Autoantibodies against chemokines post-SARS-CoV-2 infection correlate with disease course.

Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.

Prognostic Impact of Blood Lipid Profile in Patients With Advanced Solid Tumors Treated With Immune Checkpoint Inhibitors: A Multicenter Cohort Study.

BACKGROUND: Specific components of lipid profile seem to differently impact on immune activity against cancer and unraveling their prognostic role in patients with solid cancer treated with immune checkpoint inhibitors (ICIs) is needed. MATERIALS AND METHODS: We retrospectively collected baseline clinicopathological characteristics including circulating lipid profile (total cholesterol [TC], triglycerides [TG], low-density lipoproteins [LDL], high-density lipoproteins [HDL]) of patients with consecutive solid cancer treated with ICIs, and we investigated their role in predicting clinical outcomes. RESULTS: At a median follow-up of 32.9 months, among 430 enrolled patients, those with TC ≥ 200 mg/dl showed longer median progression-free survival (mPFS; 6.6 vs. 4.7 months, P = .4), although not reaching statistical significance, and significantly longer median overall survival (mOS; 19.4 vs. 10.8 months, P = .02) compared to those with TC < 200 mg/dl. Conversely, patients with TG ≥150 mg/dl displayed shorter PFS (3.4 vs. 5.1 months, P = .02) and OS (7.1 vs. 12.9 months, P = .009) compared to those with TG <150 mg/dl. TC and TG were then combined in a "LIPID score" identifying three subgroups: good-risk (GR) (TC ≥200 mg/dl and TG <150 mg/dl), intermediate-risk (IR) (TC <200 mg/dl and TG <150 mg/dl or TC ≥200 mg/dl and TG ≥150 mg/dl) and poor-risk (PR) (TC <200 mg/dl and TG ≥150 mg/dl). The mPFS of GR, IR, and PR groups was 7.8, 4.3, and 2.5 months, respectively (P = .005); mOS of GR, IR, and PR was 20.4, 12.4, and 5.3 months, respectively (P < .001). At multivariable analysis, the PR profile represented an independent poor prognostic factor for both PFS and OS. CONCLUSIONS: We developed a lipid score that defined subgroups of patients with cancer who differently benefit from ICIs. Further mechanistic insights are warranted to clarify the prognostic and predictive role of lipid profile components in patients treated with ICIs.

Minor head injury in anticoagulated patients: performance of biomarkers S100B, NSE, GFAP, UCH-L1 and Alinity TBI in the detection of intracranial injury. A prospective observational study.

OBJECTIVES: Data in literature indicate that in patients suffering a minor head injury (MHI), biomarkers serum levels could be effective to predict the absence of intracranial injury (ICI) on head CT scan. Use of these biomarkers in case of patients taking oral anticoagulants who experience MHI is very limited. We investigated biomarkers as predictors of ICI in anticoagulated patients managed in an ED. METHODS: We conducted a single-cohort, prospective, observational study in an ED. Our structured clinical pathway included a first head CT scan, 24 h observation and a second CT scan. The outcome was delayed ICI (dICI), defined as ICI on the second CT scan after a first negative CT scan. We assessed the sensitivity (SE), specificity (SP), negative predictive value (NNV) and positive predictive value (PPV) of the biomarkers S100B, NSE, GFAP, UCH-L1 and Alinity TBI in order to identify dICI. RESULTS: Our study population was of 234 patients with a negative first CT scan who underwent a second CT scan. The rate of dICI was 4.7 %. The NPV for the detection of dICI were respectively (IC 95 %): S100B 92.7 % (86.0-96.8 %,); ubiquitin C-terminal hydrolase-L1 (UCH-L1) 91.8 % (83.8-96.6 %); glial fibrillary protein (GFP) 100 % (83.2-100 %); TBI 100 % (66.4-100 %). The AUC for the detection of dICI was 0.407 for S100B, 0.563 for neuron-specific enolase (NSE), 0.510 for UCH-L1 and 0.720 for glial fibrillary acidic protein (GFAP), respectively. CONCLUSIONS: The NPV of the analyzed biomarkers were high and they potentially could limit the number of head CT scan for detecting dICI in anticoagulated patients suffering MHI. GFAP and Alinity TBI seem to be effective to rule out a dCI, but future trials are needed.

Early administration of tofacitinib in COVID-19 pneumonitis: An open randomised controlled trial.

