Effects of naloxone on calcium turnover in cows affected by milk fever.

Milk fever is a metabolic disorder of calcium homeostasis that affects about 2 to 6% of postpartum cows. Current therapy is based on the administration of calcium gluconate. On the basis of the clinical signs, and given that endorphins increase at parturition, we supposed that endogenous opioid peptides (EOP) could be responsible for this pathology. In this study, cows with milk fever were administered the opiate antagonist, Naloxone (Nx; experiment 1) or Nx with calcium salts (experiment 2). In experiment 1, Nx induced the recovery of affected cows. The effects of Nx therapy, expressed in terms of proportion of recovered cows, of cows recovering in less than 30 min and cows requiring repeated treatments, were not statistically different than those obtained by means of calcium administration (17/17, 100%; 10/17, 59% and 7/17, 41% vs. 33/35, 94%; 22/35, 63% and 11/35, 31%, respectively; NS). In experiment 2, a significantly higher ratio of cows recovered in less than 30 min in the group of animals treated with Nx in association with calcium salts, compared with the group of cows treated with the calcium traditional therapy (106/118, 90% for calcium-Nx treated cows vs. 34/62, 55% for calcium-treated cows). Moreover, in the group of cows treated with calcium-Nx, the number of cows requiring repeated treatments was significantly reduced and no unrecovered cows were observed. The results support the idea that high EOP levels interfere with inward movement of calcium through the cell membrane and with calcium activity. The association of calcium and Nx at low dosage is a safe method to treat milk fever in cows and reduces muscular complications

Towards dissecting the structural determinant of Peach latent mosaic viroid inducing mosaic symptoms

Most isolates of Peach latent mosaic viroid (PLMVd) do not incite foliar symptoms, but a few number of isolates cause peach mosaic (PM) or peach calico (PC), an extreme albino phenotype. The PC determinant has been previously mapped at an insertion of 12-13 nt folding into a hairpin capped by a U-rich loop but the PM determinant, which is not associated with a specific insertion, remains unidentified and could reside in one or more domains of the branched conformation proposed for PLMVd. To tackle this problem we have selected for further dissection one variant (GDS6), recovered from a typical PM isolate (GDS), which is very infectious and elicits consistently a characteristic PM. We have initially focused on G337, a position that appears associated with PM in multiple alignments that include GDS6 and other PM-inducing and latent variants. To determine the role of G337 in infectivity and symptoms, GF-305 peach seedlings were inoculated with in vitro transcripts of recombinant plasmids containing dimeric tandem inserts of PLMVd-cDNAs with all possible changes at this position introduced by site-directed mutagenesis. Deletion of G337 abolished infectivity, while substitutions by A, C or U incited, in most inoculated plants, PM symptoms. Cloning and sequencing showed that the A substitution at position 337 was preserved in the progeny or reverted to G, while C or U substitutions at this position were not stable and reverted to A or G in the progenies. Extending this approach to additional nucleotides of loop A, or of other PLMVd domains, may provide hints in identifying the determinant of PM. Keywords: Viroids, Pathogenesis, Peach diseas

Use of anakinra in severe COVID-19: a case report

Coronavirus Disease 19 is a global healthcare emergency with high lethality rate. Relevant inflammatory cytokine storm is associated with severity of disease and IL1 inhibition is a cornerstone treatment for hyperinflammatory diseases. We present here the case of a patient with critical COVID-19 successfully treated with IL-1 receptor antagonist (anakinra)

Clinical and pharmacological phase I study with accelerated titration design of a daily times five schedule of BBR3464, a novel cationic triplatinum complex

Objectives To define the maximum tolerated dose (MTD), the toxicity and pharmacokinetic profile of BBR3464, a novel triplatinum complex. Patients and methods Fourteen patients with advanced solid tumors not responsive to previous antitumor treatments received BBR 3464 on a daily × 5 schedule every twenty-eighth day. The drug was given as a one-hour infusion with pre-and post-treatment hydration (500 ml in one hour) and no antiemetic prophylaxis. The starting dose was 0.03 mg/m2/day. A modified accelerated titration escalation design was used. Total and free platinum (Pt) concentrations in plasma and urine were assessed by ICP-MS on days 1 and 5 of the first cycle. Results Dose was escalated four times up to 0.17 mg/m2/ day. Short-lasting neutropenia and diarrhea of late onset were dose-limiting and defined the MTD at 0.12 mg/m2 Nausea and vomiting were rare, neither neuro- nor renal toxic effects were observed. BBR3464 showed a rapid distribution phase of 1 hour and a terminal half-life of several days. At 0.17 mg/m2 plasma Cmax and AUC on day 5 were higher than on day 1, indicating drug accumulation. Approximately 10% of the equivalent dose of BBR3464 (2.2%-13.4%) was recovered in a 24-hour urine collection. Conclusions The higher than expected incidence of neutropenia and GI toxicity might be related to the prolonged half-life and accumulation of total and free Pt after daily administrations. Lack of nephrotoxicity and the low urinary excretion support the use of the drug without hydration. The single intermittent schedule has been selected for clinical developmen

