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Closed-loop models of the interactions between blood pressure (BP) and heart rate variations allow for estimation of baroreflex sensitivity (feedback effects of BP changes on heart rate) while also considering the feedforward effects of heart rate on BP. Our study is aimed at comparing modulations of feedback and feedforward couplings over 24 h in normotensive and hypertensive subjects, by assessing closed-loop baroreflex models in ambulatory conditions. Continuous intra-arterial BP recordings were performed for 24 h in eight normotensive and eight hypertensive subjects. Systolic BP (SBP) and pulse interval (PI) beat-by-beat series were analyzed by an autoregressive moving average model over consecutive 6-min running windows, estimating closed-loop feedback and feedforward gains in each window. The open-loop feedback gain was estimated for comparison. Normotensive and hypertensive patients were compared during wake (18:00–22:00) and sleep (23:00–5:00) periods by a mixed-effect linear model at p < 0.05. In both groups feedback (feedforward) gain averaged values were higher (lower) in sleep than in wake. Moreover, the closed-loop feedback gain was higher in normotensive subjects both in wake and sleep, whereas the closed-loop feedforward gain was higher in hypertensive subjects during sleep. By contrast, no significant differences were found between the normotensive and hypertensive groups for the open-loop feedback gain. Therefore, the closed-loop SBP-PI model can detect circadian alterations in the feedforward gain of PI on SBP and derangements of spontaneous baroreflex sensitivity in hypertension not detectable with the open-loop approach. These findings may help to obtain a more comprehensive assessment of the autonomic dysfunction underlying hypertension and for the in-depth evaluation of the benefits of rehabilitation procedures on autonomic cardiovascular modulation.

Background Several devices have been proposed to assess arterial stiffness in clinical daily use over the past few years, by estimating aortic pulse wave velocity (PWV) from a single measurement of brachial oscillometric blood pressure, using patented algorithms. It is uncertain if these systems are able to provide additional elements, beyond the contribution carried by age and blood pressure levels, in the definition of early vascular damage expressed by the stiffening of the arterial wall. Methods and Results The aim of our study was to compare the estimated algorithm‐based PWV values, provided by the Mobil‐O‐Graph system, with the standard noninvasive assessment of aortic PWV in patients with Marfan syndrome (ie, in subjects characterized by premature aortic stiffening and low blood pressure values). Aortic stiffness was simultaneously evaluated by carotid‐femoral PWV with a validated arterial tonometer and estimated with an arm cuff–based ambulatory blood pressure monitoring Mobil‐O‐Graph device on 103 patients with Marfan syndrome (50 men; mean±SD age, 38±15 years). Aortic PWV, estimated by the Mobil‐O‐Graph, was significantly (P

Detrended fluctuation analysis (DFA) is a popular tool in physiological and medical studies for estimating the self-similarity coefficient, α, of time series. Recent researches extended its use for evaluating multifractality (where α is a function of the multifractal parameter q) at different scales n. In this way, the multifractal-multiscale DFA provides a bidimensional surface α(q,n) to quantify the level of multifractality at each scale separately. We recently showed that scale resolution and estimation variability of α(q,n) can be improved at each scale n by splitting the series into maximally overlapped blocks. This, however, increases the computational load making DFA estimations unfeasible in most applications. Our aim is to provide a DFA algorithm sufficiently fast to evaluate the multifractal DFA with maximally overlapped blocks even on long time series, as usually recorded in physiological or clinical settings, therefore improving the quality of the α(q,n) estimate. For this aim, we revise the analytic formulas for multifractal DFA with first- and second-order detrending polynomials (i.e., DFA1 and DFA2) and propose a faster algorithm than the currently available codes. Applying it on synthesized fractal/multifractal series we demonstrate its numerical stability and a computational time about 1% that required by traditional codes. Analyzing long physiological signals (heart-rate tachograms from a 24-h Holter recording and electroencephalographic traces from a sleep study), we illustrate its capability to provide high-resolution α(q,n) surfaces that better describe the multifractal/multiscale properties of time series in physiology. The proposed fast algorithm might, therefore, make it easier deriving richer information on the complex dynamics of clinical signals, possibly improving risk stratification or the assessment of medical interventions and rehabilitation protocols.

