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Gianfranco Piccirillo,1 Federica Moscucci,1 Fabiola Mastropietri,1 Claudia Di Iorio,1 Marco Valerio Mariani,1 Marcella Fabietti,1 Gaetana M Stricchiola,1 Ilaria Parrotta,1 Gennaro Sardella,1 Massimo Mancone,1 Damiano Magrì2 1Department of Cardiovascular, Respiratory, Nephrological, Anesthesiologic, and Geriatric Sciences, Policlinico Umberto I, “La Sapienza” University of Rome, Rome, Italy; 2Department of Molecular and Clinical Medicine, S. Andrea Hospital, “Sapienza” University of Rome, Rome, Italy Objectives: To evaluate the predicative power of the electrical risk score (ERS), a noninvasive and inexpensive test obtained by means of a standard 12-lead electrocardiogram (ECG), in a cohort of elderly patients who had undergone transcatheter aortic valve replacement (TAVR).Methods: Survivors and non-survivors after TAVR at 1-year follow-up were compared in respect to the pre-procedural ERS as well as a number of other clinical and instrumental variables. ERS is composed of seven simple ECG markers: heart rate (>75 bpm); QRS duration (>110 ms); left ventricular hypertrophy (Sokolow–Lyon criteria); delayed QRS transition zone (≥ V4); frontal QRS-T angle (>90°); long QTBazett (>450 ms for men and >460 in women) or JTBazett (330 ms for men and >340 ms for women); and long Tpeak to Tend interval (Tp-e) (>89 ms). The trial was registered in ClinicalTrials.gov as NCT03145376.Results: A total of 40 patients were evaluated. During the follow-up, the all-cause mortality rate was 25% (ten patients) with 15% of cardiovascular death (six patients). The ERS was the strongest predictor of all-cause (odds ratio 3.73, 95% CI: 1.44–9.66, P

Gianfranco Piccirillo,1 Cristina Ottaviani,2 Claudia Fiorucci,1 Nicola Petrocchi,2 Federica Moscucci,1 Claudia Di Iorio,1 Fabiola Mastropietri,1 Ilaria Parrotta,1 Matteo Pascucci,1 Damiano Magrì3 1Department of Cardiovascular, Respiratory, Nephrological, Anestesiological and Geriatric Sciences, “Sapienza” University, 2Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, 3Department of Clinical and Molecular Medicine, University of Rome “Sapienza”, Rome, Italy Background: Noninvasive brain stimulation technique is an interesting tool to investigate the causal relation between cortical functioning and autonomic nervous system (ANS) responses. Objective: The objective of this report is to evaluate whether anodal transcranial direct current stimulation (tDCS) over the temporal cortex influences short-period temporal ventricular repolarization dispersion and cardiovascular ANS control in elderly subjects. Subjects and methods: In 50 healthy subjects (29 subjects younger than 60 years and 21 subjects older than 60 years) matched for gender, short-period RR and systolic blood pressure spectral variability, QT variability index (QTVI), and noninvasive hemodynamic data were obtained during anodal tDCS or sham stimulation. Results: In the older group, the QTVI, low-frequency (LF) power expressed in normalized units, the ratio between LF and high-frequency (HF) power, and systemic peripheral resistances decreased, whereas HF power expressed in normalized units and α HF power increased during the active compared to the sham condition (P

Background: COVID-19 patients with any pre-existing major cardio-vascular disease (CVD) are at the highest risk of viral infection and of developing severe disease. The pathophysiological mechanism is characterized by the viral link to angiotensin-converting enzyme 2 (ACE2) and the involvement of the endothelial system with the release of cytokines and the inflicting of direct damage to the myocardium, the induction of microthrombosis, and the initiation of alterations in oxygen diffusion. The aim of the study is to analyze the clinical course and outcomes in patients (gender-stratified) with pre-existing major CVD., Methods: Out of the 1833 (973 M/860 F) patients admitted to the Internal Medicine COVID-19 Unit of "Castelli Hospital", Lazio, Italy, from 1 January 2021 to 31 December 2021, 600 patients (320 M/280 F) with a mean age of 77 (78.6 M/75.1 F) previously had CVD. Demographic characteristics, length of the stay (LOS) and oxygen therapy were evaluated., Results: All of the CVD COVID-19 patients underwent non-invasive ventilation (NIV). CVD was linked with increased LOS (21 days F/22 M) compared to no CVD (19 days). In total, 32.7% of total patients had major CVD., Conclusions: Timely identification and evaluation of patients with pre-existing major CVD are fundamental for adequate treatment based on gender, severity, state of illness and for risk reduction.