BACKGROUND: Controversies on sub-populations most sensitive to therapy and the best timing of starting the treatment still surround the use of immunomodulatory drugs in COVID-19. OBJECTIVES: We designed a multicentre open-label randomised controlled trial to test the effect of prompt adding of tofacitinib to standard therapy for hospitalised patients affected by mild/moderate COVID-19 pneumonitis. METHODS: Patients admitted to three Italian hospitals affected by COVID-19 pneumonitis not requiring mechanical ventilation were randomised to receive standard treatment alone or tofacitinib (10 mg/bid) for 2 weeks, starting within the first 24 h from admission. RESULTS: A total of 116 patients were randomised; 49 in the experimental arm completed the 14-day treatment period, 9 discontinued tofacitinib as the disease worsened and were included in the analysis, and 1 died of respiratory failure. All 58 control patients completed the study. Clinical and demographic characteristics were similar between the study groups. In the tofacitinib group, 9/58 (15.5%) patients progressed to noninvasive ventilation (CPAP) to maintain SO2 > 93%, invasive mechanical ventilation or death by day 14 was 15.5%, significantly less than in the control group (20/58, 34.4%, RR 0,45, RRR -55%, NNT 5; p = .018). No differences in severe adverse effect incidence had been observed across the groups. CONCLUSION: High-dose tofacitinib therapy in patients with COVID pneumonitis is safe and may prevent deterioration to respiratory failure.

Use of Exploratory Factor Analysis to Assess the Fitness Performance of Youth Football Players.

ABSTRACT: Perroni, F, Castagna, C, Amatori, S, Gobbi, E, Vetrano, M, Visco, V, Guidetti, L, Baldari, C, Luigi Rocchi, MB, and Sisti, D. Use of exploratory factor analysis to assess the fitness performance of youth football players. J Strength Cond Res 37(7): e430-e437, 2023-Football performance involves several physical abilities that range in aerobic, anaerobic, and neuromuscular domains; however, little is known about their interplay in profiling individual physical attributes. This study aimed to profile physical performance in youth football players according to their training status. One hundred seven young male soccer players (age 13.5 ± 1.4 years; height 168 ± 7 cm; body mass 57.4 ± 9.6 kg; and body mass index 20.2 ± 2.1 kg·m -2 ) volunteered for this study. Players' physical performance was assessed with football-relevant field tests for sprinting (10 m sprint), vertical jump (countermovement jump), intermittent high-intensity endurance (Yo-Yo Intermittent Recovery Test Level 1, YYIRT1), and repeated sprint ability (RSA). The training status was assumed as testosterone and cortisol saliva concentrations; biological maturation was estimated using the Pubertal Development Scale. Exploratory factor analysis (EFA) revealed 3 main variables depicting anthropometric (D1, 24.9%), physical performance (D2, 18.8%), and training status (D3, 13.3%), accounting for 57.0% of total variance altogether. The level of significance was set at p ≤ 0.05. The RSA and YYIRT1 performances were largely associated with D2, suggesting the relevance of endurance in youth football. This study revealed that for youth football players, a 3-component model should be considered to evaluate youth soccer players. The EFA approach may help to disclose interindividual differences useful to talent identification and selection.

Alarming Drop in Early Stage Colorectal Cancer Diagnoses After COVID-19 Outbreak: A Real-World Analysis from the Italian COVID-DELAY Study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has triggered the disruption of health care on a global scale. With Italy tangled up in the pandemic response, oncology care has been largely diverted and cancer screenings suspended. Our multicenter Italian study aimed to evaluate whether COVID-19 has impacted access to diagnosis, staging, and treatment for patients newly diagnosed with colorectal cancer (CRC), compared with pre-pandemic time. METHODS: All consecutive new CRC patients referred to 8 Italian oncology institutions between March and December 2020 were included. Access rate and temporal intervals between date of symptoms onset, radiological and cytohistological diagnosis, treatment start and first radiological evaluation were analyzed and compared with the same months of 2019. RESULTS: A reduction (29%) in newly diagnosed CRC cases was seen when compared with 2019 (360 vs 506). New CRC patients in 2020 were less likely to be diagnosed with early stage (stages I-II-III) CRC (63% vs 78%, P < .01). Gender and sidedness were similar regardless of the year. The percentage of tumors with any mutation among BRAF, NRAS, and KRAS genes were significantly different between the 2 years (61% in 2020 vs 50% in 2019, P = .04). Timing of access to cancer diagnosis, staging, and treatment for patients with CRC has not been negatively affected by the pandemic. Significantly shorter temporal intervals were observed between symptom onset and first oncological appointment (69 vs 79 days, P = .01) and between histological diagnosis and first oncological appointment (34 vs 42 days, P < .01) during 2020 compared with 2019. Fewer CRC cases were discussed in multidisciplinary meetings during 2020 (38% vs 50%, P = .01). CONCLUSIONS: Our data highlight a significant drop in CRC diagnosis after COVID-19, especially for early stage disease. The study also reveals a remarkable setback in the multidisciplinary management of patients with CRC. Despite this, Italian oncologists were able to ensure diagnostic-therapeutic pathways proper operation after March 2020.

