Hypovitaminosis D has been associated with worse outcome in respiratory tract infections, with conflicting opinions regarding its role in Coronavirus-19 disease (COVID-19). Our study aimed to ...evaluate the possible relationship between 25-OH vitamin D (25OHD) values and the following conditions in patients hospitalized for COVID-19: prognosis, mortality, invasive (IV) and non-invasive (NIV) mechanical ventilation, and orotracheal intubation (OTI). A further objective was the analysis of a possible positive effect of supplementation with calcifediol on COVID-19 severity and prognosis. We analyzed 288 patients hospitalized at the San Giovanni di Dio Hospital in Florence and the Santa Maria alle Scotte Hospital in Siena, from November 2020 to February 2021. The 25OHD levels correlated positively with the partial pressure of oxygen and FiO2 (PaO2/FiO2) ratio (r = 0.17;
< 0.05). Furthermore, when we analyzed the patients according to the type of respiratory support, we found that 25OHD levels were markedly reduced in patients who underwent non-invasive ventilation and orotracheal intubation (OTI). The evaluation of the length of hospitalization in our population evidenced a longer duration of hospitalization in patients with severe 25OHD deficiency (<10 ng/mL). Moreover, we found a statistically significant difference in the mortality rate between patients who had 25OHD levels below 10 ng/mL and those with levels above this threshold in the total population (50.8% vs. 25.5%,
= 0.005), as well as between patients with 25OHD levels below 20 ng/mL and those with levels above that threshold (38.4% vs. 24.6%,
= 0.04). Moreover, COVID-19 patients supplemented with calcifediol presented a significantly reduced length of hospitalization (
< 0.05). Interestingly, when we analyzed the possible effects of calcifediol on mortality rate in patients with COVID-19, we found that the percentage of deaths was significantly higher in patients who did not receive any supplementation than in those who were treated with calcifediol (
< 0.05) In conclusion, we have demonstrated with our study the best prognosis of COVID-19 patients with adequate vitamin D levels and patients treated with calcifediol supplementation.
Abstract Background Neural tumors are difficult to distinguish based solely on cellularity and often require immunohistochemical staining to aid in identifying the cell lineage. This article ...investigates the potential of a Convolutional Neural Network for the histopathological classification of the three most prevalent benign neural tumor types: neurofibroma, perineurioma, and schwannoma. Methods A model was developed, trained, and evaluated for classification using the ResNet‐50 architecture, with a database of 30 whole‐slide images stained in hematoxylin and eosin (106, 782 patches were generated from and divided among the training, validation, and testing subsets, with strategies to avoid data leakage). Results The model achieved an accuracy of 70% (64% normalized), and showed satisfactory results for differentiating two of the three classes, reaching approximately 97% and 77% as true positives for neurofibroma and schwannoma classes, respectively, and only 7% for perineurioma class. The AUROC curves for neurofibroma and schwannoma classes was 0.83%, and 0.74% for perineurioma. However, the specificity rate for the perineurioma class was greater (83%) than in the other two classes (neurofibroma with 61%, and schwannoma with 60%). Conclusion This investigation demonstrated significant potential for proficient performance with a limitation regarding the perineurioma class (the limited feature variability observed contributed to a lower performance).
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug ...initiation. Biomarkers that can predict early disease activity are needed.
To estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine.
Forty-two RRMS patients (30F/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The 'no evidence of disease activity' (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs.
Three patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91).
CSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug's effect on chronic macrophage and microglia activation deserves further evaluation.