Frailty is a geriatric syndrome associated with both locomotor and cognitive decline, typically linked to chronic systemic inflammation, i.e., inflammaging . In the current study, we investigated the effect of a two-month oral supplementation with standardized extracts of H. erinaceus , containing a known amount of Erinacine A, Hericenone C, Hericenone D, and L-ergothioneine, on locomotor frailty and cerebellum of aged mice. Locomotor performances were monitored comparing healthy aging and frail mice. Cerebellar volume and cytoarchitecture, together with inflammatory and oxidative stress pathways, were assessed focusing on senescent frail animals. H. erinaceus partially recovered the aged-related decline of locomotor performances. Histopathological analyses paralleled by immunocytochemical evaluation of specific molecules strengthened the neuroprotective role of H. erinaceus able to ameliorate cerebellar alterations, i.e., milder volume reduction, slighter molecular layer thickness decrease and minor percentage of shrunken Purkinje neurons, also diminishing inflammation and oxidative stress in frail mice while increasing a key longevity regulator and a neuroprotective molecule. Thus, our present findings demonstrated the efficacy of a non-pharmacological approach, based on the dietary supplementation using H. erinaceus extract, which represent a promising adjuvant therapy to be associated with conventional geriatric treatments.

Bioactive metabolites isolated from medicinal mushrooms (MM) used as supportive treatment in conventional oncology have recently gained interest. Acting as anticancer agents, they interfere with tumor cells and microenvironment (TME), disturbing cancer development/progression. Nonetheless, their action mechanisms still need to be elucidated. Recently, using a 4T1 triple-negative mouse BC model, we demonstrated that supplementation with Micotherapy U-Care, a MM blend, produced a striking reduction of lung metastases density/number, paralleled by decreased inflammation and oxidative stress both in TME and metastases, together with QoL amelioration. We hypothesized that these effects could be due to either a direct anticancer effect and/or to a secondary/indirect impact of Micotherapy U-Care on systemic inflammation/immunomodulation. To address this question, we presently focused on apoptosis/proliferation, investigating specific molecules, i.e., PARP1, p53, BAX, Bcl2, and PCNA, whose critical role in BC is well recognized. We revealed that Micotherapy U-Care is effective to influence balance between cell death and proliferation, which appeared strictly interconnected and inversely related (p53/Bax vs. Bcl2/PARP1/PCNA expression trends). MM blend displayed a direct effect, with different efficacy extent on cancer cells and TME, forcing tumor cells to apoptosis. Yet again, this study supports the potential of MM extracts, as adjuvant supplement in the TNBC management.

In the present study, the functional role of the inwardly rectifying K + channel, Kir4.1, and large-conductance Ca 2+ -activated K + (BK) channel during cell migration in U251 cell line was investigated. We focused on polarised cells which are positive for the active-Cdc42 migration marker. The perforated patch technique was used to avoid intracellular dialysis and to maintain physiological changes in intracellular calcium. Wound healing was employed to assay migration after 24 h. Polarised cells recorded displayed different hallmarks of undifferentiated glial cells: depolarised resting membrane potential and high membrane resistance. Cells recorded outside wounded area did not display either constitutive inward or outward rectification. After migration, U251 cells were characterised by a constitutively smaller Kir4.1 and larger BK currents with a linearly related amplitude. Menthol modulation increased both currents in a linearly dependent manner, indicating a common mechanism triggered by activation of transient receptor potential melastatin 8 (TRPM8), a Ca 2+ -permeable non-selective cation channel. We hypothesised that both migration and menthol modulation would share an increase of intracellular calcium triggering the increase in Kir4.1 and BK channels. Immunocytochemistry demonstrated the cytoplasmic expression of both Kir4.1 and BK channels and a mislocation in the nucleus under basal conditions. Before and after migration, polarised cells increased the expression of Kir4.1 and BK channels both in the cytoplasm and nucleus. TEM ultrastructural analysis displayed a different nuclear distribution of Kir4.1 and BK channels. In the present study, the physiological role of Kir4.1 and BK currents at membrane potential, their involvement in migration, and the functional role of nuclear channels were discussed.