Human-rat integrated microRNAs profiling identified a new neonatal cerebral hypoxic-ischemic pathway melatonin-sensitive.

Neonatal encephalopathy (NE) is a pathological condition affecting long-term neurodevelopmental outcomes. Hypothermia is the only therapeutic option, but does not always improve outcomes; hence, researchers continue to hunt for pharmaceutical compounds. Melatonin treatment has benefitted neonates with hypoxic-ischemic (HI) brain injury. However, unlike animal models that enable the study of the brain and the pathophysiologic cascade, only blood is available from human subjects. Therefore, due to the unavailability of neonatal brain tissue, assumptions about the pathophysiology in pathways and cascades are made in human subjects with NE. We analyzed animal and human specimens to improve our understanding of the pathophysiology in human neonates. A neonate with NE who underwent hypothermia and enrolled in a melatonin pharmacokinetic study was compared to HI rats treated/untreated with melatonin. MicroRNA (miRNA) analyses provided profiles of the neonate's plasma, rat plasma, and rat brain cortexes. We compared these profiles through a bioinformatics tool, identifying Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways common to HI brain injury and melatonin treatment. After evaluating the resulting pathways and the literature, to validate the method, the key proteins expressed in HI brain injury were investigated using cerebral cortexes. The upregulated miRNAs in human neonate and rat plasma helped identify two KEGG pathways, glioma and long-term potentiation, common to HI injury and melatonin treatment. A unified neonatal cerebral melatonin-sensitive HI pathway was designed and validated by assessing the expression of protein kinase Cα (PKCα), phospho (p)-Akt, and p-ERK proteins in rat brain cortexes. PKCα increased in HI-injured rats and further increased with melatonin. p-Akt and p-ERK returned phosphorylated to their basal level with melatonin treatment after HI injury. The bioinformatics analyses validated by key protein expression identified pathways common to HI brain injury and melatonin treatment. This approach helped complete pathways in neonates with NE by integrating information from animal models of HI brain injury.

Monocyte distribution width (MDW): a useful biomarker to improve sepsis management in Emergency Department.

OBJECTIVES: Sepsis is a time-dependent and life-threating condition. Despite several biomarkers are available, none of them is completely reliable for the diagnosis. This study aimed to evaluate the diagnostic utility of monocyte distribution width (MDW) to early detect sepsis in adult patients admitted in the Emergency Department (ED) with a five part differential analysis as part of the standard clinical practice. METHODS: A prospective cohort study was conducted on 985 patients aged from 18 to 96 and included in the study between November 2019 and December 2019. Enrolled subjects were classified into four groups based on sepsis-2 diagnostic criteria: control, Systemic Inflammatory Response Syndrome (SIRS), infection and sepsis. The hematology analyzer DxH 900 (Beckman Coulter Inc.) provides the new reportable parameter MDW, included in the leukocyte 5 part differential analysis, cleared by Food and Drug administration (FDA) and European Community In-Vitro-Diagnostic Medical Device (CE IVD) marked as early sepsis indicator (ESId). RESULTS: MDW was able to differentiate the sepsis group from all other groups with Area Under the Curve (AUC) of 0.849, sensitivity of 87.3% and specificity of 71.7% at cut-off of 20.1. MDW in combination with white blood cell (WBC) improves the performance for sepsis detection with a sensitivity increased up to 96.8% when at least one of the two biomarkers are abnormal, and a specificity increased up to 94.6% when both biomarkers are abnormal. CONCLUSIONS: MDW can predict sepsis increasing the clinical value of Leukocyte 5 Part Differential analysis and supporting the clinical decision making in sepsis management at the admission to the ED.