Law no. 281, enacted by the Italian Parliament in 1991, was the first that aimed at managing urban free-roaming cats living in colonies, without killing and/or moving them from their site. It had been anticipated by the Lazio Regional Law no. 63/1988 and subsequently refined by the Lazio Regional Law no. 34/1997. These laws introduced: (i) the cats' right to live free and safe; (ii) the compulsory neutering of cats by the Veterinary Services of the Local Health Unit; (iii) the institutionalization of cat caretakers. Within this context, this paper intends to evaluate the effects of the application of the Italian laws on management of urban free-roaming cats for the years 1988 to 2018. To this end, some indicators have been built and applied to our activity data: number of censused colonies and number of cats; number of stable colonies due to neutering; number of hygiene and sanitary notifications; number of notifications to check cat welfare; number of bites by unowned free-roaming cats; number of notifications of cat poisoning. The number of citizens' requests for institutional interventions by public veterinary services in cat colonies management and, accordingly, the detection of cat colonies yet unknown, seem to confirm the interest of people to control the cat colonies in Rome in a humanitarian way, as evidenced in our data. This fact/phenomenon should be analyzed in its multiple dimensions, also including the many changes and social unrests which have affected the human-cat relationship in the last 30 years.

Objective: To investigate if invasively measured aortic pulse wave velocity (PWV) is accurately estimated by non-invasive methods purporting to assess it. Methods: One-hundred and two patients (30% female, age 65 ± 13 years) planned to undertake coronary angiography were evaluated with the following non-invasive devices: BPLab (Petr Telegin, Russia), Complior Analyse (Alam Medical, France), Mobil-O-Graph (IEM, Germany), pOpmètre (Axelife, France), PulsePen-ET, PulsePen-ETT (Diatecne, Italy) and SphygmoCor (AtCor, Australia). Aortic PWV was measured by aortic catheterization and simultaneous measurement of pressure waves above the aortic valve and at the aortic bifurcation (FS-Stiffcath, Flag Vascular, Italy). Results: The devices evaluating carotid-femoral PWV showed a very strong agreement between each other (r2 > 0.65) and with invasive aortic PWV (mean difference ± SD with invasive PWV: −0.73 ± 2.83 m/s (r2 = 0.41) for Complior-Analyse; 0.20 ± 2.54 m/s (r2 = 0.51) for PulsePen-ETT; −0.04 ± 2.33 m/s (r2 = 0.61) for PulsePen-ET; −0.61 ± 2.57 m/s (r2 = 0.49) for SphygmoCor). The finger-toe PWV, evaluated by the pOpmètre, and the PWV measured by BPLab showed a weak relationship with invasive PWV (respectively r 2 =0.12, 0.05), with carotid-femoral PWV measurements (r 2 =0.11, 0.010) and with age (r 2 =0.10, 0.06). PWV estimated with Mobil-O-Graph through a proprietary algorithm showed a good agreement with invasive PWV (mean difference ± SD = −1.01 ± 2.54 m/s; r2 = 0.51) and appeared to be strictly dependent on age-squared and peripheral systolic blood pressure (r2 > 0.99). Conclusions: Methods estimating carotid-femoral PWV should be considered the only non-invasive approach to reliably assess aortic stiffness. Aortic PWV values estimated by Mobil-O-Graph algorithm are also significantly related to invasive PWV, but do not offer any additional information on top of what provided by age and systolic blood pressure levels.

