Differences in viral kinetics between genotypes 1 and 3 of hepatitis C virus and between cirrhotic and non-cirrhotic patients during antiviral therapy

AIM： TO evaluate the impact of hepatitis C virus （HCV） infection with genotype 1 or 3 and the presence or absence of liver cirrhosis （LC） in the early viral kinetics response to treatment. METHODS： Naive patients （n = 46） treated with interferon-α （IFN-α） and ribavirin and followed up with frequent early HCV-RNA determinations were analysed. Patients were infected with genotype 1 （n = 28, 7 with LC） or 3 （n = 18, 5 with LC）. RESULTS： The first phase decline was larger in genotype 3 patients than in genotype 1 patients （1.72 vs 0.95 log IU/mL, P 〈 0.001）. The second phase slope decline was also larger in genotype 3 patients than in genotype 1 patients （0.87 vs 0.15 log/wk, P 〈 0.001）. Differences were found in both cirrhotic and non-cirrhotic patients. Genotype 1 cirrhotic patients had a slower 2^nd phase slope than non-cirrhotic patients （0.06 vs 0.18 log/wk, P 〈 0,02）. None of genotype 1 cirrhotic patients had a 1^st phase decline larger than 1 log （non-cirrhotic patients： 55%, P 〈 0.02）. A similar trend toward a slower 2nd phase slope was observed in genotype 3 cirrhotic patients but the 1^st phase slope decline was not different. Sustained viral response was higher in genotype 3 patients than in genotype 1 patients ,（72% vs 14%, P 〈 0.001） and in genotype 1 non-cirrhotic patients than in genotype 1 cirrhotic patients （19% vs 0%）. A second phase decline slower than 0.3 log per week was predictive of non-response in all groups. CONCLUSION： Genotype 3 has faster early viral decline than genotype 1. Cirrhosis correlates with a slower 2nd phase decline and possibly with a lower 1^st phase slope decline in genotype 1 patients.

Phenotypic heterogeneity in amyotrophic lateral sclerosis type 8 and modifying mechanisms of neurodegeneration

In his accounts "On longevity and shortness of life", Aristotle considered how diseased states could be interchangeably associated with long and short lifespans. He believed that the presence of opposite elements and the environment were the sole determinants of this variability.

Novel Immunogenic Epitopes in the NaPi-IIb Protein: Production of Monospecific Antibodies Using Synthetic Peptides Outlined on Isoform Specific Regions of the Type IIb Sodium-Dependent Phosphate Transporter (NaPi-IIb)

NaPi-IIb is a multiple passage protein membrane which is primarily responsible for phosphate uptake in the kidney and in the small intestine. Beyond its physiological functions, their involvement with carcinogenesis was initially described in mid-2003, due to its distinct level of expression in normal and tumor cells of the ovary. Although less common than cervical cancer, epithelial ovarian cancer is considered the most lethal gynecologic malignancy, which is mainly due to diagnosis in the advanced stages as a result of the absence of symptoms during the onset of the disease and the lack of tools for early detection. Here, we produce antibodies that are anti-synthetic peptides that are derived from the regions of second extracellular loop of NaPi-IIb, which is a non-overlapping portion of MX35 epitope. These two 15 distinct amino acid residue peptides, designated as Let#1 and Let#2, are engineered in a very thorough way to detect specific sites only in this isoform, thus excluding cross-reactivity with other carriers of the same family. The lack of immunogenicity of small peptides is surpassed by the conjugation with carrier proteins. Using immunochemical methods, we demonstrate that polyclonal antibodies that are mono-specific for the Let#1 and Let#2 peptides recognize proteins that express similar amino acid sequences during blood circulation. Additionally, using flow cytometry, we identify NaPi-IIb in NIH:OVCAR-3 cells. The clear identification of two shorter peptides on the extracellular loop of NaPi-IIb, which are far from the monoclonal antibody MX35-recognizing epitopes, adds new promising tools for ovarian cancer follow-up and staging.

