hyperthyroidism through a systematic review and meta-analysis. Methods: A literature search was performed reporting LBTs at presentation and after ATD therapy in hyperthyroid patients. A proportion meta-analysis was performed with random-effects model. Pooled data were presented with 95% confidence intervals (CI). I2 statistic index was used to quantify the heterogeneity. Sensitivity analyses for prevalence of hyperthyroid patients with at least one abnormal LBT were performed. p-Value of

Rationale: Pulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome. Circulating BMP9 (bone morphogenetic protein 9) is emerging as an important regulator of pulmonary vascular homeostasis. Objectives:To determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity and whether loss of endogenous BMP9 occurs during LPS challenge. Methods: A BMP9-neutralizing antibody was administrated to healthy adult mice, and lung vasculature was examined. Potential mechanisms were delineated by transcript analysis in human lung endothelial cells. The impact of BMP9 administration was evaluated in a murine acute lung injury model induced by inhaled LPS. Levels of BMP9 were measured in plasma from patients with sepsis and from endotoxemic mice. Measurements and Main Results: Subacute neutralization of endogenous BMP9 in mice (N = 12) resulted in increased lung vascular permeability (P = 0.022), interstitial edema (P = 0.0047), and neutrophil extravasation (P = 0.029) compared with IgG control treatment (N = 6). In pulmonary endothelial cells, BMP9 regulated transcriptome pathways implicated in vascular permeability and cell-membrane integrity. Augmentation of BMP9 signaling in mice (N = 8) prevented inhaled LPS-induced lung injury (P = 0.0027) and edema (P < 0.0001). In endotoxemic mice (N = 12), endogenous circulating BMP9 concentrations were markedly reduced, the causes of which include a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human patients with sepsis (N = 10), circulating concentratons of BMP9 were also markedly reduced (P < 0.0001). Conclusions: Endogenous circulating BMP9 is a pulmonary endothelial-protective factor, downregulated during inflammation. Exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in lung injury.

Alternaria alternata is a fungus that causes a serious disease in susceptible genotypes of citrus, particularly in mandarins. The Alternaria citri toxin (ACT) produced by the pathogen induces necrotic lesions on young leaves and fruits, defoliation and fruit drop. Here, we describe two methods of marker-assisted selection (MAS) that could be used for the early identification of Alternaria brown spot (ABS)-resistant mandarin hybrids. The first method is based on a nested PCR coupled to high resolution melting (HRM) analysis at the SNP08 locus, which is located at 0.4 cM from the ABS resistance locus, and was previously indicated as the most suitable for the selection of ABS-resistant hybrids. The method was validated on 41 mandarin hybrids of the CREA germplasm collection, and on 862 progenies generated from five crosses involving different susceptible parents. Four out of five populations showed Mendelian segregation at the analyzed locus, while a population involving Murcott tangor as male parent showed distorted segregation toward the susceptible hybrids. The second method is based on a cleaved amplified polymorphic sequences (CAPS) marker that was developed using the same primers as the nested PCR at the SNP08 locus, coupled with BccI restriction enzyme digestion. To verify the reliability of the two genotyping methods, in vitro leaf phenotyping was carried out by inoculating A. alternata spores onto young leaves of 101 hybrids, randomly chosen among the susceptible and resistant progenies. The phenotyping confirmed the SNP08 genotyping results, so the proposed method of selection based on HRM or CAPS genotyping could be routinely used as an alternative to KBioscience competitive allele specific polymerase chain reaction (KASPar) single nucleotide polymorphism (SNP) genotyping system to improve citrus breeding programs. While the study confirmed that the SNP08 marker is a reliable tool for MAS of new citrus hybrids with different genetic backgrounds, it also identified a small group of genotypes where the resistance mechanism requires further investigation.