HIV-associated progressive multifocal leukoencephalopathy. Current perspectives

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system, caused by the polyomavirus JC and occurring almost exclusively in the context of severe immune depression. AIDS represents the most common predisposing condition for PML development. Antiretroviral treatment has reduced PML incidence in HIV-infected subjects, but the disease remains a severe and life-threatening complication of AIDS, considering thus far the lack of an effective anti-JC virus (JCV) direct-acting antiviral drug. In the last decade, the use of monoclonal antibodies for treating immune-based diseases evidenced new predisposing conditions for PML development, promoting a renewed interest in PML pathogenesis. In this article, we review the current knowledge on JCV epidemiology and AIDS-associated PML incidence, JCV viral cycle, pathogenesis, and the interplay with HIV infection. We give an updated overview of diagnostic and prognostic tools available for PML diagnosis and describe past and current therapeutic approaches, including new strategies for PML cure

The burden of calcific aortic stenosis. what's behind

In Western countries, calcific aortic valve stenosis (CAS) is widely common, representing the third cause of death among cardiovascular diseases (CVD). The burden of CAS is high, with an increasing prevalence rate related to age. An efficient medical treatment, according to guidelines, lacks to prevent the development and to reduce the progression of CAS. In this context, due to the aging population and the lack of effective medical management, the prevalence is expected to double-triple within the next decades. In our review, we aim to provide an overview of the underlying mechanisms of pathogenesis and the current state of the art regarding pathophysiological insights and novel potential therapeutic targets

The bench is closer to the bedside than we think:Uncovering the ethical ties between preclinical researchers in translational neuroscience and patients in clinical trials

Millions of people worldwide currently suffer from serious neurological diseases and injuries for which there are few, and often no, effective treatments. The paucity of effective interventions is, no doubt, due in large part to the complexity of the disorders, as well as our currently limited understanding of their pathophysiology. The bleak picture for patients, however, is also attributable to avoidable impediments stemming from quality concerns in preclinical research that often escape detection by research regulation efforts. In our essay, we connect the dots between these concerns about the quality of preclinical research and their potential ethical impact on the patients who volunteer for early trials of interventions informed by it. We do so in hopes that a greater appreciation among preclinical researchers of these serious ethical consequences can lead to a greater commitment within the research community to adopt widely available tools and measures that can help to improve the quality of research

Achieving sustainable aquaculture: Historical and current perspectives and future needs and challenges

Important operational changes that have gradually been assimilated and new approaches that are developing as part of the movement toward sustainable intensive aquaculture production systems are presented via historical, current, and future perspectives. Improved environmental and economic sustainability based on increased efficiency of production continues to be realized. As a result, aquaculture continues to reduce its carbon footprint through reduced greenhouse gas emissions. Reduced use of freshwater and land resources per unit of production, improved feed management practices as well as increased knowledge of nutrient requirements, effective feed ingredients and additives, domestication of species, and new farming practices are now being applied or evaluated. Successful expansion into culture of marine species, both off and on shore, offers the potential of substantial increases in sustainable intensive aquaculture production combined with integrative efforts to increase efficiency will principally contribute to satisfying the increasing global demand for protein and food security needs

Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19)

SARS-CoV-2 is associated with a 3.4% mortality rate in patients with severe disease. The pathogenesis of severe cases remains unknown. We performed an in-depth prospective analysis of immune and inflammation markers in two patients with severe COVID-19 disease from presentation to convalescence. Peripheral blood from 18 SARS-CoV-2-infected patients, 9 with severe and 9 with mild COVID-19 disease, was obtained at admission and analyzed for T-cell activation profile, myeloid-derived suppressor cells (MDSCs) and cytokine profiles. MDSC functionality was tested in vitro. In four severe and in four mild patients, a longitudinal analysis was performed daily from the day of admission to the early convalescent phase. Early after admission severe patients showed neutrophilia, lymphopenia, increase in effector T cells, a persisting higher expression of CD95 on T cells, higher serum concentration of IL-6 and TGF-β, and a cytotoxic profile of NK and T cells compared with mild patients, suggesting a highly engaged immune response. Massive expansion of MDSCs was observed, up to 90% of total circulating mononuclear cells in patients with severe disease, and up to 25% in the patients with mild disease; the frequency decreasing with recovery. MDSCs suppressed T-cell functions, dampening excessive immune response. MDSCs decline at convalescent phase was associated to a reduction in TGF-β and to an increase of inflammatory cytokines in plasma samples. Substantial expansion of suppressor cells is seen in patients with severe COVID-19. Further studies are required to define their roles in reducing the excessive activation/inflammation, protection, influencing disease progression, potential to serve as biomarkers of disease severity, and new targets for immune and host-directed therapeutic approaches

Seasonal size variation in the predatory cladoceran Bythotrephes cederstroemii in Lake Michigan