Anaphylatoxins:From Supposed Toxin Anaphylactics to Effective Mediators of the Early Events of Inflammation

This review updates original data describing the experiments showing the complement origin of anaphylatoxins unexplainable submerged under the surface of the articles related to the subject. Next, recalls subsequent data describing the anaphylatoxins peptide nature and sequences, the cell receptors with which they interact and activate and the outcome of the cell responses. The review continues by highlighting the anaphylatoxin biological properties focusing on the unequivocal participation of these mediators in inflammation. The review concludes bringing data reinforcing the promising use of these peptides as molecular primers to create specific and efficient pharmacological antagonists.

Leukotriene-A4-Hydrolase and Basic Aminopeptidase Activities Are Related with Collagen-Induced Arthritis in a Compartment-Dependent Manner

Objective: Previous study demonstrated the involvement of basic aminopeptidase (APB) activity in the development of collagen-induced arthritis (CIA). Two zinc dependent metalloenzymes (EC 3.4.11.6 and EC 3.3.2.6) are known to exhibit concomitantly APB and leukotriene-A4-hydrolase (LT-A4-H) activities. Influence of the interrelationship between both activities on arthritic processes, however, is presently uncertain. This study aimed to compare these activities in CIA. Methods: CIA was induced in rats and arthritis was assessed macroscopically. Ultracentrifugation was used to separate soluble (S) and solubilized membrane-bound (M) fractions from peripheral blood mononuclear cells (PBMCs) and synovial tissue (ST). Enzyme immunoassay was used to measure LT-A4-H activity, and Real Time Polymerase Chain Reaction was used for evaluating EC 3.4.11.6 and EC 3.3.2.6 gene expressions. Results: The existence of genes for EC 3.3.2.6 and EC 3.4.11.6 was demonstrated in the ST. Compared with control, LT-A4-H activity increased in synovial fluid (SF) and in S-PBMCs of CIA-arthritic and CIA-resistant and in M-ST of CIA-resistant, while it decreased in M-PBMCs of CIA-arthritic and CIA-resistant. In all these locations APB activity remained unchanged or inversely correlated with LT-A4-H activity. Conclusions: LT-A4-H and APB activities in joint-related samples are associated, for the first time, with EC 3.3.2.6 and EC 3.4.11.6 genes, exhibiting a compartment-dependent differential modulation of their specificity, efficiency and/or affinity or an inverse concurrent pattern. Changes in LT-A4-H activity have implications for development or resistance to arthritis in CIA model with a potential to be a diagnostic tool.

Effects of primovaccination and booster vaccination on serum cortisol and humoral immune response in cattle

The objective of this study was to evaluate the effect of one or two doses of the anti-rabies vaccination on the serum concentration of cortisol and the humoral immune response in cattle as well as the correlation between serum cortisol concentrations and the titers of rabies-neutralizing antibodies. Nelore cattle were randomly assigned to one of three groups, which were vaccinated with one dose of rabies vaccine (group GVSR, N = 15), two doses of rabies vaccine (group GVR, N = 15) or were not vaccinated (group Gc, N = 15). A commercial liquid inactivated rabies vaccine was used. The stressors imposed on the cattle were vaccination, corral handling and the presence of people. Blood samples were collected on days 0, 30 and 60 post-vaccination. Serum cortisol concentrations were determined using a solid-phase radioimmunoassay, and rabies antibody titers were determined using a serum neutralization test with BHK21 cells (RFFIT). Both serum cortisol concentrations and antibody titers increased after the second (booster) vaccination (P < 0.05). In all the groups, the serum cortisol concentrations increased after the cattle were handled in the corral (P < 0.05). No correlation was observed between the serum cortisol concentrations and the antibody titers with any treatment or on any observation day. In conclusion, booster vaccination is indispensable for primovaccinated cattle in achieving high and protective levels of rabies antibodies. Although booster vaccination and frequent cattle handling in corrals are stressors, the response is not strong enough to cause immunosuppression in cattle.

