Management of SARS-CoV-2 Infection: Key Focus in Macrolides Efficacy for COVID-19

Macrolides (e.g., erythromycin, fidaxomicin, clarithromycin, and azithromycin) are a class of bacteriostatic antibiotics commonly employed in medicine against various gram-positive and atypical bacterial species mostly related to respiratory tract infections, besides they possess anti-inflammatory and immunomodulatory effects. Coronavirus Disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome of coronavirus 2 (SARS-CoV-2). It was first detected in Wuhan, Hubei, China, in December 2019 and resulted in a continuing pandemic. Macrolides have been extensively researched as broad adjunctive therapy for COVID-19 due to its immunostimulant abilities. Among such class of drugs, azithromycin is described as azalide and is well-known for its ability to decrease the production of pro-inflammatory cytokines, including matrix metalloproteinases, tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8. In fact, a report recently published highlighted the effectiveness of combining azithromycin and hydroxychloroquine for COVID-19 treatment. Indeed, it has been underlined that azithromycin quickly prevents SARS-CoV-2 infection by raising the levels of both interferons and interferon-stimulated proteins at the same time which reduces the virus replication and release. In this sense, the current review aims to evaluate the applications of macrolides for the treatment of COVID-19.NC-M acknowledges the Portuguese Foundation for Science and Technology under the Horizon 2020 Program (PTDC/PSI-GER/28076/2017)

Solitary metastatic clear cell carcinoma to the spleen

A 57-year-old with a 9-year history of increased abdominal girth, presented with increased abdominal pain, anemia, and acute renal failure. His past medical history was only remarkable for a previous lung cancer 21 years ago that was treated with a right upper lung lobectomy. A computed tomography (CT) scan of the patient's abdomen showed a solitary 20×20×25cm cystic splenic mass. The patient underwent an urgent splenectomy. Intra-operatively a large splenic cystic cavity was found with a solid inferior splenic mass. An exhaustive histological analysis of the splenic mass confirmed a clear cell carcinoma with low malignant potential that likely represented a metastatic lesion from the patient's previous distant lung cancer. Postoperatively the patient recovered well and at 1-year followup the patient demonstrated no further evidence of metastatic disease. This case is extremely unique and provides a very rare example of a metastatic solitary clear cell carcinoma to the spleen, with a presumed latency period of more than 20 years

Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy

Introduction: We reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells. / Methods: This study was a double-blind, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors. The primary end point was reduction of proteinuria. Secondary end points included change from baseline in estimated glomerular filtration rate (eGFR) and kidney histology. / Results: Although we could not detect significant reduction in proteinuria with fostamatinib overall, in a predetermined subgroup analysis, there was a trend for dose-dependent reduction in median proteinuria (from baseline to 24 weeks by 14%, 27%, and 36% in the placebo, fostamatinib 100 mg, and 150 mg groups, respectively) in patients with baseline urinary protein-to-creatinine ratios (UPCR) more than 1000 mg/g. Kidney function (eGFR) remained stable in all groups. Fostamatinib was well-tolerated. Side effects included diarrhea, hypertension, and increased liver enzymes. Thirty-nine patients underwent repeat biopsy showing reductions in SYK staining associated with therapy at low dose (−1.5 vs. 1.7 SYK+ cells/glomerulus in the placebo group, P < 0.05). / Conclusions: There was a trend toward reduction in proteinuria with fostamatinib in a predefined analysis of high risk patients with IgAN despite maximal care, as defined by baseline UPCR greater than 1000 mg/g. Further study may be warranted

A hyperactive sleeping beauty transposase enhances transgenesis in zebrafish embryos

Extent: 4p.Background: Transposons are useful molecular tools for transgenesis. The 'sleeping beauty' transposon is a synthetic member of the Tc1/mariner transposon family. Davidson et al. (2003) previously described a vector for zebrafish transgenesis consisting of the inverted repeats of 'sleeping beauty' flanking the gene to be transposed. Subsequently, there have been attempts to enhance the transpositional activity of 'sleeping beauty' by increasing the activity of its transposase. Recently, Mates et al. (2009) generated a hyperactive transposase giving a 100-fold increased transposition rate in mouse embryos. Findings: The aim of this experiment was to determine whether this novel hyperactive transposase enhances transgenesis in zebrafish embryos. Using our previously characterised mitfa-amyloidβ-GFP transgene, we observed an eight-fold enhancement in transient transgenesis following detection of transgene expression in melanophores by whole mount in-situ hybridisation. However, high rates of defective embryogenesis were also observed. Conclusion: The novel hyperactive 'sleeping beauty' transposase enhances the rate of transgenesis in zebrafish embryos.Morgan Newman, Michael Lardell

Stressful conditions reveal decrease in size, modification of shape but relatively stable asymmetry in bumblebee wings

