Procalcitonina e malaria

Procalcitonin (PCT), the prohormone of calcitonin, is suitable for detecting complications of infection characterized by systemic inflammatory reactions. High plasma levels are observed in severe sepsis, septic shock, serious bacterial infections and systemic inflammatory reactions. Increased PCT concentrations have been reported in both uncomplicated and severe forms of malaria. The highest values are measured in the more severe forms of the disease; in response to therapy serum concentrations quickly fall within a few days. In our study we observed pediatric patients with uncomplicated and severe forms of malaria by Plasmodium falciparum. We studied 62 patients, with age between 3 months and 10 years, hospitalized for malaria, in a rural hospital of Burundi. Our investigation confirmed data that PCT plasma levels increase during malarial infection and reduce after specific therapy such as the plasma parasite density. We reported correlation of elevated PCT values with high plasma parasite density, but we didn’t find a significant correlation between the highest plasma PCT levels and severe forms of the disease. We think it could be usefull and interesting to diffuse the PCT determination in our hospitals for the therapy follow-up in imported malaria cases

Methods for preparation and administration of lutetium-177 oxodotreotide 3.7 GBq: proceedings from an Italian advisory board

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Life during COVID-19 lockdown in Italy: the influence of cognitive state on psychosocial, behavioral and lifestyle profiles of older adults.

Few studies have examined lockdown effects on the way of living and well-being of older adults stratified by cognitive state. Since cognitive deficits are common in this population, we investigated how cognition influenced their understanding of the pandemic, socio-behavioral responses and lifestyle adaptations during lockdown, and how these factors affected their mood or memory.Telephone-based survey involving 204 older adults ≥65 y/o (median: 82) with previous assessments of cognitive state: 164 normal-old (NOLD), 24 mild-neurocognitive disorder (mild-NCD), 18 mild-moderate dementia. A structured questionnaire was developed to assess psychological and socio-behavioral variables. Logistic regression was used to ascertain their effects on mood and memory.With increasing cognitive deficits, understanding of the pandemic and the ability to follow lockdown policies, adapt to lifestyle changes, and maintain remote interactions decreased. Participants with dementia were more depressed; NOLDs remained physically and mentally active but were more bored and anxious. Sleeping and health problems independently increased the likelihood of depression (OR: 2.29; CI: 1.06-4.93;NOLD and mild-NCD groups showed similar mood-behavioral profiles suggesting better tolerance of lockdown. Those with dementia were unable to adapt and suffered from depression and cognitive complaints. To counteract lockdown effects, physical and mental activities and digital literacy should be encouraged

Remote Sensing of Forest Biomass Using GNSS Reflectometry

In this study, the capability of Global Navigation Satellite System Reflectometry in evaluating forest biomass from space has been investigated by using data coming from the TechDemoSat-1 (TDS-1) mission of Surrey Satellite Technology Ltd. and from the Cyclone Satellite System (CyGNSS) mission of NASA. The analysis has been first conducted using TDS-1 data on a local scale, by selecting five test areas located in different parts of the Earth's surface. The areas were chosen as examples of various forest coverages, including equatorial and boreal forests. Then, the analysis has been extended by using CyGNSS to a global scale, including any type of forest coverage. The peak of the Delay Doppler Map calibrated to retrieve an "equivalent" reflectivity has been exploited for this investigation and its sensitivity to forest parameters has been evaluated by a direct comparison with vegetation optical depth (VOD) derived from the Soil Moisture Active Passive L-band radiometer, with a pantropical aboveground biomass (AGB) map and then with a tree height (H) global map derived from the Geoscience Laser Altimeter System installed on-board the ICEsat satellite. The sensitivity analysis confirmed the decreasing trend of the observed equivalent reflectivity for increasing biomass, with correlation coefficients 0.31 ≤ R ≤ 0.54 depending on the target parameter (VOD, AGB, or H) and on the considered dataset (local or global). These correlations were not sufficient to retrieve the target parameters by simple inversion of the direct relationships. The retrieval has been therefore based on Artificial Neural Networks making it possible to add other inputs (e.g., the incidence angle, the signal to noise ratio, and the lat/lon information in case of global maps) to the algorithm. Although not directly correlated to the biomass, these inputs helped in improving the retrieval accuracy. The algorithm was tested on both the selected areas and globally, showing a promising ability to retrieve the target parameter, either AGB or H, with correlation coefficients R ≃ 0.8

Schwann cells ER-associated degradation contributes to myelin maintenance in adult nerves and limits demyelination in CMT1B mice

