Search

Background & Aims: SARS-Cov-2 infection manifests as a wide spectrum of clinical presentation and even now, despite the global spread of the vaccine, contagiousness is still elevated. The aim of the study was the evaluation of the impact of liver fibrosis assessed by FIB-4 and liver impairment, assessed by cytolysis indices, on intrahospital mortality in COVID-19 subjects., Methods: This is a retrospective observational cohort study, which involved 23 COVID Hospital Units in Campania Region, Italy. Exposure variables were collected during hospital admission and at discharge. According to FIB-4 values, we subdivided the overall population in three groups (FIB-4<1.45; 1.453.25), respectively group 1,2,3., Results: At the end of the study, 938 individuals had complete discharged/dead data. At admission, 428 patients were in group 1 (45.6%), 387 in group 2 (41.3%) and 123 in group 3 (13.1%). Among them, 758 (81%) subjects were discharged, while the remaining 180 (19%) individuals died. Multivariable Cox's regression model showed a significant association between mortality risk and severity of FIB-4 stages (group 3 vs group 1, HR 2.12, 95%CI 1.38-3.28, p<0.001). Moreover, Kaplan-Meier analysis described a progressive and statistically significant difference (p<0.001 Log-rank test) in mortality according to FIB-4 groups. Among discharged subjects, 507 showed a FIB-4<1.45 (66.9%, group 1), 182 a value 1.453.25 (9.0%, group 3). Among dead subjects, 42 showed a FIB-4<1.45 (23.3%, group 1), 62 a value 1.453.25 (42.3%, group 3)., Conclusions: FIB-4 value is significantly associated with intrahospital mortality of COVID-19 patients. During hospitalization, particularly in patients with worse outcomes, COVID-19 seems to increase the risk of acute progression of liver damage., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Galiero et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Aims: The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has fundamentally reshaped the landscape of global public health, with some people suffering more adverse clinical outcomes than others. The aim of this study is to deepen our understanding of the specific impact of acute kidney injury (AKI) on the in-hospital mortality in octogenarian patients with COVID-19., Methods: This is a prospective observational cohort study, which involved 23 COVID-19 hospital units in the Campania Region, Italy. Exposure variables were collected during hospital admission and at discharge. Only patients aged ≥80 years were deemed eligible for the study., Results: 197 patients were included in the study (median age 83.0 [82.0-87.0] years; 51.5% men), with a median duration of hospitalization of 15.0 [8.0-25.0] days. From the multivariable Cox regression analysis, after the application of Šidák correction, only the respiratory rate (HR 1.09, 95% CI: 1.04 to 1.14; p < 0.001) and AKI development (HR: 3.40, 95% CI: 1.80 to 6.40; p < 0.001) were independently associated with the primary outcome. Moreover, the Kaplan-Meier analysis showed a significantly different risk of in-hospital mortality between patients with and without AKI (log-rank: <0.0001)., Conclusions: In our investigation, we identified a significant association between AKI and mortality rates among octogenarian patients admitted for COVID-19. These findings raise notable concerns and emphasize the imperative for vigilant monitoring of this demographic cohort.

Background. Evidence has shown a close association between COVID-19 infection and renal complications in both individuals with previously normal renal function and those with chronic kidney disease (CKD). Methods. The aim of this study is to evaluate the in-hospital mortality of SARS-CoV-2 patients according to their clinical history of CKD or estimated glomerular filtration rate (eGFR). This is a prospective multicenter observational cohort study which involved adult patients (≥18 years old) who tested positive with SARS-CoV-2 infection and completed their hospitalization in the period between November 2020 and June 2021. Results. 1246 patients were included in the study, with a mean age of 64 years (SD 14.6) and a median duration of hospitalization of 15 days (IQR 9−22 days). Cox’s multivariable regression model revealed that mortality risk was strongly associated with the stage of renal impairment and the Kaplan−Meier survival analysis showed a progressive and statistically significant difference (p < 0.0001) in mortality according to the stage of CKD. Conclusion. This study further validates the association between CKD stage at admission and mortality in patients hospitalized for COVID-19. The risk stratification based on eGFR allows clinicians to identify the subjects with the highest risk of intra-hospital mortality despite the duration of hospitalization.

In order to evaluate the efficacy of oral supplementation with 3 g of arginine per day associated with creatine, L-carnitine, aspartic acid, magnesium, selenium and vitamins C and E (Argivit© Aesculapius Farmaceutici) in the prevention and treatment of sarcopenia in patients with COVID-19-related pneumonia, we conducted a parallel randomized study comparing it with standard therapy alone. Forty patients on standard therapy plus supplementation were compared with a control group of 40 patients, all hospitalized at the sub-intensive care unit of the Del Mare Hospital in Naples, with a clinical diagnosis of SARS-CoV-2 infection and COVID-19 pneumonia. Muscle strength was assessed with the handgrip test and muscle ultrasound. Arginine-supplemented patients had an average grip strength of 23.5 at the end of hospitalization compared with 22.5 in the untreated group with less reduction, showing statistical significance ( p < 0.001). In the same way, the thickness of the vastus lateralis quadriceps femoris muscle measured at the end of hospitalization showed less reduction on ultrasound, with a higher average value in the group receiving treatment than in the group of patients without supplementation ( p < 0.001). Upon discharge there was a 58.40% reduction in ventilation days in patients with arginine supplementation compared with the control group.

Background: we have observed the effect of insomnia treatment in clinical and prognostic differences of patients admitted for COVID-19 pneumonia in respiratory sub-intensive units that were administered a prolonged-release melatonin 2 mg (PRM 2 mg) therapy versus a group of patients out of therapy., Materials and Methods: We evaluated 40 patients on prolonged-release melatonin 2 mg (PRM 2 mg) therapy versus a control group of 40 patients out of therapy., Results: patients in the PRM 2 mg group had a shorter duration of therapy with non-invasive ventilation (5.2 ± 3.0 vs. 12.5 ± 4.2; p < 0.001), with a shorter stay in sub-intensive care (12.3 ± 3.2 vs. 20.1 ± 6.1; p < 0.001), and, therefore, a shorter overall duration of hospitalization (31.3 ± 6.8 vs. 34.3 ± 6.9 p = 0.03). In addition, a lower incidence of delirium was found (2.2 ± 1.1 vs. 3.3 ± 1.3; p < 0.001)., Conclusions: A significant increase in sleep hours and a reduction in delirium episodes occurs in hospitalized insomniac patients treated with PRM 2 mg, compared to untreated patients. Based on these preliminary results, we can assume that there are benefits of prolonged-release melatonin 2 mg in COVID-19 therapy.

