Concomitant Neuronal Tau Deposition and FKBP52 Decrease Is an Early Feature of Different Human and Experimental Tauopathies.

BACKGROUND: Pathological tau proteins constitute neurofibrillary tangles that accumulate in tauopathies including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and familial frontotemporal lobar degeneration (FTLD-Tau). We previously showed that the FKBP52 immunophilin interacts functionally with tau and strongly decreases in AD brain neurons in correlation with tau deposition. We also reported that FKBP52 co-localizes with autophagy-lysosomal markers and an early pathological tau isoform in AD neurons, suggesting its involvement in autophagic tau clearance. OBJECTIVE: Our objective was to evaluate if differences in neuronal FKBP52 expression levels and subcellular localization might be detected in AD, PSP, familial FTLD-Tau, and in the hTau-P301 S mouse model compared to controls. METHODS: Cell by cell immunohistofluorescence analyses and quantification of FKBP52 were performed on postmortem brain samples of some human tauopathies and on hTau-P301 S mice spinal cords. RESULTS: We describe a similar FKBP52 decrease and its localization with early pathological tau forms in the neuronal autophagy-lysosomal pathway in various tauopathies and hTau-P301 S mice. We find that FKBP52 decreases early during the pathologic process as it occurs in rare neurons with tau deposits in the marginally affected frontal cortex region of AD Braak IV brains and in the spinal cord of symptomless 1-month-old hTau-P301 S mice. CONCLUSION: As FKBP52 plays a significant role in cellular signaling and conceivably in tau clearance, our data support the idea that the prevention of FKBP52 decrease or the restoration of its normal expression at early pathologic stages might represent a new potential therapeutic approach in tauopathies including AD, familial FTLD-Tau, and PSP.

Efficacy of recanalization therapy for ischemic stroke: multicenter hospital network experience.

PURPOSE: Stroke is a leading cause of long-term disability with high mortality rate in the first year after the event. In Campania, mechanical thrombectomy treatment significantly increases in the last 3 years, as well as hospitals delivering acute stroke treatments. The aim of this study is to demonstrate how a full opening of our stroke network improves stroke management and stroked patients' survival in Campania. MATERIAL AND METHODS: In Federico II University Hospital of Naples acting as a HUB center of 7 peripheral SPOKE hospitals in regional territory, 68 patients with acute ischemic stroke were evaluated with NIHSS and m-RS clinical scores and neuroradiological ASPECT scores, from January 1 to December 31, 2021. At hospital discharge, NIHSS score and three months after m-RS score were re-assessed to evaluate the therapeutic effects. RESULTS: Forty-two of 68 patients (63%) admitted to our hub center had ischemic acute stroke at CT evaluation; 29 patients had ASPECT score > 7 (69%), and 6 a score < 7 (14%). At admission, NIHSS score mean value was 10.75, and m-RS score mean value was 0.74. At discharge, NIHSS score mean value was 7.09. After three months, m-RS score mean value was 0.74. DISCUSSION: The inter-company agreement between Federico II University and several peripheral hospitals allows an absolute and relative increase in endovascular mechanical thrombectomy and intravenous thrombolysis procedures, with a relative prevalence of mechanical thrombectomy. A regional implementation of the stroke multi-disciplinary care system is hardly needed to ensure the optimum treatment for the largest number of patients, improving patient's outcome.

Reshaping of Italian Echocardiographic Laboratories Activities during the Second Wave of COVID-19 Pandemic and Expectations for the Post-Pandemic Era.

BACKGROUND: Cardiology divisions reshaped their activities during the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to analyze the organization of echocardiographic laboratories and echocardiography practice during the second wave of the COVID-19 pandemic in Italy, and the expectations for the post-COVID era. METHODS: We analyzed two different time periods: the month of November during the second wave of the COVID-19 pandemic (2020) and the identical month during 2019 (November 2019). RESULTS: During the second wave of the COVID-19 pandemic, the hospital activity was partially reduced in 42 (60%) and wholly interrupted in 3 (4%) echocardiographic laboratories, whereas outpatient echocardiographic activity was partially reduced in 41 (59%) and completely interrupted in 7 (10%) laboratories. We observed an important change in the organization of activities in the echocardiography laboratory which reduced the operator-risk and improved self-protection of operators by using appropriate personal protection equipment. Operators wore FFP2 in 58 centers (83%) during trans-thoracic echocardiography (TTE), in 65 centers (93%) during transesophageal echocardiography (TEE) and 63 centers (90%) during stress echocardiography. The second wave caused a significant reduction in number of echocardiographic exams, compared to November 2019 (from 513 ± 539 to 341 ± 299 exams per center, -34%, p < 0.001). On average, there was a significant increase in the outpatient waiting list for elective echocardiographic exams (from 32.0 ± 28.1 to 45.5 ± 44.9 days, +41%, p < 0.001), with a reduction of in-hospital waiting list (2.9 ± 2.4 to 2.4 ± 2.0 days, -17%, p < 0.001). We observed a large diffusion of point-of-care cardiac ultrasound (88%), with a significant increase of lung ultrasound usage in 30 centers (43%) during 2019, extended to all centers in 2020. Carbon dioxide production by examination is an indicator of the environmental impact of technology (100-fold less with echocardiography compared to other cardiac imaging techniques). It was ignored in 2019 by 100% of centers, and currently it is considered potentially crucial for decision-making in cardiac imaging by 65 centers (93%). CONCLUSIONS: In one year, major changes occurred in echocardiography practice and culture. The examination structure changed with extensive usage of point-of-care cardiac ultrasound and with lung ultrasound embedded by default in the TTE examination, as well as the COVID-19 testing.