In the peripheral nervous system (PNS) myelinating Schwann cells synthesize large amounts of myelin protein zero (P0) glycoprotein, an abundant component of peripheral nerve myelin. In humans, mutations in P0 cause the demyelinating Charcot-Marie-Tooth 1B (CMT1B) neuropathy, one of the most diffused genetic disorders of the PNS. We previously showed that several mutations, such as the deletion of serine 63 (P0-S63del), result in misfolding and accumulation of P0 in the endoplasmic reticulum (ER), with activation of the unfolded protein response (UPR). In addition, we observed that S63del mouse nerves display the upregulation of many ER-associated degradation (ERAD) genes, suggesting a possible involvement of this pathway in the clearance of the mutant P0. In ERAD in fact, misfolded proteins are dislocated from the ER and targeted for proteasomal degradation. Taking advantage of inducible cells that express the ER retained P0, here we show that the P0-S63del glycoprotein is degraded via ERAD. Moreover, we provide strong evidence that the Schwann cell-specific ablation of the ERAD factor Derlin-2 in S63del nerves exacerbates both the myelin defects and the UPR in vivo, unveiling a protective role for ERAD in CMT1B neuropathy. We also found that lack of Derlin-2 affects adult myelin maintenance in normal nerves, without compromising their development, pinpointing ERAD as a previously unrecognized player in preserving Schwann cells homeostasis in adulthood. Finally, we provide evidence that treatment of S63del peripheral nerve cultures with N-Acetyl-D-Glucosamine (GlcNAc), known to enhance protein quality control pathways in C.elegans, ameliorates S63del nerve myelination ex vivo. Overall, our study suggests that potentiating adaptive ER quality control pathways might represent an appealing strategy to treat both conformational and age-related PNS disorders

Schwann cells ER-associated degradation contributes to myelin maintenance in adult nerves and limits demyelination in CMT1B mice

In the peripheral nervous system (PNS) myelinating Schwann cells synthesize large amounts of myelin protein zero (P0) glycoprotein, an abundant component of peripheral nerve myelin. In humans, mutations in P0 cause the demyelinating Charcot-Marie-Tooth 1B (CMT1B) neuropathy, one of the most diffused genetic disorders of the PNS. We previously showed that several mutations, such as the deletion of serine 63 (P0-S63del), result in misfolding and accumulation of P0 in the endoplasmic reticulum (ER), with activation of the unfolded protein response (UPR). In addition, we observed that S63del mouse nerves display the upregulation of many ER-associated degradation (ERAD) genes, suggesting a possible involvement of this pathway in the clearance of the mutant P0. In ERAD in fact, misfolded proteins are dislocated from the ER and targeted for proteasomal degradation. Taking advantage of inducible cells that express the ER retained P0, here we show that the P0-S63del glycoprotein is degraded via ERAD. Moreover, we provide strong evidence that the Schwann cell-specific ablation of the ERAD factor Derlin-2 in S63del nerves exacerbates both the myelin defects and the UPR in vivo, unveiling a protective role for ERAD in CMT1B neuropathy. We also found that lack of Derlin-2 affects adult myelin maintenance in normal nerves, without compromising their development, pinpointing ERAD as a previously unrecognized player in preserving Schwann cells homeostasis in adulthood. Finally, we provide evidence that treatment of S63del peripheral nerve cultures with N-Acetyl-D-Glucosamine (GlcNAc), known to enhance protein quality control pathways in C.elegans, ameliorates S63del nerve myelination ex vivo. Overall, our study suggests that potentiating adaptive ER quality control pathways might represent an appealing strategy to treat both conformational and age-related PNS disorders. Author summary Charcot-Marie-Tooth neuropathies are a large family of peripheral nerve disorders, showing extensive clinical and genetic heterogeneity. Although strong advances have been made in the identification of genes and mutations involved, effective therapies are still lacking. Intracellular retention of abnormal proteins has been recently suggested as one of the pathogenetic events that might underlie several conformational neuropathies. To limit the toxic effects of accumulated mutant proteins, cells have developed efficient protein quality control systems aimed at optimizing both protein folding and degradation. Here we show that ER-associated degradation limits Schwann cells stress and myelin defects caused by the accumulation of a mutant myelin protein into the ER. In addition, we also describe for the first time the importance of Schwann cells ERAD in preserving myelin integrity in adult nerves, showing that genetic ERAD impairment leads to a late onset, motor-predominant, peripheral neuropathy in vivo. Effort in the design of strategies that potentiate ERAD and ER quality controls is therefore highly desirable

HIF-1 activation induces doxorubicin resistance in MCF7 3-D spheroids via P-glycoprotein expression: a potential model of the chemo-resistance of invasive micropapillary carcinoma of the breast