Background: Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients. Objectives: To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients. Study Design: Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores. Results: Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs. Conclusions: In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Di Castelnuovo, Costanzo, Antinori, Berselli, Blandi, Bonaccio, Bruno, Cauda, Gialluisi, Guaraldi, Menicanti, Mennuni, My, Parruti, Patti, Perlini, Santilli, Signorelli, Stefanini, Vergori, Ageno, Aiello, Agostoni, Al Moghazi, Arboretti, Aucella, Barbieri, Barchitta, Bartoloni, Bologna, Bonfanti, Caiano, Carrozzi, Cascio, Castiglione, Chiarito, Ciccullo, Cingolani, Cipollone, Colomba, Colombo, Crosta, Dalena, Dal Pra, Danzi, D'Ardes, de Gaetano Donati, Di Gennaro, Di Tano, D'Offizi, Filippini, Maria Fusco, Gaudiosi, Gentile, Gini, Grandone, Guarnieri, Lamanna, Larizza, Leone, Lio, Losito, Maccagni, Maitan, Mancarella, Manuele, Mapelli, Maragna, Marra, Maresca, Marotta, Mastroianni, Mazzitelli, Mengozzi, Menichetti, Milic, Minutolo, Molena, Mussinelli, Mussini, Musso, Odone, Olivieri, Pasi, Perroni, Petri, Pinchera, Pivato, Poletti, Ravaglia, Rossato, Rossi, Sabena, Salinaro, Sangiovanni, Sanrocco, Scorzolini, Sgariglia, Simeone, Spinicci, Trecarichi, Veronesi, Vettor, Vianello, Vinceti, Visconti, Vocciante, De Caterina, Iacoviello and The COVID-19 RISK and Treatments (CORIST) Collaboration.)

Topics: Functional Magnetic Resonance Imaging (fMRI) evaluation of HyberBaric Oxygen Therapy (HBOT) effects on chronic cerebral stroke Patients (Pts). Introduction: Our aim was to evaluate with fMRI, in a 3 Tesla system, the functional effects of HBOT on the Central Nervous System (CNS) in four Pts with established ischaemic and haemorrhagic cerebral strokes (2 Pts each). To our knowledge, no author used this Magnetic Resonance (MR) technique for this purpose, till now. Methods: All four Pts underwent a fMRI study before and after 40 HBOT sessions, with a time window of a few days. They carried out two language (text listening, silent word-verb generation) and two motor (hand and foot movements) tasks (30 s On-Off block paradigms). Results: After HBOT, all Pts reported a clinical improvement, mostly concerning language fluency and motor paresis. fMRI analysis demonstrated an increase in both the extent and the statistical significance of most of the examined eloquent areas. Conclusions: These changes were consistent with the clinical improvement in all Pts, suggesting a possible role of fMRI in revealing neuronal functional correlates of neuronal plasticity and HBOT-related neoangiogenesis. Although only four Pts were examined, fMRI proved to be a sensitive, non-invasive and reliable modality for monitoring neuronal functional changes before and after HBOT.

Background: Italy has been the first Western country to be heavily affected by the spread of SARS-COV-2 infection and among the pioneers of the clinical management of pandemic. To improve the outcome, identification of patients at the highest risk seems mandatory., Objectives: Aim of this study is to identify comorbidities and clinical conditions upon admission associated with in-hospital mortality in several COVID Centers in Campania Region (Italy)., Methods: COVOCA is a multicentre retrospective observational cohort study, which involved 18 COVID Centers throughout Campania Region, Italy. Data were collected from patients who completed their hospitalization between March-June 2020. The endpoint was in-hospital mortality, assessed either from data at discharge or death certificate, whilst all exposure variables were collected at hospital admission., Results: Among 618 COVID-19 hospitalized patients included in the study, 143 in-hospital mortality events were recorded, with a cumulative incidence of about 23%. At multivariable logistic analysis, male sex (OR 2.63, 95%CI 1.42-4.90; p = 0.001), Chronic Liver Disease (OR 5.88, 95%CI 2.39-14.46; p<0.001) and malignancies (OR 2.62, 95%CI 1.21-5.68; p = 0.015) disclosed an independent association with a poor prognosis, Glasgow Coma Scale (GCS) and Respiratory Severity Scale allowed to identify at higher mortality risk. Sensitivity analysis further enhanced these findings., Conclusion: Mortality of patients hospitalized for COVID-19 appears strongly affected by both clinical conditions on admission and comorbidities. Originally, we observed a very poor outcome in subjects with a chronic liver disease, alongside with an increase of hepatic damage., Competing Interests: The authors have declared that no competing interests exist.

Background and Aims: There is poor knowledge on characteristics, comorbidities and laboratory measures associated with risk for adverse outcomes and in-hospital mortality in European Countries. We aimed at identifying baseline characteristics predisposing COVID-19 patients to in-hospital death., Methods and Results: Retrospective observational study on 3894 patients with SARS-CoV-2 infection hospitalized from February 19th to May 23rd, 2020 and recruited in 30 clinical centres distributed throughout Italy. Machine learning (random forest)-based and Cox survival analysis. 61.7% of participants were men (median age 67 years), followed up for a median of 13 days. In-hospital mortality exhibited a geographical gradient, Northern Italian regions featuring more than twofold higher death rates as compared to Central/Southern areas (15.6% vs 6.4%, respectively). Machine learning analysis revealed that the most important features in death classification were impaired renal function, elevated C reactive protein and advanced age. These findings were confirmed by multivariable Cox survival analysis (hazard ratio (HR): 8.2; 95% confidence interval (CI) 4.6-14.7 for age ≥85 vs 18-44 y); HR = 4.7; 2.9-7.7 for estimated glomerular filtration rate levels <15 vs ≥ 90 mL/min/1.73 m 2 ; HR = 2.3; 1.5-3.6 for C-reactive protein levels ≥10 vs ≤ 3 mg/L). No relation was found with obesity, tobacco use, cardiovascular disease and related-comorbidities. The associations between these variables and mortality were substantially homogenous across all sub-groups analyses., Conclusions: Impaired renal function, elevated C-reactive protein and advanced age were major predictors of in-hospital death in a large cohort of unselected patients with COVID-19, admitted to 30 different clinical centres all over Italy., Competing Interests: Declaration of Competing Interest All Authors declare no competing interests., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

We recently reported that expression of the costimulatory molecule and microbial sensor SLAMF1 (signaling lymphocytic activation molecule family 1, also known as CD150) is lost in chronic lymphocytic leukemia (CLL) patients characterized by a shorter overall survival. SLAMF1 modulates CLL responses to chemokines and regulates autophagy. Loss of SLAMF1 renders CLL cells relatively unresponsive to autophagy-inducing drugs, including B-cell CLL/lymphoma 2 (BCL2) inhibitors.