Background/aim: Degenerative aortic valve stenosis (AS) is associated to ventricular arrhythmias and sudden cardiac death, as well as mental stress in specific patients. In such a context, substrate, autonomic imbalance as well as repolarization dispersion abnormalities play an undoubted role. Aim of the study was to evaluate the increase of premature ventricular contractions (PVC) and complex ventricular arrhythmias during mental stress in elderly patients candidate to the transcatheter aortic valve replacement (TAVR)., Methods: In eighty-one elderly patients with AS we calculated several short-period RR- and QT-derived variables at rest, during controlled breathing and during mild mental stress, the latter being represented by a mini-mental state evaluation (MMSE)., Results: All the myocardial repolarization dispersion markers worsened during mental stress ( p < 0.05). Furthermore, during MMSE, low frequency component of the RR variability increased significantly both as absolute power (LF RR ) and normalized units (LF RRN U ) ( p < 0.05) as well as the low-high frequency ratio (LF RR /HF RR ) ( p < 0.05). Eventually, twenty-four (30%) and twelve (15%) patients increased significantly PVC and, respectively, complex ventricular arrhythmias during the MMSE administration. At multivariate logistic regression analysis, the standard deviation of QTend (QTe sd ), obtained at rest, was predictive of increased PVC (odd ratio: 1.54, 95% CI 1.14-2.08; p = 0.005) and complex ventricular arrhythmias (odd ratio: 2.31, 95% CI 1.40-3.83; p = 0.001) during MMSE. The QTe sd showed the widest sensitive-specificity area under the curve for the increase of PVC (AUC: 0.699, 95% CI: 0.576-0.822, p < 0.05) and complex ventricular arrhythmias (AUC: 0.801, 95% CI: 0.648-0.954, p < 0.05)., Conclusion: In elderly with AS ventricular arrhythmias worsened during a simple cognitive assessment, this events being a possible further burden on the outcome of TAVR. QTe sd might be useful to identify those patients with the highest risk of ventricular arrhythmias. Whether the TAVR could led to a QTe sd reduction and, hence, to a reduction of the arrhythmic burden in this setting of patients is worthy to be investigated.

Epidemiological data indicate that subjects affected by obesity have an increased risk of developing mood disorders. The relationship between obesity and mood disorders is bidirectional. We assessed whether a Hericium erinaceus treatment improved depression, anxiety, sleep, and binge eating disorders after 8 weeks of supplementation in subjects affected by overweight or obesity under a low calorie diet regimen. Looking for a possible clinical biomarker, we assessed the serum balance between brain-derived neurotrophic factor (BDNF) and its precursor pro-BDNF before and after H. erinaceus supplementation. Seventy-seven volunteers affected by overweight or obesity were recruited at the offices of the Department of Preventive Medicine, Luigi Devoto Clinic of Work, Obesity Centre, at the IRCCS Foundation Policlinico Hospital of Milan (Italy). Patients were recruited only if they had a mood and/or sleep disorder and/or were binge eating as evaluated through self-assessment questionnaires. We used two different enzyme-linked immunosorbent assays kits to discriminate circulating levels of pro-BDNF and BDNF. Eight weeks of oral H. erinaceus supplementation decreased depression, anxiety, and sleep disorders. H. erinaceus supplementation improved mood disorders of a depressive-anxious nature and the quality of the nocturnal rest. H. erinaceus increased circulating pro-BDNF levels without any significant change in BDNF circulating levels.