BACKGROUND: Invasive micropapillary carcinoma (IMPC) of the breast is a distinct and aggressive variant of luminal type B breast cancer that does not respond to neoadjuvant chemotherapy. It is characterized by small pseudopapillary clusters of cancer cells with inverted cell polarity. To investigate whether hypoxia-inducible factor-1 (HIF-1) activation may be related to the drug resistance described in this tumor, we used MCF7 cancer cells cultured as 3-D spheroids, which morphologically simulate IMPC cell clusters. METHODS: HIF-1 activation was measured by EMSA and ELISA in MCF7 3-D spheroids and MCF7 monolayers. Binding of HIF-1α to MDR-1 gene promoter and modulation of P-glycoprotein (Pgp) expression was evaluated by ChIP assay and FACS analysis, respectively. Intracellular doxorubicin retention was measured by spectrofluorimetric assay and drug cytotoxicity by annexin V-FITC measurement and caspase activity assay. RESULTS: In MCF7 3-D spheroids HIF-1 was activated and recruited to participate to the transcriptional activity of MDR-1 gene, coding for Pgp. In addition, Pgp expression on the surface of cells obtained from 3-D spheroids was increased. MCF7 3-D spheroids accumulate less doxorubicin and are less sensitive to its cytotoxic effects than MCF7 cells cultured as monolayer. Finally, HIF-1α inhibition either by incubating cells with 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (a widely used HIF-1α inhibitor) or by transfecting cells with specific siRNA for HIF-1α significantly decreased the expression of Pgp on the surface of cells and increased the intracellular doxorubicin accumulation in MCF7 3-D spheroids. CONCLUSIONS: MCF7 breast cancer cells cultured as 3-D spheroids are resistant to doxorubicin and this resistance is associated with an increased Pgp expression in the plasma membrane via activation of HIF-1. The same mechanism may be suggested for IMPC drug resistance

ADA2 regulates inflammation and hematopoietic stem cell emergence via the A_2bR pathway in zebrafish

Deficiency of adenosine deaminase 2 (DADA2) is an inborn error of immunity caused by loss-of-function mutations in the adenosine deaminase 2 (ADA2) gene. Clinical manifestations of DADA2 include vasculopathy and immuno-hematological abnormalities, culminating in bone marrow failure. A major gap exists in our knowledge of the regulatory functions of ADA2 during inflammation and hematopoiesis, mainly due to the absence of an ADA2 orthologue in rodents. Exploring these mechanisms is essential for understanding disease pathology and developing new treatments. Zebrafish possess two ADA2 orthologues, cecr1a and cecr1b, with the latter showing functional conservation with human ADA2. We establish a cecr1b-loss-of-function zebrafish model that recapitulates the immuno-hematological and vascular manifestations observed in humans. Loss of Cecr1b disrupts hematopoietic stem cell specification, resulting in defective hematopoiesis. This defect is caused by induced inflammation in the vascular endothelium. Blocking inflammation, pharmacological modulation of the A2r pathway, or the administration of the recombinant human ADA2 corrects these defects, providing insights into the mechanistic link between ADA2 deficiency, inflammation and immuno-hematological abnormalities. Our findings open up potential therapeutic avenues for DADA2 patients

Managing the Dual Nature of Iron to Preserve Health

Because of its peculiar redox properties, iron is an essential element in living organisms, being involved in crucial biochemical processes such as oxygen transport, energy production, DNA metabolism, and many others. However, its propensity to accept or donate electrons makes it potentially highly toxic when present in excess and inadequately buffered, as it can generate reactive oxygen species. For this reason, several mechanisms evolved to prevent both iron overload and iron deficiency. At the cellular level, iron regulatory proteins, sensors of intracellular iron levels, and post-transcriptional modifications regulate the expression and translation of genes encoding proteins that modulate the uptake, storage, utilization, and export of iron. At the systemic level, the liver controls body iron levels by producing hepcidin, a peptide hormone that reduces the amount of iron entering the bloodstream by blocking the function of ferroportin, the sole iron exporter in mammals. The regulation of hepcidin occurs through the integration of multiple signals, primarily iron, inflammation and infection, and erythropoiesis. These signals modulate hepcidin levels by accessory proteins such as the hemochromatosis proteins hemojuvelin, HFE, and transferrin receptor 2, the serine protease TMPRSS6, the proinflammatory cytokine IL6, and the erythroid regulator Erythroferrone. The deregulation of the hepcidin/ferroportin axis is the central pathogenic mechanism of diseases characterized by iron overload, such as hemochromatosis and iron-loading anemias, or by iron deficiency, such as IRIDA and anemia of inflammation. Understanding the basic mechanisms involved in the regulation of hepcidin will help in identifying new therapeutic targets to treat these disorders