Background: One of the effects of oncogenic signaling is metabolic reprogramming of tumor cells to support anabolic growth, opening the way to therapeutic targeting of metabolic pathways., Methods: We studied NAD biosynthesis in BRAF inhibitor (BRAFi)-resistant (BiR) melanoma cell lines. Data in cell lines were confirmed by immunohistochemistry in biopsies from 17 patients with metastatic melanoma (MM) before and after the acquisition of resistance to BRAFi. Therapeutic potential of NAD biosynthesis inhibitors was determined by invitro monitoring cell growth and death and in mouse xenograft models. Mice (n = 6-10 mice/group) were treated with nicotinamide phosphoribosyltranferase inhibitor (NAMPTi), BRAFi, or their combination, and tumor growth and survival were analyzed. All statistical tests were two-sided., Results: BiR cells had higher NAD levels compared with their BRAFi-sensitive counterparts (P < .001 and P = .001 for M14 and A375, respectively) and with normal melanocytes (P < .001), achieved through transcriptional upregulation of the enzyme NAMPT, which became the master regulator of NAD synthesis. Conversely, treatment with BRAFi or MEK inhibitors decreased NAMPT expression and cellular NAD levels. Robust NAMPT upregulation was documented in tissue biopsies from MM patients after development of resistance to BRAFi (P < .001). Treatment of melanoma cells with NAMPTi depleted NAD and ATP, depolarized mitochondrial membrane, and led to reactive oxygen species production, blocking cells in the G2/M phase and inducing apoptosis. Treatment of BiR xenografts with NAMPTi improved mouse survival (median survival of vehicle-treated mice was 52 days vs 100 days for NAMPTi-treated ones in M14/BiR, while in A375/BiR median survival of vehicle-treated mice was 23.5 days vs 43 days for NAMPTi-treated ones, P < .001)., Conclusions: BiR melanoma cells overexpress NAMPT, which acts as a connecting element between BRAF oncogenic signaling and metabolism, becoming an actionable target for this subset of MM patients., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

PD-L1 is expressed by a subset of patients with metastatic melanoma (MM) with an unfavorable outcome. Its expression is increased in cells resistant to BRAF or MEK inhibitors (BRAFi or MEKi). However, the function and regulation of expression of PD-L1 remain incompletely understood.After generating BRAFi- and MEKi-resistant cell lines, we observed marked up-regulation of PD-L1 expression. These cells were characterized by a common gene expression profile with up-regulation of genes involved in cell movement. Consistently, in vitro they showed significantly increased invasive properties. This phenotype was controlled in part by PD-L1, as determined after silencing the molecule. Up-regulation of PD-L1 was due to post-transcriptional events controlled by miR-17-5p, which showed an inverse correlation with PD-L1 mRNA. Direct binding between miR-17-5p and the 3'-UTR of PD-L1 mRNA was demonstrated using luciferase reporter assays.In a cohort of 80 BRAF-mutated MM patients treated with BRAFi or MEKi, constitutive expression of PD-L1 in the absence of immune infiltrate, defined the patient subset with the worst prognosis. Furthermore, PD-L1 expression increased in tissue biopsies after the metastatic lesions became resistant to BRAFi or MEKi. Lastly, plasmatic miR-17-5p levels were higher in patients with PD-L1+ than PD-L1- lesions.In conclusion, our findings indicate that PD-L1 expression induces a more aggressive behavior in melanoma cells. We also show that PD-L1 up-regulation in BRAFi or MEKi-resistant cells is partly due to post-transcriptional mechanisms that involve miR-17-5p, suggesting that miR-17-5p may be used as a marker of PD-L1 expression by metastatic lesions and ultimately a predictor of responses to BRAFi or MEKi.

It has been hypothesized that cysteine cathepsins (CTs) along with matrix metalloproteases (MMPs) may work in conjunction in the proteolysis of mature dentin matrix. The aim of this study was to verify simultaneously the distribution and presence of cathepsins B (CT-B) and K (CT-K) in partially demineralized dentin; and further to evaluate the activity of CTs and MMPs in the same tissue. The distribution of CT-B and CT-K in sound human dentin was assessed by immunohistochemistry. A double-immunolabeling technique was used to identify, at once, the occurrence of those enzymes in dentin. Activities of CTs and MMPs in dentin extracts were evaluated spectrofluorometrically. In addition, in situ gelatinolytic activity of dentin was assayed by zymography. The results revealed the distribution of CT-B and CT-K along the dentin organic matrix and also indicated co-occurrence of MMPs and CTs in that tissue. The enzyme kinetics studies showed proteolytic activity in dentin extracts for both classes of proteases. Furthermore, it was observed that, at least for sound human dentin matrices, the activity of MMPs seems to be predominant over the CTs one., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to evaluate the performance of Edmonton Frail Scale (EFS) on frailty assessment in association with multi-dimensional conditions assessed with specific screening tools and to explore the prevalence of frailty by gender., Methods: We enrolled 366 hospitalised patients (women\men: 251\115), mean age 81.5 years. The EFS was given to the patients to evaluate their frailty. Then we collected data concerning cognitive status through Mini-Mental State Examination (MMSE), health status (evaluated with the number of diseases), functional independence (Barthel Index and Activities Daily Living; BI, ADL, IADL), use of drugs (counting of drugs taken every day), Mini Nutritional Assessment (MNA), Geriatric Depression Scale (GDS), Skeletal Muscle Index of sarcopenia (SMI), osteoporosis and functionality (Handgrip strength)., Results: According with the EFS, the 19.7% of subjects were classified as non frail, 66.4% as apparently vulnerable and 13.9% with severe frailty. The EFS scores were associated with cognition (MMSE: β = 0.980; p < 0.01), functional independence (ADL: β = -0.512; p < 0.00); (IADL: β = -0.338; p < 0.01); use of medications (β = 0.110; p < 0.01); nutrition (MNA: β = -0.413; p < 0.01); mood (GDS: β = -0.324; p < 0.01); functional performance (Handgrip: β = -0.114, p < 0.01) (BI: β = -0.037; p < 0.01), but not with number of comorbidities (β = 0.108; p = 0.052). In osteoporotic patients versus not-osteoporotic patients the mean EFS score did not differ between groups (women: p = 0.365; men: p = 0.088), whereas in Sarcopenic versus not-Sarcopenic patients, there was a significant differences in women: p < 0.05., Conclusions: This study suggests that measuring frailty with EFS is helpful and performance tool for stratifying the state of fragility in a group of institutionalized elderly. As matter of facts the EFS has been shown to be associated with several geriatric conditions such independence, drugs assumption, mood, mental, functional and nutritional status.