Frailty is a geriatric syndrome associated with both locomotor and cognitive decline, implicated in both poor quality of life and negative health outcomes. One central question surrounding frailty is whether phenotypic frailty is associated with the cognitive impairment during aging. Using spontaneous behavioral tests and by studying the dynamic change during aging, we demonstrated that the two form of vulnerability, locomotor and recognition memory decline, develop in parallel and therefore, integration of the motoric and cognitive evaluations are imperative. We developed an integrated frailty index based on both phenotypic and recognition memory performances. Hericium erinaceus ( H. erinaceus ) is a medicinal mushroom that improves recognition memory in mice. By using HPLC-UV-ESI/MS analyses we obtained standardized amounts of erinacine A and hericenones C and D in H. erinaceus extracts, that were tested in our animal model of physiological aging. Two-month oral supplementation with H. erinaceus reversed the age-decline of recognition memory. Proliferating cell nuclear antigen (PCNA) and doublecortin (DCX) immunohistochemistry in the hippocampus and cerebellum in treated mice supported a positive effect of an H. erinaceus on neurogenesis in frail mice.

Background: Sugammadex is a relatively new molecule that reverses neuromuscular block induced by rocuronium. The particular structure of sugammadex traps the cyclopentanoperhydrophenanthrene ring of rocuronium in its hydrophobic cavity. Dexamethasone shares the same steroidal structure with rocuronium. Studies in vitro have demonstrated that dexamethasone interacts with sugammadex, reducing its efficacy. In this study, we investigated the clinical relevance of this interaction and its influence on neuromuscular reversal., Methods: In this retrospective case-control study, we analyzed data from 45 patients divided into 3 groups: dexamethasone after induction group (15 patients) treated with 8 mg dexamethasone as an antiemetic drug shortly after induction of anesthesia; dexamethasone before reversal group (15 patients) treated with dexamethasone just before sugammadex injection; and control group (15 patients) treated with 8 mg ondansetron. All groups received 0.6 mg/kg rocuronium at induction, 0.15 mg/kg rocuronium at train-of-four ratio (TOF) 2 for neuromuscular relaxation, and 2 mg/kg sugammadex for reversal at the end of the procedure at TOF2. Neuromuscular relaxation was monitored with a TOF-Watch® system., Results: The control group had a recovery time of 154 ± 54 seconds (mean ± SD), the dexamethasone after induction group 134 ± 55 seconds, and the dexamethasone before reversal group 131 ± 68 seconds. The differences among groups were not statistically significant (P = 0.5141)., Conclusions: Our results show that the use of dexamethasone as an antiemetic drug for the prevention of postoperative nausea and vomiting does not interfere with reversal of neuromuscular blockade with sugammadex in patients undergoing elective surgery with general anesthesia in contrast to in vitro studies that support this hypothesis.

General anesthetics and contrast media can cause anaphylactic as well as anaphylactoid reactions. These events are of great concern to radiologists and anesthesiologists because of their relatively high prevalence, possible threat to life, and medical-legal consequences. Points discussed in this review are the critical evaluation of risk factors affecting prevention strategies, the need to be aware of pathogenic mechanisms relevant to prevention strategies, the use of alternative products if a culprit agent is known, the recognition of early signs of a reaction, the need to keep records of reactions on a patient's medical chart, the planning of prophylactic therapy, recommended actions after a reaction to an anesthetic or contrast medium, and the suggested establishment of allergy-anesthesiology centers to improve cooperation, and medical-legal issues. As any drug or contrast medium administered during general anesthesia or a diagnostic procedure can induce a potentially life-threatening or fatal event even in the absence of any evident risk factor in the patient's medical history or clinical status, we usually premedicate susceptible individuals at least to attenuate the severity of an unpredictable reaction, although we cannot rely on the efficacy of premedication to completely prevent a severe event. These recommendations, which are based on the literature and on the experience of our working group, aim to provide useful information for physicians and other specialists who operate in the absence of an allergy consultant.