Abstract Breast radiological density is a determinant of breast cancer risk and of mammography sensitivity and may be used to personalize screening approach. We first analyzed the reproducibility of ...visual density assessment by eleven experienced radiologists classifying a set of 418 digital mammograms: reproducibility was satisfactory on a four (BI-RADS D1–2–3–4: weighted kappa = 0.694–0.844) and on a two grade (D1-2 vs D3-4: kappa = 0.620–0.851), but subjects classified as with dense breast would range between 25.1 and 50.5% depending on the classifying reader. Breast density was then assessed by computer using the QUANTRA software which provided systematically lower density percentage values as compared to visual classification. In order to predict visual classification results in discriminating dense and non-dense breast subjects on a two grade scale (D3-4 vs, D1-2) the best fitting cut off value observed for QUANTRA was ≤22.0%, which correctly predicted 88.6% of D1-2, 89.8% of D3-4, and 89.0% of total cases. Computer assessed breast density is absolutely reproducible, and thus to be preferred to visual classification. Thus far few studies have addressed the issue of adjusting computer assessed density to reproduce visual classification, and more similar comparative studies are needed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Traumatic brain injury (TBI) is a major health and socioeconomic problem affecting the world. This condition results from the application of external physical force to the brain which leads to ...transient or permanent structural and functional impairments. TBI has been shown to be a risk factor for neurodegeneration which can lead to Parkinson’s disease (PD) for example. In this study, we wanted to explore the development of PD-related pathology in the context of an experimental model of TBI and the potential ability of Coriolus versicolor and Hericium erinaceus to prevent neurodegenerative processes. Traumatic brain injury was induced in mice by controlled cortical impact. Behavioral tests were performed at various times: the animals were sacrificed 30 days after the impact and the brain was processed for Western blot and immunohistochemical analyzes. After the head injury, a significant decrease in the expression of tyrosine hydroxylase and the dopamine transporter in the substantia nigra was observed, as well as significant behavioral alterations that were instead restored following daily oral treatment with Hericium erinaceus and Coriolus versicolor. Furthermore, a strong increase in neuroinflammation and oxidative stress emerged in the vehicle groups. Treatment with Hericium erinaceus and Coriolus versicolor was able to prevent both the neuroinflammatory and oxidative processes typical of PD. This study suggests that PD-related molecular events may be triggered on TBI and that nutritional fungi such as Hericium erinaceus and Coriolus versicolor may be important in redox stress response mechanisms and neuroprotection, preventing the progression of neurodegenerative diseases such as PD.
Abstract
Background
People with human immunodeficiency virus (PWH) are at increased risk for comorbidities, and plasma interleukin 6 (IL-6) levels are among the most robust predictors of these ...outcomes. Tocilizumab (TCZ) blocks the receptor for IL-6, inhibiting functions of this cytokine.
Methods
This was a 40-week, placebo-controlled, crossover trial (NCT02049437) where PWH on stable antiretroviral therapy (ART) were randomized to receive 3 monthly doses of TCZ or matching placebo intravenously. Following a 10-week treatment period and a 12-week washout, participants were switched to the opposite treatment. The primary endpoints were safety and posttreatment levels of C-reactive protein (CRP) and CD4+ T-cell cycling. Secondary endpoints included changes in inflammatory indices and lipid levels.
Results
There were 9 treatment-related toxicities of grade 2 or greater during TCZ administration (mostly neutropenia) and 2 during placebo administration. Thirty-one of 34 participants completed the study and were included in a modified intent-to-treat analysis. TCZ reduced levels of CRP (median decrease, 1819.9 ng/mL, P < .0001; effect size, 0.87) and reduced inflammatory markers in PWH, including D-dimer, soluble CD14, and tumor necrosis factor receptors. T-cell cycling tended to decrease in all maturation subsets after TCZ administration, but was only significant among naive CD4 T cells. Lipid levels, including lipid classes that have been related to cardiovascular disease risk, increased during TCZ treatment.
Conclusions
TCZ is safe and decreases inflammation in PWH; IL-6 is a key driver of the inflammatory environment that predicts morbidity and mortality in ART-treated PWH. The clinical significance of lipid elevations during TCZ treatment requires further study.
Clinical Trials Registration. NCT02049437.
Inhibition of IL-6 activity by tocilizumab had profound effects on immune activation/inflammation and lipid profiles in people with treated HIV infection.
Involvement of the microbiome in many different scalp conditions has been investigated over the years. Studies on the role of the scalp microbiome in specific diseases, such as those involving hair ...growth alterations like non-cicatricial androgenetic alopecia (AGA), alopecia areata (AA) and cicatricial alopecia lichen planopilaris, are of major importance. In the present work, we highlighted the differences in microbial populations inhabiting the scalp of AA subjects and a healthy sample cohort by using an integrated approach relying on metagenomic targeted 16S sequencing analysis, urine metabolomics, and human marker gene expression. Significant differences in genera abundances (
< 0.05) were found in the hypodermis and especially the dermis layer. Based on 16S sequencing data, we explored the differences in predicted KEGG pathways and identified some significant differences in predicted pathways related to the AA pathologic condition such as flagellar, assembly, bacterial chemotaxis, mineral absorption, ABC transporters, cellular antigens, glycosaminoglycan degradation, lysosome, sphingolipid metabolism, cell division, protein digestion and absorption, and energy metabolism. All predicted pathways were significantly enhanced in AA samples compared to expression in healthy samples, with the exceptions of mineral absorption, and ABC transporters. We also determined the expression of
α,
, and
genes and explored the relationships between human gene expression levels and microbiome composition by Pearson's correlation analysis; here, significant correlations both positive (SOD vs.
) and negative (
and
vs.