In the neocortex, critical periods (CPs) of plasticity are closed following the accumulation of perineuronal nets (PNNs) around parvalbumin (PV)-positive inhibitory interneurons. However, how PNNs tune cortical function and plasticity is unknown. We found that PNNs modulated the gain of visual responses and γ-oscillations in the adult mouse visual cortex in vivo, consistent with increased interneuron function. Removal of PNNs in adult V1 did not affect GABAergic neurotransmission from PV cells, nor neuronal excitability in layer 4. Importantly, PNN degradation coupled to sensory input potentiated glutamatergic thalamic synapses selectively onto PV cells. In the absence of PNNs, increased thalamic PV-cell recruitment modulated feed-forward inhibition differently on PV cells and pyramidal neurons. These effects depended on visual input, as they were strongly attenuated by monocular deprivation in PNN-depleted adult mice. Thus, PNNs control visual processing and plasticity by selectively setting the strength of thalamic recruitment of PV cells.

The long-underestimated role of extracellular vesicles in cancer is now reconsidered worldwide by basic and clinical scientists, who recently highlighted novel and crucial activities of these moieties. Extracellular vesicles are now considered as king transporters of specific cargoes, including molecular components of parent cells, thus mediating a wide variety of cellular activities both in normal and neoplastic tissues. Here, we discuss the multifunctional activities and underlying mechanisms of extracellular vesicles in neuroblastoma, the most frequent common extra-cranial tumor in childhood. The ability of extracellular vesicles to cross-talk with different cells in the tumor microenvironment and to modulate an anti-tumor immune response, tumorigenesis, tumor growth, metastasis and drug resistance will be pinpointed in detail. The results obtained on the role of extracellular vesicles may represent a panel of suggestions potentially useful in practice, due to their involvement in the response to chemotherapy, and, moreover, their ability to predict resistance to standard therapies—all issues of clinical relevance.

Multiple myeloma (MM) is a hematological disease characterized by the proliferation and accumulation of malignant plasmacells (PCs) in the bone marrow (BM). Despite widespread use of high-dose chemotherapy in combination with autologous stem cell transplantation (ASCT) and the introduction of novel agents (immunomodulatory drugs, IMiDs, and proteasome inhibitors, PIs), the prognosis of MM patients is still poor. CD38 is a multifunctional cell-surface glycoprotein with receptor and ectoenzymatic activities. The very high and homogeneous expression of CD38 on myeloma PCs makes it an attractive target for novel therapeutic strategies. Several anti-CD38 monoclonal antibodies have been, or are being, developed for the treatment of MM, including daratumumab and isatuximab. Here we provide an in-depth look atCD38 biology, the role of CD38 in MM progression and its complex interactions with the BM microenvironment, the importance of anti-CD38 monoclonal antibodies, and the main mechanisms of antibody resistance. We then review a number of multiparametric flow cytometry techniques exploiting CD38 antigen expression on PCs to diagnose and monitor the response to treatment in MM patients.

Monoclonal antibodies (mAbs) were initially considered as a possible “magic bullet” for in vivo elimination of tumor cells. mAbs represented the first step: however, as they were murine in nature (the earliest experience on the field), they were considered unfit for human applications. This prompted the development of techniques for cloning the variable regions of conventional murine antibodies, genetically mounted on human IgG. The last step in this years-long process was the design for the preparation of fully human reagents. The choice of the target molecule was also problematic, since cancer-specific targets are quite limited in number. To overcome this obstacle in the planning phases of antibody-mediated therapy, attention was focused on a set of normal molecules, whose quantitative distribution may balance a tissue-dependent generalized expression. The results and clinical success obtained with anti-CD20 mAbs revived interest in this type of strategy. Using multiple myeloma (MM) as a tumor model was challenging first of all because the plasma cells and their neoplastic counterpart eluded the efforts of the Workshop on Differentiation Antigens to find a target molecule exclusively expressed by these cells. For this reason, attention was turned to surface molecules which fulfill the requisites of being reasonably good targets, even if not specifically restricted to tumor cells. In 2009, we proposed CD38 as a MM target in virtue of its expression: it is absent on early hematological progenitors, has variable but generalized limited expression by normal cells, but is extremely high in plasma cells and in myeloma. Further, regulation of its expression appeared to be dependent on a variety of factors, including exposure to all-trans retinoic acid (ATRA), a potent and highly specific inducer of CD38 expression in human promyelocytic leukemia cells that are now approved for in vivo use. This review discusses the history of human CD38, from its initial characterization to its targeting in antibody-mediated therapy of human myeloma.