Objectives: We evaluated the time-behavior of changes in collateral circulation after successful percutaneous coronary intervention (PCI) with drug-eluting stents (DES) in chronic (>1 month) total occlusions (CTO), and assessed their relationship with myocardial ischemia., Background: It has been hypothesized that the immediate reduction of collateral flow after PCI of CTO could expose the patients to a higher risk of future ischemic events in the case of vessel reocclusion., Methods: In 42 patients with CTO, two consecutive balloon inflations and final DES deployment were performed after positioning of a pressure guidewire. Minimal lumen diameter (MLD), diameter stenosis (DS), angiographic collateral grading (Rentrop score), myocardial (FFRmyo), coronary (FFRcor), and collateral fractional flow reserve (FFRcoll) were evaluated. Chest pain and the sum of ST-segment elevation (SigmaST) were analyzed to document the occurrence and extent of myocardial ischemia., Results: Percutaneous coronary intervention induced a progressive improvement of indexes of stenosis severity (MLD, DS, Thrombolysis in Myocardial Infarction flow, FFRmyo, and FFRcor) and a rapid reduction in collateral circulation (FFRcoll and Rentrop score). A progressive worsening of ischemia at each balloon inflation occurred, concomitant with the reduction of collateral circulation. At linear regression analysis, an inverse relationship of FFRcoll with SigmaST (R2 = 0.352, p < 0.001) and angina pain score (R(2) = 0.247, p < 0.001) was observed., Conclusions: In CTO, collateral circulation, which provides most coronary flow at baseline, rapidly declines after successful stent implantation and the restoration of an antegrade flow. This rapid de-recruitment of collaterals is likely to put such patients at risk of future ischemic events.

Background: Recurrent syncope represents a debilitating disorder and quality of life deteriorates as a function of recurrence of symptoms. Although the administration of beta-blockers, vasoconstrictors, fludrocortisone, and serotonin reuptake inhibitors may be helpful in preventing episodes, many patients are intolerant of or respond poorly to these agents. Orthostatic training has been reported to be effective in preventing refractory syncope. Thus, to determine whether a tilt training program could prevent symptoms in adolescents, the following controlled study was undertaken., Methods and Results: Forty-seven consecutive adolescents (18 male and 29 female, mean age 16.0+/-2.2 years) with recurrent syncope and positive head-up tilt test refractory to previous traditional therapies were distributed between 2 groups, depending on their consent (24 patients) or refusal (controls, 23 patients) to enter the program. Orthostatic training was started, in the presence of a family member, with a series of 5 in-hospital sessions. The 24 patients and their relatives were then instructed to perform the tilt training at home by standing against a wall twice a day for a planned duration of up to 40 minutes, depending on the in-hospital orthostatic tolerance. Head-up tilt response was reevaluated after 1 month, and the clinical effect was noted over a mean follow-up of 18. 2+/-5.3 months (range 15 to 23); 26.1% of patients in the control group and 95.8% of patients in the training group became tilt-negative (P<0.0001). Spontaneous syncope was observed in 56.5% versus 0% in the control and training group, respectively (P<0.0001)., Conclusions: Orthostatic training was found to significantly improve symptoms of adolescents with neurocardiogenic syncope unresponsive to or intolerant of traditional medications. Twice-a-day training sessions of 40 minutes were well accepted by patients.

Objectives: The purpose of the study was to determine whether the well tolerated serotonin reuptake inhibitor paroxetine hydrochloride could prevent vasovagal syncope in patients resistant to or intolerant of previous traditional therapies., Background: Serotonergic mechanisms play a major role in the processes leading to neurocardiogenic vasovagal syncope, and serotonin reuptake inhibitors have been reported to be effective in preventing refractory syncope., Methods: Sixty-eight consecutive patients (26 men and 42 women, mean age 44.7+/-16.5 years) with recurrent syncope and positive head-up tilt test and in whom standard therapies with beta-adrenergic blocking agents, vagolytic, negative inotropic or mineral corticoid agents were ineffectual or poorly tolerated were referred for study. Patients randomly received either paroxetine at 20 mg once a day or a placebo. A head-up tilt test was then reperformed after one month of treatment, and the clinical effect was noted over a mean follow-up of 25.4+/-7.9 months., Results: The response rates (negative tilt test) after one month of treatment were 61.8% versus 38.2% (p < 0.001) in the paroxetine and placebo groups, respectively. During follow-up spontaneous syncope was reported in six patients (17.6%) in the paroxetine group as compared to 18 patients (52.9%) in the placebo group (p < 0.0001). Only one patient (2.9%) asked to be discontinued from the drug for severe side effects., Conclusions: Paroxetine was found to significantly improve the symptoms of patients with vasovagal syncope unresponsive to or intolerant of traditional medications and was well tolerated by patients.