Human activities can generate a wide variety of direct and indirect effects on animals, which can manifest as environmental and genetic stressors. Several phenotypic markers have been proposed as indicators of these stressful conditions but have displayed contrasting results, depending, among others, on the phenotypic trait measured. Knowing the worldwide decline of multiple bumblebee species, it is important to understand these stressors and link them with the drivers of decline. We assessed the impact of several stressors (i.e. natural toxin-, parasite-, thermic- and inbreeding-stress) on both wing shape and size and their variability as well as their directional and fluctuating asymmetries. The total data set includes 650 individuals of Bombus terrestris (Hymenoptera: Apidae). Overall wing size and shape were affected by all the tested stressors. Except for the sinigrin (e.g. glucosinolate) stress, each stress implies a decrease of wing size. Size variance was affected by several stressors, contrary to shape variance that was affected by none of them. Although wing size directional and fluctuating asymmetries were significantly affected by sinigrin, parasites and high temperatures, neither directional nor fluctuating shape asymmetry was significantly affected by any tested stressor. Parasites and high temperatures led to the strongest phenotype modifications. Overall size and shape were the most sensitive morphological traits, which contrasts with the common view that fluctuating asymmetry is the major phenotypic marker of stress

Insect Pollinated Crops, Insect Pollinators and US Agriculture: Trend Analysis of Aggregate Data for the Period 1992–2009

In the US, the cultivated area (hectares) and production (tonnes) of crops that require or benefit from insect pollination (directly dependent crops: apples, almonds, blueberries, cucurbits, etc.) increased from 1992, the first year in this study, through 1999 and continued near those levels through 2009; aggregate yield (tonnes/hectare) remained unchanged. The value of directly dependent crops attributed to all insect pollination (2009 USD) decreased from $14.29 billion in 1996, the first year for value data in this study, to$10.69 billion in 2001, but increased thereafter, reaching $15.12 billion by 2009. The values attributed to honey bees and non-Apis pollinators followed similar patterns, reaching$11.68 billion and $3.44 billion, respectively, by 2009. The cultivated area of crops grown from seeds resulting from insect pollination (indirectly dependent crops: legume hays, carrots, onions, etc.) was stable from 1992 through 1999, but has since declined. Production of those crops also declined, albeit not as rapidly as the decline in cultivated area; this asymmetry was due to increases in aggregate yield. The value of indirectly dependent crops attributed to insect pollination declined from$15.45 billion in 1996 to $12.00 billion in 2004, but has since trended upward. The value of indirectly dependent crops attributed to honey bees and non-Apis pollinators, exclusive of alfalfa leafcutter bees, has declined since 1996 to$5.39 billion and $1.15 billion, respectively in 2009. The value of alfalfa hay attributed to alfalfa leafcutter bees ranged between$4.99 and $7.04 billion. Trend analysis demonstrates that US producers have a continued and significant need for insect pollinators and that a diminution in managed or wild pollinator populations could seriously threaten the continued production of insect pollinated crops and crops grown from seeds resulting from insect pollination

Prolonged Application of High Fluid Shear to Chondrocytes Recapitulates Gene Expression Profiles Associated with Osteoarthritis

BACKGROUND: Excessive mechanical loading of articular cartilage producing hydrostatic stress, tensile strain and fluid flow leads to irreversible cartilage erosion and osteoarthritic (OA) disease. Since application of high fluid shear to chondrocytes recapitulates some of the earmarks of OA, we aimed to screen the gene expression profiles of shear-activated chondrocytes and assess potential similarities with OA chondrocytes. METHODOLOGY/PRINCIPAL FINDINGS: Using a cDNA microarray technology, we screened the differentially-regulated genes in human T/C-28a2 chondrocytes subjected to high fluid shear (20 dyn/cm(2)) for 48 h and 72 h relative to static controls. Confirmation of the expression patterns of select genes was obtained by qRT-PCR. Using significance analysis of microarrays with a 5% false discovery rate, 71 and 60 non-redundant transcripts were identified to be ≥2-fold up-regulated and ≤0.6-fold down-regulated, respectively, in sheared chondrocytes. Published data sets indicate that 42 of these genes, which are related to extracellular matrix/degradation, cell proliferation/differentiation, inflammation and cell survival/death, are differentially-regulated in OA chondrocytes. In view of the pivotal role of cyclooxygenase-2 (COX-2) in the pathogenesis and/or progression of OA in vivo and regulation of shear-induced inflammation and apoptosis in vitro, we identified a collection of genes that are either up- or down-regulated by shear-induced COX-2. COX-2 and L-prostaglandin D synthase (L-PGDS) induce reactive oxygen species production, and negatively regulate genes of the histone and cell cycle families, which may play a critical role in chondrocyte death. CONCLUSIONS/SIGNIFICANCE: Prolonged application of high fluid shear stress to chondrocytes recapitulates gene expression profiles associated with osteoarthritis. Our data suggest a potential link between exposure of chondrocytes/cartilage to abnormal mechanical loading and the pathogenesis/progression of OA