Background: For the growing numbers of obese elderly with diabetes, the glucagon-like peptide-1 (GLP-1) receptor analogue (liraglutide) appears a safe way to promote and maintain substantial weight loss. Given this background, the aim of this study was to assess the effect of the liraglutide treatment, at doses up to 3.0 mg per day, on the body composition, focusing on sarcopenia, in overweight and obese elderly with type 2 diabetes mellitus (T2DM)., Methods: A perspective study was carried out in overweight and obese T2DM patients with HbA1c equal to 7.0 % (53 mmol/mol) ~10.0 % (86), under 3-month treatment (at least) of maximal dose of metformin at stable regime, and additional liraglutide at doses up to 3.0 mg per day. Body composition markers such as skeletal muscle index (SMI), android and gynoid fat mass, and arms and legs fat free mass, was measured by dual-energy X-ray densitometry (DXA) at baseline and after 24 weeks of liraglutide treatment. Glucose control was also carried out by glucose and HbA1c., Results: Nine subjects (male/female 6/3, mean age 68.22 ± 3.86 years, BMI 32.34 ± 4.89 kg/m 2 ) were evaluated. We noted a median decrease in BMI (-0.78 kg/m 2 ), weight (-2000 g), fat mass (-1498 g) and android fat (-0.9 %), and a increase in SMI (+0.03 kg/m 2 ) from baseline. Glycemic control also improved, with a median change HbA1c of -0.80 %., Conclusions: Twenty-four weeks of liraglutide treatment was associated with reductions in fat mass and android fat. In addition, in order to prevent sarcopenia, it preserved the muscular tropism.

Hazelnuts are rich in monounsaturated fatty acids and antioxidant bioactive substances: their consumption has been associated with a decreased risk of cardiovascular disease events. A systematic review and a meta-analysis was performed to combine the results from several trials and to estimate the pooled (overall) effect of hazelnuts on blood lipids and body weight outcomes. Specifically, a Bayesian random effect meta-analysis of mean differences of Δ-changes from baseline across treatment (MDΔ) (i.e., hazelnut-enriched diet vs. control diet) has been conducted. Nine studies representing 425 participants were included in the analysis. The intervention diet lasted 28-84 days with a dosage of hazelnuts ranging from 29 to 69 g/day. Out of nine studies, three randomized studies have been meta-analyzed showing a significant reduction in low-density lipoprotein (LDL) cholesterol (pooled MDΔ = -0.150 mmol/L; 95% highest posterior density interval (95%HPD) = -0.308; -0.003) in favor of a hazelnut-enriched diet. Total cholesterol showed a marked trend toward a decrease (pooled MDΔ = -0.127 mmol/L; 95%HPD = -0.284; 0.014) and high-density lipoprotein (HDL) cholesterol remained substantially stable (pooled MDΔ = 0.002 mmol/L; 95%HPD = -0.140; 0.147). No effects on triglycerides (pooled MDΔ = 0.045 mmol/L; 95%HPD = -0.195; 0.269) and body mass index (BMI) (pooled MDΔ = 0.062 kg/m²; 95%HPD = -0.293; 0.469) were found. Hazelnut-enriched diet is associated with a decrease of LDL and total cholesterol, while HDL cholesterol, triglycerides and BMI remain substantially unchanged., Competing Interests: The authors declare that they have no competing interests.

The chronic lymphocytic leukemia (CLL) niche is a closed environment where leukemic cells derive growth and survival signals through their interaction with macrophages and T lymphocytes. Here, we show that the CLL lymph node niche is characterized by overexpression and activation of HIF-1α, which increases adenosine generation and signaling, affecting tumor and host cellular responses. Hypoxia in CLL lymphocytes modifies central metabolic pathways, protects against drug-driven apoptosis, and induces interleukin 10 (IL-10) production. In myeloid cells, it forces monocyte differentiation to macrophages expressing IRF4, IDO, CD163, and CD206, hallmarks of the M2 phenotype, which promotes tumor progression. It also induces IL-6 production and enhances nurturing properties. Low oxygen levels decrease T-cell proliferation, promote glycolysis, and cause the appearance of a population of PD-1 + and IL-10-secreting T cells. Blockade of the A2A adenosine receptor counteracts these effects on all cell populations, making leukemic cells more susceptible to pharmacological agents while restoring immune competence and T-cell proliferation. Together, these results indicate that adenosine signaling through the A2A receptor mediates part of the effects of hypoxia. They also suggest that therapeutic strategies to inhibit the adenosinergic axis may be useful adjuncts to chemotherapy or tyrosine kinase inhibitors in the treatment of CLL patients., Competing Interests: Conflict-of-interest disclosure: The authors declare that there is no conflict of interest.

The differential diagnosis between multiple system atrophy with predominant parkinsonism (MSA-P) and Parkinson's disease (PD) may be challenging at disease onset. Levodopa responsiveness helps distinguish the two groups, but studies evaluating this issue using objective standardized tests are scanty. We retrospectively examined the extent of levodopa response by an objective kinetic-dynamic test in a series of patients prospectively followed up for a parkinsonian syndrome and eventually diagnosed as MSA-P or PD. Sixteen MSA-P and 31 PD patients under chronic levodopa therapy received a first morning fasting dose of levodopa/benserazide (100/25 mg) or levodopa/carbidopa (125/12.5 or 100/25 mg) and underwent simultaneous serial assessments of plasma levodopa concentration and alternate finger tapping frequency up to 3 h post dosing. The main levodopa pharmacodynamic variables were the maximum percentage increase in tapping frequency over baseline values (ΔTapmax %) and the area under the tapping effect-time curve (AUCTap). Levodopa pharmacokinetics did not show significant differences between MSA-P and PD, whereas both the magnitude and overall extent of levodopa tapping effect were markedly reduced in the MSA-P group (p < 0.001). The combined use of specific cut-off values for both the main pharmacodynamic variables, ΔTapmax % <20% and AUCTap <1900 [(tapping/min)·min], correctly discriminated 15 out of 16 MSA-P patients from PD patients. A combined estimation of these pharmacodynamic variables after a subacute low levodopa dose may be a simple and practical clinical tool to aid the differential diagnosis between MSA-P and PD.