Determinants of reduction of coronary flow reserve in patients with type 2 diabetes mellitus or arterial hypertension without angiographically determined epicardial coronary stenosis.

BACKGROUND: Coronary flow reserve (CFR) may be reduced even in the absence of coronary artery disease. We investigated the determinants of CFR impairment in Type 2 diabetes mellitus (DM2) and in arterial hypertension (HTN) without epicardial coronary artery stenosis. METHODS: Twenty-eight patients with DM2 and 27 with HTN, both with normal coronary angiography, and 18 healthy controls underwent transthoracic echocardiography, including Doppler recording of the distal left anterior descending artery, at rest as well as after high-dose dipyridamole. Coronary flow reserve was calculated as the hyperemic to resting coronary diastolic peak velocities ratio. RESULTS: The three groups were comparable for sex, age, and heart rate. Systolic and mean blood pressures were higher in DM2 and HTN patients than in control subjects. Diabetic and hypertensive patients had a higher left-ventricular mass index (LVMi) and relative wall thickness, impaired diastolic indexes, and lower CFR compared with control subjects (P = .02 and P = .03, respectively) because of lower hyperemic coronary velocity (P = .005 and P = .004, respectively). After a multilinear regression analysis (using age, sex, HTN status, DM2 status, smoking, total cholesterol/HDL-cholesterol ratio, and LVMi as potential determinants), the LVMi increase was the main predictor of the reduction of CFR, adjusted for mean BP (P < .0001), in the pooled population, with a minor contribution of age (P = .03), HTN status (P = .02), and DM2 status (P = .03). CONCLUSIONS: In Type 2 DM and HTN without epicardial coronary stenosis, an impairment of CFR is demonstrable. This is partly explained by an increased left-ventricular mass, able to condition the hyperemic stimulation of myocardial blood flow.

Carvedilol increases two-year survivalin dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial.

OBJECTIVES: We sought to evaluate the effects of carvedilol on mortality and morbidity in dialysis patients with dilated cardiomyopathy. BACKGROUND: Several lines of evidence support the concept that therapy with beta-blocking agents reduces morbidity and mortality in patients with congestive heart failure (HF), but the demonstration of such a survival benefit in dialysis patients with dilated cardiomyopathy is still lacking. METHODS: A total of 114 dialysis patients with dilated cardiomyopathy were randomized to receive either carvedilol or placebo in addition to standard therapy. A first analysis was performed at one year and was followed by an additional follow-up period of 12 months. RESULTS: Two-year echocardiographic data revealed a significant attenuation of pathologic remodeling, with smaller cavity diameters and higher ejection fractions in the active treatment group than in the placebo group. At two years, 51.7% of the patients died in the carvedilol group, compared with 73.2% in the placebo group (p < 0.01). Furthermore, there were significantly fewer cardiovascular deaths (29.3%) and hospital admissions (34.5%) among patients receiving carvedilol than among those receiving a placebo (67.9% and 58.9%, respectively; p < 0.00001). The exploratory analyses revealed that fatal myocardial infarctions, fatal strokes, and hospital admissions for worsening HF were lower in the carvedilol group than in the placebo group. A reduction in sudden deaths and pump-failure deaths was also observed, though it did not reach statistical significance. CONCLUSIONS: Carvedilol reduced morbidity and mortality in dialysis patients with dilated cardiomyopathy. These data suggest the use of carvedilol in all dialysis patients with chronic HF.

Sustained-release diltiazem reduces myocardial ischemic episodes in end-stage renal disease: a double-blind, randomized, crossover, placebo-controlled trial.

End-stage renal disease (ESRD) patients receiving maintenance hemodialysis and suffering from coronary artery disease (CAD) often receive doses of calcium channel antagonists that are too low. This may be the result of physician's desire to avoid adverse side effects during hemodialysis. The aim of this study was the assessment of the safety and efficacy of incremental doses of diltiazem for the treatment of myocardial ischemia in ERSD patients with CAD to identify the optimal dose of the drug. A total of 196 chronic hemodialysis patients were enrolled with CAD showing more than 5 min of transient myocardial ischemia during a 48-h Holter ECG monitoring. A double-blind, randomized, crossover, placebo-controlled trial design was used. Incremental doses of diltiazem (120 to 240 mg/d) were administered in 4 mo. With a dose of 120 and 180 mg/d, a significant reduction in the number and duration of total and symptomatic ischemic episodes was observed (P < 0.001), but the number and the duration of silent ischemic episodes were not reduced. Conversely, the efficacy on silent myocardial ischemia was obtained with a dosage of diltiazem of 240 mg/d (P < 0.001). In addition, with a sustained-release formulation (120 mg twice daily), the efficacy was similar to that obtained with four 60-mg tablets, but the safety was improved, especially during hemodialytic session. The circadian variations analysis of transient ischemic episodes showed a significant reduction in both ischemic peaks observed at baseline only with 240 mg/d of diltiazem. The findings emphasize that sustained-release diltiazem (120 mg twice daily) can be largely useful in uremic patients with CAD on maintenance dialysis. Diltiazem reduces the number and the duration of silent ischemic episodes, has a good tolerability, and positively modifies the circadian pattern of ischemic episodes.