, and
) were highlighted. Finally, we inspected volatile organic metabolite profiles in urinary samples and detected statistically significant differences (menthol, methanethiol, dihydrodehydro-beta-ionone, 2,5-dimethylfuran, 1,2,3,4, tetrahydro-1,5,7-trimethylnapthalene) when comparing AA and healthy subject groups. This multiple comparison approach highlighted potential traits associated with AA and their relationship with the microbiota inhabiting the scalp, opening up novel therapeutic interventions in such kind of hair growth disorders mainly by means of prebiotics, probiotics, and postbiotics.
Alzheimer’s disease (AD) is the principal cause of dementia, and its incidence increases with age. Altered antioxidant systems and inflammation have an important role in the etiology of ...neurodegenerative disorders. In this study, we evaluated the effects of Hericium erinaceus, a nutritional mushroom with important antioxidant effects, in a rat model of AD. Animals were injected with 70 mg/Kg of AlCl3 daily for 6 weeks, and Hericium erinaceus was administered daily by gavage. Before the experiment’s end date, behavioral test training was performed. At the end of the study, behavioral changes were assessed, and the animals were euthanized. Brain tissues were harvested for further analysis. AlCl3 mainly accumulates in the hippocampus, the principal region of the brain involved in memory functions and learning. Hericium erinaceus administration reduced behavioral changes and hippocampal neuronal degeneration. Additionally, it reduced phosphorylated Tau levels, aberrant APP overexpression, and β-amyloid accumulation. Moreover, Hericium erinaceus decreased the pro-oxidative and pro-inflammatory hippocampal alterations induced by AD. In particular, it reduced the activation of the NLRP3 inflammasome components, usually activated by increased oxidative stress during AD. Collectively, our results showed that Hericium erinaceus has protective effects on behavioral alteration and histological modification associated with AD due to the modulation of the oxidative and inflammatory pathways, as well as regulating cellular brain stress.
•WT1 rs16754 polymorphism correlates with a better OS and EFS in AML patients.•WT1 SNP rs16754 correlates with a better OS in AML patients treated with HMAs.•We developed a novel PNA based assay to ...identify WT1 rs16754 polymorphism.
Acute myeloid leukemia is a genetically heterogeneous disease characterized by the accumulation of mutations in hematopoietic progenitor cells. For its heterogeneity, prognostic markers are very useful for therapeutic choice. The most important prognostic markers are age, white blood cell count, chromosomal alterations and gene mutations. Recent works have studied the prognostic significance of WT1 polymorphisms and mutations, highlighting the role of SNP rs16754 as a positive prognostic factor in AML patients. Nevertheless, the data are still unclear. To investigate the role of WT1 rs16754 polymorphism in AML, we designed a new tool for the detection using PNA directed PCR Clamping technology. Our data were able to establish a correlation between SNP rs16754 and the clinical outcome. Our results support the hypothesis that rs16754 polymorphism is an independent positive prognostic molecular marker that could be useful for therapeutic choice. In view of this, we described a novel assay faster, more sensitive and cheaper than DNA sequencing. The assay allows evaluating WT1 rs16754 polymorphism in diagnostic routine to improve prognostic information faster and without over-costing for diagnostic laboratories.
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I
is crucial to satisfy several mitochondrial functions including energy metabolism and oxidative phosphorylation. Patients affected by Myelodysplastic Syndromes (MDS) and acute myeloid leukemia ...(AML) are frequently characterized by iron overload (IOL), due to continuous red blood cell (RBC) transfusions. This event impacts the overall survival (OS) and it is associated with increased mortality in lower-risk MDS patients. Accordingly, the oral iron chelator Deferasirox (DFX) has been reported to improve the OS and delay leukemic transformation. However, the molecular players and the biological mechanisms laying behind remain currently mostly undefined. The aim of this study has been to investigate the potential anti-leukemic effect of DFX, by functionally and molecularly analyzing its effects in three different leukemia cell lines, harboring or not p53 mutations, and in human primary cells derived from 15 MDS/AML patients. Our findings indicated that DFX can lead to apoptosis, impairment of cell growth only in a context of IOL, and can induce a significant alteration of mitochondria network, with a sharp reduction in mitochondrial activity. Moreover, through a remarkable reduction of Murine Double Minute 2 (MDM2), known to regulate the stability of p53 and p73 proteins, we observed an enhancement of p53 transcriptional activity after DFX. Interestingly, this iron depletion-triggered signaling is enabled by p73, in the absence of p53, or in the presence of a p53 mutant form. In conclusion, we propose a mechanism by which the increased p53 family transcriptional activity and protein stability could explain the potential benefits of iron chelation therapy in terms of improving OS and delaying leukemic transformation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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