Background . High HDL-cholesterol (HDL-C) values are negatively correlated with cardiovascular diseases. This review analyses the effect of the supplementation with various Mediterranean diet products (artichoke, bergamot, and olive oil) and Asian diet products (red yeast rice) on the HDL-C value in dyslipidemic subjects. Methods . A systematic review has been done involving all the English written studies published from the 1st of January 1958 to the 31st of March 2016. Results . The results of this systematic review indicate that the dietary supplementation with red yeast rice, bergamot, artichoke, and virgin olive oil has promising effects on the increase of HDL-C serum levels. The artichoke leaf extract and virgin olive oil appear to be particularly interesting, while bergamot extract needs further research and the effect of red yeast rice seems to be limited to patients with previous myocardial infarction. Conclusions . Various MediterrAsian diet products or natural extracts may represent a potential intervention treatment to raise HDL-C in dyslipidemic subjects.

Chronic lymphocytic leukemia (CLL) is a variable disease; therefore, markers to identify aggressive forms are essential for patient management. Here, we have shown that expression of the costimulatory molecule and microbial sensor SLAMF1 (also known as CD150) is lost in a subset of patients with an aggressive CLL that associates with a shorter time to first treatment and reduced overall survival. SLAMF1 silencing in CLL-like Mec-1 cells, which constitutively express SLAMF1, modulated pathways related to cell migration, cytoskeletal organization, and intracellular vesicle formation and recirculation. SLAMF1 deficiency associated with increased expression of CXCR4, CD38, and CD44, thereby positively affecting chemotactic responses to CXCL12. SLAMF1 ligation with an agonistic monoclonal antibody increased ROS accumulation and induced phosphorylation of p38, JNK1/2, and BCL2, thereby promoting the autophagic flux. Beclin1 dissociated from BCL2 in response to SLAMF1 ligation, resulting in formation of the autophagy macrocomplex, which contains SLAMF1, beclin1, and the enzyme VPS34. Accordingly, SLAMF1-silenced cells or SLAMF1(lo) primary CLL cells were resistant to autophagy-activating therapeutic agents, such as fludarabine and the BCL2 homology domain 3 mimetic ABT-737. Together, these results indicate that loss of SLAMF1 expression in CLL modulates genetic pathways that regulate chemotaxis and autophagy and that potentially affect drug responses, and suggest that these effects underlie unfavorable clinical outcome experienced by SLAMF1(lo) patients.

The frequency, presentation, prognosis, and treatment of myocardial ischemia differ in men and women. A large proportion of women who have "normal" coronary arteries on angiography without any significant evidence of flow-limiting disease also have biochemical or imaging evidence of myocardial ischemia. In these women it is believed to be a dysfunction of coronary microcirculation and/or macrocirculation, or vasotonic angina (VA), that leads to abnormal vasoconstriction, and potentially to myocardial infarction, ventricular arrhythmias, and sudden death. Despite having a "normal" or near normal coronary angiography, these women should therefore undergo additional testing with acetylcholine to assess endothelial function. Long-term survival is believed to be relatively good. Predictors of poorer prognosis include documentation of severe endothelial dysfunction and presence of concurrent angiographycally visible coronary atherosclerosis. Because atherosclerosis is common in patients with VA, medical and lifestyle interventions for preventing or treating atherosclerosis should be implemented when appropriate. Angiotensin converting enzyme inhibitors are the mainstays of medical therapy for VA. Other agents have been tried with variable success, including beta-blockers. There are no available data on any specific treatment of VA in women (versus men).

Objective: Adding antimicrobial/anti-MMP quaternary ammonium methacrylates (QAMs) to comonomer blends should not weaken the mechanical properties of dental resins. This work evaluated the degree conversion and mechanical properties of BisGMA/TEGDMA/HEMA (60:30:10) containing 0-15 mass% QAMs A-E (A: 2-acryloxyethyltrimethyl ammonium chloride; B: [3-(methacryloylamino)propyl]trimethylammonium chloride; C: [2-(methacryloxy)ethyl] trimethyl ammonium chloride; D: diallyldimethyl ammonium chloride; E: 2-(methacryloyloxy) ethyltrimethyl ammonium methyl sulfate., Methods: Unfilled resins with and without QAM were placed on ATR-FTIR and light-polymerized for 20s in a thin film at 30°C. Unfilled resin beams were casted from square hollow glass tubings. Half of the beams were tested after 3 days of drying (control); the other half were tested wet after 3 days of water storage., Results: Addition of QAMs in control resins significantly increased conversion 600 s after light termination, with the exception of 5% MAPTAC (p<0.05). Increase of QAM content within a formulation significantly increased conversion. Control beams gave dry Young's moduli of ∼700 MPa. Addition of 5, 10 or 15 mass% QAMs produced significant reductions in dry Young's moduli except for 5% B or C. 15 mass% A, B and C lowered the wet Young's moduli of the resin beams by more than 30%. The ultimate tensile stress (UTS) of control dry resin was 89±11 MPa. Addition of 5-10 mass% QAMs had no adverse effect on the dry UTS. After water storage, the UTS of all resin blends fell significantly (p<0.05), especially when 15 wt% QAMs was added. Control dry beams gave fracture toughness (KIC) values of 0.88±0.1 MPa m(1/2). Wet values were significantly higher at 1.02±0.06 (p<0.05). KIC of dry beams varied from 0.85±0.08 at 5% QAMs to 0.49±0.05 at 15% QAMs. Wet beams gave KIC values of 1.02±0.06 MPa m(1/2) that fell to 0.23±0.01 at 15% QAMs., Significance: Addition of 10% QAMs increased the degree of conversion of unfilled resins, but lowered wet toughness and UTS; addition of 15% QAMs lowered the mechanical properties of wet resins below acceptable levels., (Copyright © 2014 Academy of Dental Materials. All rights reserved.)