Adherence to and effectiveness of lenalidomide after 1 year of treatment in a real world setting.

BACKGROUND: In combination with dexamethasone, lenalidomide is prescribed in the oral treatment of Multiple Myeloma for patients who have received at least one previous therapy. OBJECTIVE: The objective of this study is to evaluate medication adherence to lenalidomide of Multiple Myeloma patients, as well as Progression Free Survival and Overall Survival one year from the beginning of the treatment. SETTING: The study was carried out in Pescara Hospital, in Italy. All Multiple Myeloma patients who began lenalidomide therapy between January 1, 2012 and June 30, 2016 were included in our study. METHODS: Adherence to treatment was calculated by using the ratio between the Received Daily Dose and the Prescribed Daily Dose. Effectiveness in real world has been evaluated as Progression Free Survival and Overall Survival one year from the beginning of the treatment.Main outcomes measure: We assessed medication adherence and effectiveness of lenalidomide in the treatment of Multiple Myeloma. RESULTS: Adherence to the overall mean treatment was 0.73 ± 0.15, relative to 81 patients evaluated in our study. 32% of patients achieved an adherence equal to or greater than 80%. Real-life effectiveness in terms of Progression Free Survival and Overall Survival showed values of ​​53.75% and 88%, respectively, one year from the beginning of treatment. CONCLUSION: The analysis of adherence in Multiple Myeloma patients treated with lenalidomide one year from the beginning of therapy reveal a concerning lack of adherence. Moreover, the lack of correlation of the levels of adherence with patient-related variables shows that, in the case of Multiple Myeloma, adherence is not related to personal, social and environmental characteristics that may determine each patient's correct treatment implementation, but is directly influenced by disease evolution.

Sex and HDAC4 Differently Affect the Pathophysiology of Amyotrophic Lateral Sclerosis in SOD1-G93A Mice.

Amyotrophic Lateral Sclerosis (ALS) is a devastating adult-onset neurodegenerative disease, with ineffective therapeutic options. ALS incidence and prevalence depend on the sex of the patient. Histone deacetylase 4 (HDAC4) expression in skeletal muscle directly correlates with the progression of ALS, pointing to the use of HDAC4 inhibitors for its treatment. Contrarily, we have found that deletion of HDAC4 in skeletal muscle worsened the pathological features of ALS, accelerating and exacerbating skeletal muscle loss and negatively affecting muscle innervations in male SOD1-G93A (SOD1) mice. In the present work, we compared SOD1 mice of both sexes with the aim to characterize ALS onset and progression as a function of sex differences. We found a global sex-dependent effects on disease onset and mouse lifespan. We further investigated the role of HDAC4 in SOD1 females with a genetic approach, and discovered morpho-functional effects on skeletal muscle, even in the early phase of the diseases. The deletion of HDAC4 decreased muscle function and exacerbated muscle atrophy in SOD1 females, and had an even more dramatic effect in males. Therefore, the two sexes must be considered separately when studying ALS.

Rituximab for eosinophilic granulomatosis with polyangiitis: a systematic review of observational studies.

OBJECTIVE: To analyse the available evidence about the use of rituximab (RTX) and other biologic agents in eosinophilic granulomatosis with polyangiitis (EGPA) patients and to provide useful findings to inform the design of future, reliable clinical trials. METHODS: A systematic review was performed. A systematic search was conducted in PubMed/MEDLINE, Scopus, Web of Science and the Cochrane library databases on RTX, and an extensive literature search was conducted on other biologic agents. RESULTS: Forty-five papers pertinent to our questions were found: 16 retrospective cohort studies, 8 case series, 3 prospective cohort studies and 18 single case reports, for a total of 368 EGPA patients. More than 80% of evaluable patients achieved complete or partial remission with a tendency towards a higher rate of complete response in the pANCA-positive subgroup. CONCLUSION: Although the majority of the evaluable EGPA patients treated with RTX appears to achieve complete remission, we strongly believe that a number of sources of heterogeneity impair a clear interpretation of results and limit their transferability in clinical practice. Differences in design, enrolment criteria, outcome definition and measurement make a comparison among data obtained from studies on RTX and other biologic agents unreliable.

Effectiveness of clinical decision support systems and telemedicine on outcomes of depression: a cluster randomized trial in general practice.