Mapping Meaning : Critical Cartographies for Participatory Water Management in Taita Hills, Kenya

Participation of local people is often neglected in natural resource management, which leads to failure to understand the social aspects and historical construction of environmental problems. Participatory mapping can enhance the communication of local spatial knowledge for management processes and challenge the official maps and other spatial representations produced by state authorities and scientists. In this study, we analyze what kind of social meanings can be revealed through a multimethod participatory mapping process focusing on water resources in Taita Hills, Kenya. The participatory mapping clearly complicates the simplified image of the physical science mappings, typically depicting natural water supply, by addressing the impacts of contamination, inadequate infrastructure, poverty, distance to the sources, and restrictions in their uses on people's access to water. Moreover, this shared exercise is able to trigger discussion on issues that cannot always be localized but still contribute to place making. Local historical accounts reveal the social and political drivers of the current water-related problems, making explicit the political ecology dynamics in the area.Peer reviewe

Real-world Outcomes of Relapsed/Refractory Diffuse Large B-cell Lymphoma Treated With Polatuzumab Vedotin-based Therapy.

After FDA and EMA approval of the regimen containing polatuzumab vedotin plus rituximab and bendamustine (PolaBR), eligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients in Italy were granted early access through a Named Patient Program. A multicentric observational retrospective study was conducted focusing on the effectiveness and safety of PolaBR in everyday clinical practice. Fifty-five patients were enrolled. There were 26 females (47.3%), 32 patients were primary refractory and 45 (81.8%) resulted refractory to their last therapy. The decision to add or not bendamustine was at physician's discretion. Thirty-six patients underwent PolaBR, and 19 PolaR. The 2 groups did not differ in most of baseline characteristics. The final overall response rate was 32.7% (18.2% complete response rate), with a best response rate of 49.1%. Median disease-free survival was reached at 12 months, median progression-free survival at 4.9 months and median overall survival at 9 months, respectively. Overall, 88 adverse events (AEs) were registered during treatment in 31 patients, 22 of grade ≥3. Eight cases of neuropathy occurred, all of grades 1-2 and all related to polatuzumab. The two groups of treatment did not differ for effectiveness endpoints but presented statistically significant difference in AEs occurrence, especially in hematological AEs, in AEs of grade equal or greater than 3 and in incidence of neuropathy. Our data add useful information on the effectiveness of Pola(B)R in the setting of heavily pretreated DLBCL and may also suggest a better tolerability in absence of bendamustine without compromise of efficacy

SUBTYPES OF MATURE T AND NK CELL LYMPHOMAS ACCORDING TO 2016 WHO CLASSIFICATION. PRELIMINARY REPORT OF THE INTERNATIONAL PROSPECTIVE T‐CELL PROJECT 2.0

n/

NR1H3 (LXRα) is associated with pro-inflammatory macrophages, predicts survival and suggests potential therapeutic rationales in diffuse large b-cell lymphoma

The role of macrophages (Mo) and their prognostic impact in diffuse large B-cell lymphomas (DLBCL) remain controversial. By regulating the lipid metabolism, Liver-X-Receptors (LXRs) control Mo polarization/inflammatory response, and their pharmacological modulation is under clinical investigation to treat human cancers, including lymphomas. Herein, we surveyed the role of LXRs in DLBCL for prognostic purposes. Comparing bulk tumors with purified malignant and normal B-cells, we found an intriguing association of NR1H3, encoding for the LXR-α isoform, with the tumor microenvironment (TME). CIBERSORTx-based purification on large DLBCL datasets revealed a high expression of the receptor transcript in M1-like pro-inflammatory Mo. By determining an expression cut-off of NR1H3, we used digital measurement to validate its prognostic capacity on two large independent on-trial and real-world cohorts. Independently of classical prognosticators, NR1H3high patients displayed longer survival compared with NR1H3low cases and a high-resolution Mo GEP dissection suggested a remarkable transcriptional divergence between subgroups. Overall, our findings indicate NR1H3 as a Mo-related biomarker identifying patients at higher risk and prompt future preclinical studies investigating its mouldability for therapeutic purposes