Multiple myeloma (MM) derives from malignant transformation of plasma cells (PC), which accumulate in the bone marrow (BM), where microenvironment supports tumor growth and inhibits anti-tumor immune responses. Adenosine (ADO), an immunosuppressive molecule, is produced within MM patients' BM by adenosinergic ectoenzymes, starting from ATP (CD39/CD73) or NAD+ [CD38/CD203a(PC-1)/CD73]. These ectoenzymes form a discontinuous network expressed by different BM cells. We investigated the expression and function of ectoenzymes on microvesicles (MVs) isolated from BM plasma samples of patients with MM, using asymptomatic forms of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) as controls. The percentage of MVs expressing ectoenzymes at high levels was higher when derived from MM patients than controls. BM CD138+ PC from MM patients expressed high levels of all ectoenzymes. Paired MVs samples confirmed a higher percentage of MVs with high ectoenzymes expression in MM patients than controls. Pooled MVs from MM patients or controls were tested for ADO production. The catabolism of ATP, NAD+, ADPR and AMP to ADO was higher in MVs from MM patients than in those from controls. In conclusion, our results confirmed the hypothesis that MVs in MM niche are main contributor of ADO production. The ability of MVs to reach biological fluids strongly support the view that MVs may assume diagnostic and pathogenetic roles.

Background Acute exposure to high‐altitude hypobaric hypoxia induces a blood pressure rise in hypertensive humans, both at rest and during exercise. It is unclear whether this phenomenon reflects specific blood pressure hyperreactivity or rather an upward shift of blood pressure levels. We aimed at evaluating the extent and rate of blood pressure rise during exercise in hypertensive subjects acutely exposed to high altitude, and how these alterations can be counterbalanced by antihypertensive treatment. Methods and Results Fifty‐five subjects with mild hypertension, double‐blindly randomized to placebo or to a fixed‐dose combination of an angiotensin‐receptor blocker (telmisartan 80 mg) and a calcium‐channel blocker (nifedipine slow release 30 mg), performed a cardiopulmonary exercise test at sea level and after the first night's stay at 3260 m altitude. High‐altitude exposure caused both an 8 mm Hg upward shift (P

Introduction: The observed association between depressive symptoms and cognitive performances has not been previously clarified in patients with amyotrophic lateral sclerosis (pALS). In fact, the use of cognitive measures often not accommodating for motor disability has led to heterogeneous and not conclusive findings about this issue. The aim of the present study was to evaluate the relationship between cognitive and depressive/anxiety symptoms by means of the recently developed Edinburgh Cognitive and Behavioral ALS Screen (ECAS), a brief assessment specifically designed for pALS.Methods: Sample included 168 pALS (114 males, 54 females); they were administered two standard cognitive screening tools (FAB; MoCA) and the ECAS, assessing different cognitive domains, including ALS-specific (executive functions, verbal fluency, and language tests) and ALS non-specific subtests (memory and visuospatial tests). Two psychological questionnaires for depression and anxiety (BDI; STAI/Y) were also administered to patients. Pearson’s correlation coefficient was used to assess the degree of association between cognitive and psychological measures.Results: Depression assessment negatively correlated with the ECAS, more significantly with regard to the executive functions subdomain. In particular, Sentence Completion and Social Cognition subscores were negatively associated with depression levels measured by BDI total score and Somatic-Performance symptoms subscore. Conversely, no significant correlations were observed between depression level and cognitive functions as measured by traditional screening tools for frontal abilities (FAB) and global cognition (MoCA) assessment. Finally, no significant correlations were observed between state/trait anxiety and the ECAS.Discussion and conclusion: This represents the first study focusing on the relationship between cognitive and psychological components in pALS by means of the ECAS, the current gold standard for ALS cognitive-behavioral assessment. If confirmed by further investigations, the observed association between depression and executive functions suggests the need for a careful screening and treatment of depression, to avoid overestimation of cognitive involvement and possibly improve cognitive performances in ALS.