BACKGROUND: Computerized Clinical Decision Support Systems (CCDSS) are information technology tools, designed to improve clinical decision-making. Telemedicine is a health care service delivery using videoconferencing, telephone or messaging technologies. OBJECTIVES: Our project aimed at testing the effectiveness of a composite CCDSS and telemedicine approach designed to treat depression in primary care. METHODS: This cluster randomized trial involved four GP clinics located in Northern Italy. Two clinics were assigned to the experimental protocol, and two served as controls. The study compared the telemedicine group (TG), in which GPs had access to a CCDSS platform, with the control group (CG) in which GPs provided treatment as usual (TAU). Patients scoring ≥11 on Patient Heath Questionnaire and ≥26 on the Inventory of Depressive Symptomatology-Self-Report were eligible for participation. Patients were also administered the World Health Organization Quality of Life-BREF to assess quality of life and Medical Interview Satisfaction Scale 21 to assess satisfaction with the medical interview. RESULTS: Overall, 2810 patients were screened and 66 in the experimental group and 32 in the CG passed the screening stages and met inclusion criteria. The percentage of remitters at 6 months was significantly higher in the TG than in the CG group (24.1% versus 3.1%, χ 2 = 6.6, P = 0.01). This difference remained significant after adjusting for baseline confounders. Physical and psychological quality of life improved significantly from baseline in both groups. Patients reported, on average, good satisfaction with the medical interview. CONCLUSIONS: Our study showed that a combined CCDSS and telemedicine approach may be more effective than the TAU offered by GPs to patients with depression. TRIAL REGISTRATION: The trial was registered on https://clinicaltrials.gov/ on 5 October 2012 with identifier: NCT01701791. The first participant was enrolled on 5 May 2014 and the study was completed on May 2016.

Relationship-based care model in paediatrics: A randomized controlled trial to implement the parents' perception of the quality of nursing care.

AIM: To evaluate whether the application of the Relationship-based care model as a new treatment, called "Take 5 min", affects the level of anxiety, depression, and perceived quality of nursing care of parents of paediatric patients and the work satisfaction of the nursing staff. DESIGN: Single-blind randomized controlled trial. METHODS: The trial was performed from February-July 2016. The trial was conducted with one intervention (N = 101) and one control group (N = 90). Nurses applied the treatment named "Take 5 Minutes", which consisted of dedicating some short time (from 5 to 10 min) to the relationship with the parents using specifically designed communication strategies. The primary outcome was the evaluation of anxiety and depression of parents; the secondary was the parent perceived quality of nursing care. RESULTS: In the experimental group, participants had a lower level of anxiety and depression and highlighted that the effect of the "Take 5 Minutes" was proportional to the initial seriousness of parents' anxiety and depression. Higher scores for the perception of the quality of care were given from the parents of the experimental group. CONCLUSION: The "Take 5 Minutes" treatment offered to parents of paediatric patients demonstrated significant improvements in terms of their anxiety, depression, and perceived quality of nursing care. IMPACT: Caregivers of paediatric patients are subject to psychological disorders such as depression and anxiety. The communication by the nursing community is of fundamental importance in the management of anxiety and depression in the caregivers of hospitalized patients. Caregivers who received the "Take 5 Minutes" treatment demonstrated a significant decrease in anxiety and depression compared with the control group caregivers. The perceived level of quality of nursing care showed a significant increase in the group of caregivers who received the T5M treatment. The RBC model does not require extra costs for health organizations and can be applied during the usual practice of care. Practices such as T5M could become part of paediatric patient care guidelines and nurses should be trained to apply them. TRIAL REGISTRATION NUMBER: Padua Research: ID No. 10,034; ClinicalTrials.gov: ID No. NCT04199429.

Displaced Myonuclei in Cancer Cachexia Suggest Altered Innervation.

An idiopathic myopathy characterized by central nuclei in muscle fibers, a hallmark of muscle regeneration, has been observed in cancer patients. In cancer cachexia skeletal muscle is incapable of regeneration, consequently, this observation remains unaccounted for. In C26-tumor bearing, cachectic mice, we observed muscle fibers with central nuclei in the absence of molecular markers of bona fide regeneration. These clustered, non-peripheral nuclei were present in NCAM-expressing muscle fibers. Since NCAM expression is upregulated in denervated myofibers, we searched for additional makers of denervation, including AchRs, MUSK, and HDAC. This last one being also consistently upregulated in cachectic muscles, correlated with an increase of central myonuclei. This held true in the musculature of patients suffering from gastrointestinal cancer, where a progressive increase in the number of central myonuclei was observed in weight stable and in cachectic patients, compared to healthy subjects. Based on all of the above, the presence of central myonuclei in cancer patients and animal models of cachexia is consistent with motor neuron loss or NMJ perturbation and could underlie a previously neglected phenomenon of denervation, rather than representing myofiber damage and regeneration in cachexia. Similarly to aging, denervation-dependent myofiber atrophy could contribute to muscle wasting in cancer cachexia.

Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia.

INTRODUCTION: Neonates with hypoxic-ischemic encephalopathy (HIE) undergoing hypothermia may benefit from adjunctive therapy with melatonin. However, melatonin safety, pharmacokinetics (PK), and dosage in this sensitive population are still unknown. METHODS AND RESULTS: This study assessed the PK and safety of melatonin enteral administration to neonates with HIE undergoing hypothermia. Melatonin was infused at 0.5 mg/kg in five neonates with HIE undergoing hypothermia. Infusion started 1 hour after the neonates reached the target temperature of 33.5°C. Blood samples were collected before and at selective times after melatonin infusion. Abdominal complications or clinically significant changes in patients' vital signs were not found during or after melatonin. The peak plasma concentration reached 0.25 µg/mL. The area under the curve in 24 hours was 4.35 µg/mL*h. DISCUSSION: Melatonin half-life and clearance were prolonged, and the distribution volume decreased compared to adults. In silico simulation estimated that the steady state can be reached after four infusions. Hypothermia does not affect melatonin PK. In humans high blood concentrations with lower doses can be achieved compared to animal experimentation, although intravenous administration is advised in the neonate population. Our study is a preparatory step for future clinical studies aimed at assessing melatonin efficacy in HIE.

Muscular viscoelastic characteristics of athletes participating in the European Master Indoor Athletics Championship.

PURPOSE: To investigate how the viscoelastic characteristics of muscles (non-neural tone, elasticity and stiffness) vary as a function of age and gender in a sample of track and field master athletes. To compare these findings with data on related sedentary subjects in literature. METHODS: A total of 390 athletes (aged 35-99) were assessed during the European Master Athletics Indoor Championship 2016. A non-invasive measurement device called MyotonPro was used to measure tone, stiffness, and elasticity in the biceps brachii and rectus femoris muscles at rest. Linear regression analysis was used to assess the correlation between age and the measured parameters. To compare our results with previously reported data, we stratified participants according to gender and age. RESULTS: Tone was found to not be dependent on age, whereas stiffness was found to be age dependent. Elasticity was found to be both physical activity and age dependent. Tone (only for men), elasticity, and stiffness were lower in master athletes than in sedentary subjects. CONCLUSIONS: Tone, elasticity, and stiffness change with aging; nevertheless, our findings suggest that physical activity can delay the effects of muscular aging, improving fitness in older people.

Melatonin Pharmacokinetics Following Oral Administration in Preterm Neonates.

Melatonin possesses potential efficacy in perinatal brain injuries, and has been proposed as adjunctive pharmacological therapy in combination with hypothermia in the clinical setting. However, the pharmacokinetics of melatonin in preterm and term newborns is still unknown. The aim of this study was to analyze the pharmacokinetics of melatonin after intragastric administration in preterm infants. Preterm newborns were enrolled 24-72 h after birth, and randomly assigned to three groups receiving a single bolus of 0.5 mg·kg-1 melatonin, or 3 boluses of 1 or 5 mg·kg-1 of melatonin at 24-h intervals. Blood samples were collected before and at selective times after melatonin administration. The half-life of melatonin in plasma ranged from 7.98 to 10.94 h, and the area under the curve (AUC) from 10.48 to 118.17 µg·mL-1·h-1. Our results indicate a different pharmacokinetic profile in premature newborns, compared to adults and experimental animals. The high peak plasma concentrations and the long half-life indicate that in the neonatal clinical setting, it is possible to obtain and maintain high serum concentrations using a single administration of melatonin repeated every 12/24 h.

Dietary Flaxseed Mitigates Impaired Skeletal Muscle Regeneration: in Vivo, in Vitro and in Silico Studies.