Poly(hydroxyalkanoates) (PHAs) are polyesters formed by saturated short chain hydroxyacids, among which 3-hydroxybutanoic (HB) and 3-hydroxypentanoic (3-hydroxyvalerate, HV) are the most common monomers of homopolymers (e.g. poly(3-hydroxybutyrate), PHB) and copolymers (e.g. poly(3-hydroxybutyrate-co-3-hydroxyhexanoate), PHB-HC). The most widely used approach for their determination is the polymer methanolysis followed by gas chromatography-mass spectrometry (GC-MS) analysis of the methylated monomers; this procedure generally requires the use of additional reagents (e.g. sulfuric acid) and is performed with harmful chlorinated solvents, such as chloroform. The development of fast routine solventless methods for the quantitative determination of PHAs and their monomeric composition is highly desirable to reduce sample pretreatment, speed up the analysis and decrease overall costs. It has been reported that under thermal treatment (e.g. pyrolysis, Py), PHAs are degraded in high yield (>40%, w/wPHA) into the corresponding 2-alkenoic acid (e.g. crotonic acid from PHB). This work aimed at investigating this reaction for direct analysis of PHAs in bacterial cells. The sample was directly subjected to pyrolysis and trapped pyrolysis products were analyzed by GC-FID. Off-line Py/GC-FID was first optimized on pure polymers with different monomer composition (PHB, PHB-HV, PHB-HC) and then applied to bacterial samples deriving from both mixed microbial cultures or selected strains, containing various types and amounts of PHAs. The Py/GC-FID method provided RSD <15% range, limit of detection of 100μg (1% PHAs in biomass), and results comparable to that of methanolysis (R(2)=0.9855), but with minimal sample pretreatment., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: The objective of this study was to determine if Gluma dentin desensitizer (5.0% glutaraldehyde and 35% HEMA in water) can inhibit the endogenous MMPs of dentin matrices in 60 s and to evaluate its effect on dentin matrix stiffness and dry mass weight., Methods: Dentin beams of 2 mm×1 mm×6 mm were obtained from extracted human third molars coronal dentin. To measure the influence of Gluma treatment time on total MMP activity of dentin, beams were dipped in 37% phosphoric acid (PA) for 15 s and rinsed in water. The acid-etched beams were then dipped in Gluma for 5, 15, 30 or 60 s, rinsed in water and incubated into SensoLyte generic MMP substrate (AnaSpec, Inc.) for 60 min. Controls were dipped in water for 60 s. Additional beams of 1 mm×1 mm×6 mm were completely demineralized in 37% PA for 18 h, rinsed and used to evaluate changes on the dry weight and modulus of elasticity (E) after 60 s of Gluma treatment followed by incubation in simulated body fluid buffer for 0, 1 or 4 weeks. E was measured by 3-pt flexure., Results: Gluma treatment inhibited total MMP activity of acid-etched dentin by 44, 50, 84, 86% after 5, 15, 30 or 60 s of exposure, respectively. All completely demineralized dentin beams lost stiffness after 1 and 4 weeks, with no significant differences between the control and Gluma-treated dentin. Gluma treatment for 60 s yielded significantly less dry mass loss than the control after 4 weeks., Significance: The use of Gluma may contribute to the preservation of adhesive interfaces by its cross-linking and inhibitory properties of endogenous dentin MMPs., (Copyright © 2014 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.)

Objectives: The aim of this study was to investigate the adhesive stability over time of a multi-mode one-step adhesive applied using different bonding techniques on human coronal dentine. The hypotheses tested were that microtensile bond strength (μTBS), interfacial nanoleakage expression and matrix metalloproteinases (MMPs) activation are not affected by the adhesive application mode (following the use of self-etch technique or with the etch-and-rinse technique on dry or wet dentine) or by ageing for 24h, 6 months and 1year in artificial saliva., Methods: Human molars were cut to expose middle/deep dentine and assigned to one of the following bonding systems (N=15): (1) Scotchbond Universal (3M ESPE) self-etch mode, (2) Scotchbond Universal etch-and-rinse technique on wet dentine, (3) Scotchbond Universal etch-and-rinse technique on dry dentine, and (4) Prime&Bond NT (Dentsply De Trey) etch-and-rinse technique on wet dentine (control). Specimens were processed for μTBS test in accordance with the non-trimming technique and stressed to failure after 24h, 6 months or 1 year. Additional specimens were processed and examined to assay interfacial nanoleakage and MMP expression., Results: At baseline, no differences between groups were found. After 1 year of storage, Scotchbond Universal applied in the self-etch mode and Prime&Bond NT showed higher μTBS compared to the other groups. The lowest nanoleakage expression was found for Scotchbond Universal applied in the self-etch mode, both at baseline and after storage. MMPs activation was found after application of each tested adhesive., Conclusions: The results of this study support the use of the self-etch approach for bonding the tested multi-mode adhesive system to dentine due to improved stability over time., Clinical Significance: Improved bonding effectiveness of the tested universal adhesive system on dentine may be obtained if the adhesive is applied with the self-etch approach., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Growing number of publication has proved an increasing of cellular function of the Fanconi anemia proteins. To chromosome stability and DNA repair new roles have been attributed to FA proteins in oxidative stress response and homeostasis, immune response and cytokines sensibility, gene expression. Our work shows a new role for FA-A protein: the organization of the cellular structure. By 2D-PAGE of FA-A and correct fibroblasts treated and untreated with H2O2 we identify different expression of protein involved in the structural organization of nucleus, intermediate filaments and mitochondria. Immunofluorescence and electronic microscopy analysis clearly show an already altered cellular structure in normal culture condition and this worsted after oxidative stress. FA-A cell appears structurally prone to physiologic stress and this could explain part of the phenotype of FA cells., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Multiple system atrophy (MSA) is a neurodegenerative disease characterised by cardiovascular autonomic failure and/or urinary dysfunctions, associated with parkinsonism, cerebellar and/or corticospinal signs, usually leading to death after an average of 7 years. We describe the disease course of five patients diagnosed with probable MSA (4 with predominant parkinsonism and 1 with predominant cerebellar ataxia) who survived for more than 15 years and were followed throughout the disease course at our department. Cardiovascular autonomic dysfunction of any severity occurred late (mean latency from disease onset 9.4 ± 5 years) in this subgroup of MSA patients. The time of involvement of the urogenital system was more variable (from 0 to 14 years after disease onset) and manifested with symptoms of storage disorders (urinary urgency, frequency and incontinence) and erectile dysfunction in men. Conversely complains suggestive of urinary voiding dysfunction (incomplete bladder emptying and urinary retention) were not recorded and patients required catheterization only late in the disease course. In conclusion, our study showed that late onset of both cardiovascular autonomic failure and urinary voiding disorders may be positive prognostic factors in MSA irrespective of the MSA subtype.

We have previously demonstrated that intraperitoneal injections of 2'-O-methyl-phosphorothioate (2'OMePS) antisense oligoribonucleotides adsorbed onto a cationic core-shell nanoparticles (NPs), termed ZM2, provoke dystrophin restoration in the muscles of mdx mice. The aim of the present work was to evaluate the oral route as an alternative way of administration for ZM2-antisense oligoribonucleotides complexes. The biodistribution and elimination of nanoparticles were evaluated after single and multiple oral doses of IR-dye conjugated nanoparticles. Labeled nanoparticles were tracked in vivo as well as in tissue cryosections, urines and feces by Odyssey infrared imaging system, and revealed a permanence in the intestine and abdominal lymph nodes for 72 hours to 7 days before being eliminated. We subsequently tested alginate-free and alginate-encapsulated ZM2-antisense oligoribonucleotides (AON) complexes orally administered 2 and 3 times per week, respectively, in mdx mice for a total of 12 weeks. Treatment with alginate ZM2-AON induced a slight dystrophin rescue in diaphragm and intestine smooth muscles, while no dystrophin was detected in alginate-free ZM2-AON treated mice. These data encourage further experiments on oral administration testing of NP and AON complexes, possibly translatable in oligoribonucleotides-mediated molecular therapies.