BACKGROUND:In pulmonary hypertension (PH), both wedge pressure elevation (PAWP) and a precapillary component may affect right ventricular (RV) afterload. These changes may contribute to RV failure and prognosis. We aimed at describing the different haemodynamic phenotypes of patients with PH due to left heart disease (LHD) and at characterizing the impact of pulmonary haemodynamics on RV function and outcome PH-LHD. METHODS:Patients with PH-LHD were compared with treatment-naïve idiopathic/heritable pulmonary arterial hypertension (PAH, n = 35). PH-LHD patients were subdivided in Isolated post-capillary PH (IpcPH: diastolic pressure gradient, DPG3 WU, n = 27), and "intermediate" PH-LHD (either DPG

Iron overload-related heart failure is the principal cause of death in transfusion dependent patients, including those with Thalassemia Major. Linking cardiac siderosis measured by T2* to therapy improves outcomes. T1 mapping can also measure iron; preliminary data suggests it may have higher sensitivity for iron, particularly for early overload (the conventional cut-point for no iron by T2* is 20ms, but this is believed insensitive). We compared T1 mapping to T2* in cardiac iron overload.In a prospectively large single centre study of 138 Thalassemia Major patients and 32 healthy controls, we compared T1 mapping to dark blood and bright blood T2* acquired at 1.5T. Linear regression analysis was used to assess the association of T2* and T1. A "moving window" approach was taken to understand the strength of the association at different levels of iron overload.The relationship between T2* (here dark blood) and T1 is described by a log-log linear regression, which can be split in three different slopes: 1) T2* low, 30ms, weak relationship. All subjects with T2*20ms, 38% had low T1 with most of the subjects in the T2* range 20-30ms having a low T1.In established cardiac iron overload, T1 and T2* are concordant. However, in the 20-30ms T2* range, T1 mapping appears to detect iron. These data support previous suggestions that T1 detects missed iron in 1 out of 3 subjects with normal T2*, and that T1 mapping is complementary to T2*. The clinical significance of a low T1 with normal T2* should be further investigated.

BACKGROUND AND OBJECTIVE:The presence of executive deficits in patients with Amyotrophic Lateral Sclerosis is well established, even if standardized measures are difficult to obtain due to progressive physical disability of the patients. We present clinical data concerning a newly developed measure of cognitive flexibility, administered by means of Eye-Tracking (ET) technology in order to bypass verbal-motor limitations. METHODS:21 ALS patients and 21 age-and education-matched healthy subjects participated in an ET-based cognitive assessment, including a newly developed test of cognitive flexibility (Arrows and Colors Cognitive Test-ACCT) and other oculomotor-driven measures of cognitive functions. A standard screening of frontal and working memory abilities and global cognitive efficiency was administered to all subjects, in addition to a psychological self-rated assessment. For ALS patients, a clinical examination was also performed. RESULTS:ACCT successfully discriminated between patients and healthy controls, mainly concerning execution times obtained at different subtests. A qualitative analysis performed on error distributions in patients highlighted a lower prevalence of perseverative errors, with respect to other type of errors. Correlations between ACCT and other ET-based frontal-executive measures were significant and involved different frontal sub-domains. Limited correlations were observed between ACCT and standard 'paper and pencil' cognitive tests. CONCLUSIONS:The newly developed ET-based measure of cognitive flexibility could be a useful tool to detect slight frontal impairments in non-demented ALS patients by bypassing verbal-motor limitations through the oculomotor-driven administration. The findings reported in the present study represent the first contribution towards the development of a full verbal-motor free executive test for ALS patients.