BACKGROUND: Diets enriched with n-3 polyunsaturated fatty acids (n-3 PUFAs) have been shown to exert a positive impact on muscle diseases. Flaxseed is one of the richest sources of n-3 PUFA acid α-linolenic acid (ALA). The aim of this study was to assess the effects of flaxseed and ALA in models of skeletal muscle degeneration characterized by high levels of Tumor Necrosis Factor-α (TNF). METHODS: The in vivo studies were carried out on dystrophic hamsters affected by muscle damage associated with high TNF plasma levels and fed with a long-term 30% flaxseed-supplemented diet. Differentiating C2C12 myoblasts treated with TNF and challenged with ALA represented the in vitro model. Skeletal muscle morphology was scrutinized by applying the Principal Component Analysis statistical method. Apoptosis, inflammation and myogenesis were analyzed by immunofluorescence. Finally, an in silico analysis was carried out to predict the possible pathways underlying the effects of n-3 PUFAs. RESULTS: The flaxseed-enriched diet protected the dystrophic muscle from apoptosis and preserved muscle myogenesis by increasing the myogenin and alpha myosin heavy chain. Moreover, it restored the normal expression pattern of caveolin-3 thereby allowing protein retention at the sarcolemma. ALA reduced TNF-induced apoptosis in differentiating myoblasts and prevented the TNF-induced inhibition of myogenesis, as demonstrated by the increased expression of myogenin, myosin heavy chain and caveolin-3, while promoting myotube fusion. The in silico investigation revealed that FAK pathways may play a central role in the protective effects of ALA on myogenesis. CONCLUSIONS: These findings indicate that flaxseed may exert potent beneficial effects by preserving skeletal muscle regeneration and homeostasis partly through an ALA-mediated action. Thus, dietary flaxseed and ALA may serve as a useful strategy for treating patients with muscle dystrophies.

Multiparameter analysis of apoptosis in puromycin-treated Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, a typical apoptotic phenotype is induced by some stress factors such as sugars, acetic acid, hydrogen peroxide, aspirin and age. Nevertheless, no data have been reported for apoptosis induced by puromycin, a damaging agent known to induce apoptosis in mammalian cells. We treated S. cerevisiae with puromycin to induce apoptosis and evaluated the percentage of dead cells by using Hoechst 33342 staining, transmission electron microscopy (TEM) and Annexin V flow cytometry (FC) analysis. Hoechst 33342 fluorescence images were processed to acquire parameters to use for multiparameter analysis [and perform a principal component analysis, (PCA)]. Cell viability was evaluated by Rhodamine 123 (Rh 123) and Acridine Orange microscope fluorescence staining. The results show puromycin-induced apoptosis in S. cerevisiae, and the PCA analysis indicated that the increasing percentage of apoptotic cells delineated a well-defined graph profile. The results were supported by TEM and FC. This study gives new insights into yeast apoptosis using puromycin as inducer agent, and PCA analysis may complement molecular analysis facilitating further studies to its detection.

Shades of vulnerability: latent structures of clinical caseness in prodromal and early phases of schizophrenia.

The underlying structures of clinical caseness and need of care in prodromal (i.e., at-risk) and early phases of schizophrenia remain poorly characterized in their essential psycho-behavioral coherence. To identify the schizophrenia proneness-related subtypes within a population of young help-seekers referred to a dedicated, community-based early detection program (Programma 2000). A sample of consecutive referrals (n = 168) for suspected psychosis or first-episode schizophrenia spectrum psychosis received a detailed clinical assessment, including the early recognition inventory for the retrospective assessment of the onset of schizophrenia checklist. We used exploratory factor analysis (EFA) to determine the underlying dimensional structure and latent class analysis (LCA) to identify putative vulnerability subtypes. EFA identified four factors: dysphoria (irritability tension), paranoid autocentrism, introversive withdrawal, and disturbed subjective experience. LCA distinguished three classes, interpretable as carrying different degrees of "proneness to schizophrenia psychosis," which best captured the underlying continuum of clinical severity. The validity of the three classes was supported by distinct patterns of association with major clinical variables (i.e., diagnostic staging at referral). Vulnerability to schizophrenia psychosis in young help-seekers may manifest in three major clinical prototypes, presenting common levels of dysphoria and social withdrawal but different degrees of paranoid autocentrism and disturbed subjective experience. Overall, the results provide the empirical background to dissect shared features of clinical caseness from more schizophrenia-specific vulnerability components. This is of value for the refinement of the clinical staging model as well as for the pragmatic implementation of multiple-gate screening programs.