Chronic lymphocytic leukemia (CLL) cells display features consistent with a defect in apoptosis and exhibit prolonged survival in vivo. Survival of these malignant cells is influenced by interactions with non-leukemic cells located in permissive niches in lymphoid organs. Leukemic cells subvert the normal architecture of the lymphoid organs, recruiting stromal cells, dendritic cells and T lymphocytes, all reported as playing active roles in the survival and proliferation of CLL. The same survival-promoting environment also rescues/protects leukemic cells from cytotoxic therapies, giving way to disease relapse. This review summarizes and discusses current knowledge about the intricate network of soluble and cell-bound signals regulating the life and death of CLL cells in different districts. At the same time, it seeks to hone in on which discrete molecular elements are best suited as targets for treating this still incurable disease., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Human CD38, an ecto-enzyme and a receptor, performs as an independent negative prognostic marker for patients with chronic lymphocytic leukemia (CLL), a hematological malignancy characterized by the accumulation of a population of mature B lymphocytes expressing CD5. Patients with a CD38⁺ CLL clone display a more aggressive form of the disease with earlier treatment requirements and ultimately shorter overall survival than patients with a CD38⁻ clone. Several lines of evidence indicate that CD38 is not only a diagnostic marker but also a key element in the molecular network regulating disease maintenance and progression. First, CD38 is a receptor that induces proliferation and increases survival of CLL cells. Second, CD38 signals facilitate access of CLL cells to growth-favorable districts. This is achieved by enhancing i) chemotaxis towards CXCL12, ii) integrin-mediated adhesion and iii) matrix metalloprotease synthesis and secretion. Third, blocking monoclonal antibodies targeting CD38 impair CLL homing to spleen and bone marrow in xenograft models. These functions appear to be modulated by frontal interactions with CD31 as well as by lateral associations on the CLL membrane to form a large supramolecular complex similar to the invadosomes of epithelial cells. Our understanding has evolved from considering CD38 as a marker of unfavorable prognosis to recognizing its function as a disease modifier. Studies in the next few years will likely determine whether the molecule can also serve as a target for new therapies, using monoclonal antibodies, inhibitors of the enzymatic activity or both.

Prelamin A is the precursor protein of lamin A, a major constituent of the nuclear lamina in higher eukaryotes. Increasing attention to prelamin A processing and function has been given after the discovery, from 2002 to 2004, of diseases caused by prelamin A accumulation. These diseases, belonging to the group of laminopathies and mostly featuring LMNA mutations, are characterized, at the clinical level, by different degrees of accelerated aging, and adipose tissue, skin and bone abnormalities. The outcome of studies conducted in the last few years consists of three major findings. First, prelamin A is processed at different rates under physiological conditions depending on the differentiation state of the cell. This means that, for instance, in muscle cells, prelamin A itself plays a biological role, besides production of mature lamin A. Secondly, prelamin A post-translational modifications give rise to different processing intermediates, which elicit different effects in the nucleus, mostly by modification of the chromatin arrangement. Thirdly, there is a threshold of toxicity, especially of the farnesylated form of prelamin A, whose accumulation is obviously linked to cell and organism senescence. The present review is focused on prelamin A-mediated nuclear envelope modifications that are upstream of chromatin dynamics and gene expression mechanisms regulated by the lamin A precursor.

Activation of Akt-mediated signaling pathways is crucial for survival, differentiation, and regeneration of muscle cells. A proteomic-based search for novel substrates of Akt was therefore undertaken in C(2)C(12) murine muscle cells exploiting protein characterization databases in combination with an anti-phospho-Akt substrate antibody. A Scansite database search predicted Ankrd2 (Ankyrin repeat domain protein 2, also known as ARPP) as a novel substrate of Akt. In vitro and in vivo studies confirmed that Akt phosphorylates Ankrd2 at Ser-99. Moreover, by kinase assay with recombinant Akt1 and Akt2, as well as by single-isoform silencing, we demonstrated that Ankrd2 is a specific substrate of Akt2. Ankrd2 is typically found in skeletal muscle cells, where it mediates the transcriptional response to stress conditions. In an attempt to investigate the physiological implications of Ankrd2 phosphorylation by Akt2, we found that oxidative stress induced by H(2)O(2) triggers this phosphorylation. Moreover, the forced expression of a phosphorylation-defective mutant form of Ankrd2 in C(2)C(12) myoblasts promoted a faster differentiation program, implicating Akt-dependent phosphorylation at Ser-99 in the negative regulation of myogenesis in response to stress conditions.

Nicotinamide adenine dinucleotide (NAD(+)) is an essential co-enzyme that can be released in the extracellular milieu. Here, it may elicit signals through binding purinergic receptors. Alternatively, NAD(+) may be dismantled to adenosine, up-taken by cells and transformed to reconstitute the intracellular nucleotide pool. An articulated ecto-enzyme network is responsible for the nucleotide-nucleoside conversion. CD38 is the main mammalian enzyme that hydrolyzes NAD(+), generating Ca(2+)-active metabolites. Evidence suggests that this extracellular network may be altered or used by tumor cells to (i) nestle in protected areas, and (ii) evade the immune response. We have exploited chronic lymphocytic leukemia as a model to test the role of the ecto-enzyme network, starting by analyzing the individual elements that make up the whole picture., (Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Human CD38 is a cell surface molecule endowed with multiple functions. As an enzyme, it catalyzes the production of Ca2+ active metabolites, predominantly cADPR and ADPR. As a receptor, it regulates the activation of an intracellular signaling pathway, generally linked to lymphocyte activation and proliferation in physiological conditions. The finding that CD38 behaves as an independent negative prognostic factor in CLL patients was the starting point for investigations into the functional role of the molecule in the neoplastic context. Data accumulating in over a decade concur to define a model where CD38 is a central element of a large supramolecular complex that includes surface signaling receptors, chemokine receptors, adhesion molecules and matrix metalloproteases. Expression of CD38 within this supramolecular complex makes signal transduction as well as chemotaxis and homing more efficient, suggesting that the molecule is an integrator of proliferative and migratory signals. These data indicate that CD38 is not only a reliable disease marker but also a functional molecule in the CLL context. The next decade will likely tell whether it can also be a useful therapeutic target.