1.  Dry weight, body length and spine length were measured for the exotic cladoceran Bythotrephes cederstroemii collected from offshore and inshore stations in southeastern Lake Michigan. Average dry weight of each developmental stage exhibited seasonal variation by a factor of more than 5. 2.  Mean dry weight of Bythotrephes was closely correlated with water temperature. Contrary to the inverse relationship between water temperature and body size frequently observed for other invertebrates, the dry weight of Bythotrephes increased at higher ambient temperatures. 3.  No significant correlation was observed between abundances of major zooplankton taxa and the dry weight of Bythotrephes . An indirect effect of temperature on prey consumption may cause seasonal variation in dry weight of Bythotrephes in Lake Michigan. 4.  Distances between adjacent pairs of barbs, added to the caudal spine with each moult, are significantly shorter in Bythotrephes which produce resting eggs. Less material investment in the exoskeleton of sexually reproducing females was observed in favour of growth and reproduction.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74641/1/j.1365-2427.1994.tb00842.x.pd

The ε3 and ε4 Alleles of Human APOE Differentially Affect Tau Phosphorylation in Hyperinsulinemic and Pioglitazone Treated Mice

Impaired insulin signalling is increasingly thought to contribute to Alzheimer's disease (AD). The ε4 isoform of the APOE gene is the greatest genetic risk factor for sporadic, late onset AD, and is also associated with risk for type 2 diabetes mellitus (T2DM). Neuropathological studies reported the highest number of AD lesions in brain tissue of ε4 diabetic patients. However other studies assessing AD pathology amongst the diabetic population have produced conflicting reports and have failed to show an increase in AD-related pathology in diabetic brain. The thiazolidinediones (TZDs), peroxisome proliferator-activated receptor gamma agonists, are peripheral insulin sensitisers used to treat T2DM. The TZD, pioglitazone, improved memory and cognitive functions in mild to moderate AD patients. Since it is not yet clear how apoE isoforms influence the development of T2DM and its progression to AD, we investigated amyloid beta and tau pathology in APOE knockout mice, carrying human APOEε3 or ε4 transgenes after diet-induced insulin resistance with and without pioglitazone treatment.Male APOE knockout, APOEε3-transgenic and APOEε4-transgenic mice, together with background strain C57BL6 mice were kept on a high fat diet (HFD) or low fat diet (LFD) for 32 weeks, or were all fed HFD for 32 weeks and during the final 3 weeks animals were treated with pioglitazone or vehicle.All HFD animals developed hyperglycaemia with elevated plasma insulin. Tau phosphorylation was reduced at 3 epitopes (Ser396, Ser202/Thr205 and Thr231) in all HFD, compared to LFD, animals independent of APOE genotype. The introduction of pioglitazone to HFD animals led to a significant reduction in tau phosphorylation at the Ser202/Thr205 epitope in APOEε3 animals only. We found no changes in APP processing however the levels of soluble amyloid beta 40 was reduced in APOE knockout animals treated with pioglitazone

Docosahexaenoic Acid-Derived Neuroprotectin D1 Induces Neuronal Survival via Secretase- and PPARγ-Mediated Mechanisms in Alzheimer's Disease Models

Neuroprotectin D1 (NPD1) is a stereoselective mediator derived from the omega-3 essential fatty acid docosahexaenoic acid (DHA) with potent inflammatory resolving and neuroprotective bioactivity. NPD1 reduces Aβ42 peptide release from aging human brain cells and is severely depleted in Alzheimer's disease (AD) brain. Here we further characterize the mechanism of NPD1's neurogenic actions using 3xTg-AD mouse models and human neuronal-glial (HNG) cells in primary culture, either challenged with Aβ42 oligomeric peptide, or transfected with beta amyloid precursor protein (βAPP)sw (Swedish double mutation APP695sw, K595N-M596L). We also show that NPD1 downregulates Aβ42-triggered expression of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) and of B-94 (a TNF-α-inducible pro-inflammatory element) and apoptosis in HNG cells. Moreover, NPD1 suppresses Aβ42 peptide shedding by down-regulating β-secretase-1 (BACE1) while activating the α-secretase ADAM10 and up-regulating sAPPα, thus shifting the cleavage of βAPP holoenzyme from an amyloidogenic into the non-amyloidogenic pathway. Use of the thiazolidinedione peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone, the irreversible PPARγ antagonist GW9662, and overexpressing PPARγ suggests that the NPD1-mediated down-regulation of BACE1 and Aβ42 peptide release is PPARγ-dependent. In conclusion, NPD1 bioactivity potently down regulates inflammatory signaling, amyloidogenic APP cleavage and apoptosis, underscoring the potential of this lipid mediator to rescue human brain cells in early stages of neurodegenerations