Analysing vaccine efficacy evaluated in phase 3 clinical trials carried out during outbreaks

In this paper we examine several definitions of vaccine efficacy(VE)that we found in the literature,for diseases that express themselves in outbreaks,that is,when the force of infection grows in time,reaches a maximum and then vanishes.The fact that the disease occurs in outbreaks results in several problems that we analyse.We propose a mathematical model that allows the calculation of VE for several scenarios.Vaccine trials usually needs a large number of volunteers that must be enrolled.Ideally,all volunteers should be enrolled in approximately the same time,but this is generally impossible for logistic reasons and they are enrolled in a fashion that can be replaced by a continuous density function(for example,a Gaussian function).The outbreak can also be replaced by a continuous density function,and the use of these density functions simplifies the calculations.Assuming,for example Gaussian functions,one of the problems one can immediately notice is that the peak of the two curves do not occur at the same time.The model allows us to conclude:First,the calculated vaccine efficacy decreases when the force of infection increases;Second,the calculated vaccine efficacy decreases when the gap between the peak in the force of infection and the peak in the enrollment rate increases;Third,different trial protocols can be simulated with this model;different vaccine efficacy definitions can be calculated and in our simulations,all result are approximately the same.The final,and perhaps most important conclusion of our model,is that vaccine efficacy calculated during outbreaks must be carefully examined and the best way we can suggest to overcome this problem is to stratify the enrolled volunteer's in a cohort-by-cohort basis and do the survival analysis for each cohort,or apply the Cox proportional hazards model for each cohort.

Modelling the test, trace and quarantine strategy to control the COVID-19 epidemic in the state of São Paulo, Brazil

Testing for detecting the infection by SARS-CoV-2 is the bridge between the lockdown and the opening of society.In this paper we modelled and simulated a test-trace-andquarantine strategy to control the COVID-19 outbreak in the State of São Paulo,Brasil.The State of São Paulo failed to adopt an effective social distancing strategy,reaching at most 59%in late March and started to relax the measures in late June,dropping to 41%in 08 August.Therefore,São Paulo relies heavily on a massive testing strategy in the attempt to control the epidemic.Two alternative strategies combined with economic evaluations were simulated.One strategy included indiscriminately testing the entire population of the State,reaching more than 40 million people at a maximum cost of 2.25 billion USD,that would reduce the total number of cases by the end of 2020 by 90%.The second strategy investigated testing only symptomatic cases and their immediate contacts e this strategy reached a maximum cost of 150 million USD but also reduced the number of cases by 90%.The conclusion is that if the State of São Paulo had decided to adopt the simulated strategy on April the 1st,it would have been possible to reduce the total number of cases by 90%at a cost of 2.25 billion US dollars for the indiscriminate strategy but at a much smaller cost of 125 million US dollars for the selective testing of symptomatic cases and their contacts.

Climatic niche breadths of the Atlantic Forest snakes do not increase with increasing latitude

The climatic niche is a central concept for understanding species distribution,with current and past climate interpreted as strong drivers of present and historical-geographical ranges.Our aim is to understand whether Atlantic Forest snakes follow the general geographical pattern of increasing species climatic niche breadths with increasing latitude.We also tested if there is a tradeoff between temperature and precipitation niche breadths of species in order to understand if species with larger breadths of one niche dimension have stronger dispersal constraints by the other due to narrower niche breadths.Niche breadths were calculated by the subtraction of maximal and minimal values of temperature and precipitation across species ranges.We implemented Phylogenetic Generalized Least Squares to measure the relationship between temperature and precipitation niche breadths and latitude.We also tested phylogenetic signals by Lambda statistics to analyze the degree of phylogenetic niche conservatism to both niche dimensions.Temperature niche breadths were not related to latitude.Precipitation niche breadths decreased with increasing latitude and presented a high phylogenetic signal,that is,significant phylogenetic niche conservatism.We rejected the tradeoff hypotheses of temperature and precipitation niche breadths.Our results also indicate that precipitation should be an important ecological constraint affecting the geographical distribution of snake lineages across the South American Atlantic Forest.We then provide a general view of how phylogenetic niche conservatism could impact the patterns of latitudinal variation of climatic niches across this biodiversity hotspot.