Lamin A, a protein component of the nuclear lamina, is synthesized as a precursor named prelamin A, whose multi-step maturation process involves different protein intermediates. As demonstrated in laminopathies such as familial partial lipodystrophy, mandibuloacral dysplasia, Werner syndrome, Hutchinson-Gilford progeria syndrome and restrictive dermopathy, failure of prelamin A processing results in the accumulation of lamin A protein precursors inside the nucleus which dominantly produces aberrant chromatin structure. To understand if nuclear lamina components may be involved in prelamin A chromatin remodeling effects, we investigated barrier-to-autointegration factor (BAF) localization and expression in prelamin A accumulating cells. BAF is a DNA-binding protein that interacts directly with histones, lamins and LEM-domain proteins and has roles in chromatin structure, mitosis and gene regulation. In this study, we show that the BAF heterogeneous localization between nucleus and cytoplasm observed in HEK293 cycling cells changes in response to prelamin A accumulation. In particular, we observed that the accumulation of lamin A, non-farnesylated prelamin A and farnesylated carboxymethylated lamin A precursors induce BAF nuclear translocation. Moreover, we show that the treatment of human fibroblasts with prelamin A interfering drugs results in similar changes. Finally, we report that the accumulation of progerin, a truncated form of farnesylated and carboxymethylated prelamin A identified in Hutchinson-Gilford progeria syndrome cells, induces BAF recruitment in the nucleus. These findings are supported by coimmunoprecipitation of prelamin A or progerin with BAF in vivo and suggest that BAF could mediate prelamin A-induced chromatin effects., (© 2010 Landes Bioscience)

The contact time (CT) and the ratio between the duration of braking (BP) and propulsion phase (PP) during the support are two mechanical parameters that are relevant for the performance in sprinting. Several different kinematic methods have been used to estimate the BP-PP transition point, with some disagreements among studies. The purpose of this study was to compare three criteria to individuate that point: the maximum knee flexion (KNEEFLEX), the maximum fall of the COM (COMVERT) and the horizontal COM acceleration (COMHORIZ). It was hypothesized that these three events would take place in different instants, representing different moments of the step cycle. The kinematic analysis was performed through stereophotogrammetry on seven male middle-level sprinters (mean + or - SD height: 180 + or - 5 cm; body mass: 75 + or - 11 kg; personal best on 100 m: 10.96 + or - 0.45 s). The COMVERT expressed as percentage of CT (mean + or - SD 31.73 + or - 8.29%) was on average strongly anticipated compared to both KNEEFLEX (45.07 + or -3.60%, p < 0.01) and COMHORIZ (56.86 + or - 8.56%, p < 0.01). The approximately 12% difference between KNEEFLEX and COMHORIZ was also statistically significant (p < 0.01). The 40-60% relative proportion of BP and PP considered to be optimal in the literature, was reflected in this study only by the KNEEFLEX criterion. Given the importance of BP time as a reference parameter to assess the training status and efficacy of training interventions, it looks necessary both from a scientific and applied perspective to consider a standardized criterion to identify the BP-PP transition point., (Copyright 2009 Elsevier B.V. All rights reserved.)

Lamin A/C is a nuclear lamina constituent mutated in a number of human inherited disorders collectively referred to as laminopathies. The occurrence and significance of lamin A/C interplay with signaling molecules is an old question, suggested by pioneer studies performed in vitro. However, this relevant question has remained substantially unanswered, until data obtained in cellular and organismal models of laminopathies have indicated two main aspects of lamin A function. The first aspect is that lamins establish functional interactions with different protein platforms, the second aspect is that lamin A/C activity and altered function may elicit different effects in different cells and tissue types and even in different districts of the same tissue. Both these observations strongly suggest that signaling mechanisms targeting lamin A/C or its binding partners may regulate such a plastic behavior. A number of very recent data show involvement of kinases, as Akt and Erk, or phosphatases, as PP1 and PP2, in lamin A-linked cellular mechanisms. Moreover, altered activation of signaling in laminopathies and rescue of the pathological phenotype in animal models by inhibitors of signaling pathways, strongly suggest that signaling effectors related to lamin A/C may be implicated in the pathogenesis of laminopathies and may represent targets of therapeutic intervention. In face of such an open perspective of basic and applied research, we review current evidence of lamin A/C interplay with signaling molecules, with particular emphasis on the lamin A-Akt interaction and on the biological significance of their relationship.

Background Information: Emerin is a nuclear envelope protein that contributes to nuclear architecture, chromatin structure, and gene expression through its interaction with various nuclear proteins. In particular, emerin is molecularly connected with the nuclear lamina, a protein meshwork composed of lamins and lamin-binding proteins underlying the inner nuclear membrane. Among nuclear lamina components, lamin A is a major emerin partner. Lamin A, encoded by the LMNA gene (lamin A/C gene), is produced as a precursor protein (prelamin A) that is post-transcriptionally modified at its C-terminal region where the CaaX motif triggers a sequence of modifications, including farnesylation, carboxymethylation, and proteolytic cleavage by ZMPSTE 24 (zinc metalloproteinase Ste24) metalloproteinase. Impairment of the lamin A maturation pathway causing lamin A precursor accumulation is linked to the development of rare diseases such as familial partial lipodystrophy, MADA (mandibuloacral dysplasia), the Werner syndrome, Hutchinson-Gilford progeria syndrome and RD (restrictive dermopathy)., Results: In the present study, we show that emerin and different prelamin A forms influence each other's localization. We show that the accumulation of non-farnesylated as well as farnesylated carboxymethylated lamin A precursors in human fibroblasts modifies emerin localization. On the contrary, emerin absence at the inner nuclear membrane leads to unprocessed (non-farnesylated) prelamin A aberrant localization only. Moreover, we observe that the restoration of emerin expression in emerin-null cells induces the recovery of non-farnesylated prelamin A localization., Conclusion: These results indicate that emerin-prelamin A interplay influences nuclear organization. This finding may be relevant to the understanding of laminopathies.

Lamin A is a component of the nuclear lamina mutated in a group of human inherited disorders known as laminopathies. Among laminopathies, progeroid syndromes and lipodystrophies feature accumulation of prelamin A, the precursor protein which, in normal cells, undergoes a multi-step processing to yield mature lamin A. It is of utmost importance to characterize the prelamin A form accumulated in each laminopathy, since existing evidence shows that drugs acting on protein processing can improve some pathological aspects. We report that two antibodies raised against differently modified prelamin A peptides show a clear specificity to full-length prelamin A or carboxymethylated farnesylated prelamin A, respectively. Using these antibodies, we demonstrated that inhibition of the prelamin A endoprotease ZMPSTE24 mostly elicits accumulation of full-length prelamin A in its farnesylated form, while loss of the prelamin A cleavage site causes accumulation of carboxymethylated prelamin A in progeria cells. These results suggest a major role of ZMPSTE24 in the first prelamin A cleavage step.