Objective: To compare the short-term repeatability of aortic pulse wave velocity (PWV) measures obtained with non-invasive devices. Methods: In 102 patients planned to undertake a cardiac catheterization (65±13 years, 70.6% males) duplicate non-invasive measures of PWV, 15-minutes apart, were obtained with 4 devices measuring two-points carotid-femoral PWV and the related pulse transit time (PTT): Complior (AlamMedical), PulsePenETT, PulsePenET (DiaTecne), SphygmoCor (AtCorMedical), and with 2 devices estimating PWV from the oscillometric cuff-derived brachial wave: BPLab (Petr Telegin), Mobil-O-Graph (IEM). PWV and carotid-femoral PTT measurements were compared using coefficients of variation (CV%) and their confidence intervals (CI). Results: Devices evaluating carotid-femoral PWV showed a good repeatability (CV%[CI]: Complior: 8.8 [7.3–10.1]; PulsePen ETT: 8.0 [6.2–9.5]; PulsePen ET: 5.8 [4.9–6.6]; SphygmoCor: 9.5 [7.7–11.0]), whereas the repeatability of PWV estimated by cuff-based devices was for the BPLab = 5.5 [4.2–6.6] and for the Mobil-O- Graph = 3.4 [2.9–3.8]). A tendency toward a lower repeatability of carotid-femoral PWV was present for greater arterial stiffness, while repeatability of carotid-femoral PTT was not related to its mean values. Differences between repeated PWV measurements were not correlated with blood pressure (R2 = 0.005) or heart rate variations (R2 = 0.013). Conclusions: Short-term repeatability of PWV measures was good, with some differences between different devices. A greater repeatability was observed in devices estimating PTT from a cuff-based measurement, compared to devices measuring carotid-femoral PTT, owing to the algorithm of calculation of PWV (Mobil-O-Graph) or to the procedure of correction which eliminates highly variable PWV values (BPLab). Repeatability of PWV is not influenced by blood pressure or heart rate variations. For carotid-femoral PWV, the repeatability of measures is lower for higher PWV values.

3’ polyadenylation is a key step in eukaryotic mRNA biogenesis. In mammalian cells, this process is dependent on the recognition of the hexanucleotide AAUAAA motif in the pre-mRNA polyadenylation signal by the cleavage and polyadenylation specificity factor (CPSF) complex. A core CPSF complex comprising CPSF160, WDR33, CPSF30 and Fip1 is sufficient for AAUAAA motif recognition, yet the molecular interactions underpinning its assembly and mechanism of PAS recognition are not understood. Based on cross-linking-coupled mass spectrometry, crystal structure of the CPSF160-WDR33 subcomplex and biochemical assays, we define the molecular architecture of the core human CPSF complex, identifying specific domains involved in inter-subunit interactions. In addition to zinc finger domains in CPSF30, we identify using quantitative RNA-binding assays an N-terminal lysine/arginine-rich motif in WDR33 as a critical determinant of specific AAUAAA motif recognition. Together, these results shed light on the function of CPSF in mediating PAS-dependent RNA cleavage and polyadenylation.

BackgroundMarfan syndrome is characterized by aortic root dilation, beginning in childhood. Data about aortic pulsatile hemodynamics and stiffness in pediatric age are currently lacking. Methods and ResultsIn 51 young patients with Marfan syndrome (12.0±3.3 years), carotid tonometry was performed for the measurement of central pulse pressure, pulse pressure amplification, and aortic stiffness (carotid‐femoral pulse wave velocity). Patients underwent an echocardiogram at baseline and at 1 year follow‐up and a genetic evaluation. Pathogenetic fibrillin‐1 mutations were classified between “dominant negative” and “haploinsufficient.” The hemodynamic parameters of patients were compared with those of 80 sex, age, blood pressure, and heart‐rate matched controls. Central pulse pressure was significantly higher (38.3±12.3 versus 33.6±7.8 mm Hg; P=0.009), and pulse pressure amplification was significantly reduced in Marfan than controls (17.9±15.3% versus 32.3±17.4%; P