Slow Progressors Research Articles

Personalized Prediction of Glaucoma Progression Under Different Target Intraocular Pressure Levels Using Filtered Forecasting Methods

To generate personalized forecasts of how patients with open-angle glaucoma (OAG) experience disease progression at different intraocular pressure (IOP) levels to aid clinicians with setting personalized target IOPs. Secondary analyses using longitudinal data from 2 randomized controlled trials. Participants with moderate or advanced OAG from the Collaborative Initial Glaucoma Treatment Study (CIGTS) or the Advanced Glaucoma Intervention Study (AGIS). By using perimetric and tonometric data from trial participants, we developed and validated Kalman Filter (KF) models for fast-, slow-, and nonprogressing patients with OAG. The KF can generate personalized and dynamically updated forecasts of OAG progression under different target IOP levels. For each participant, we determined how mean deviation (MD) would change if the patient maintains his/her IOP at 1 of 7 levels (6, 9, 12, 15, 18, 21, or 24 mmHg) over the next 5 years. We also model and predict changes to MD over the same time horizon if IOP is increased or decreased by 3, 6, and 9 mmHg from the level attained in the trials. Personalized estimates of the change in MD under different target IOP levels. A total of 571 participants (mean age, 64.2 years; standard deviation, 10.9) were followed for a mean of 6.5 years (standard deviation, 2.8). Our models predicted that, on average, fast progressors would lose 2.1, 6.7, and 11.2 decibels (dB) MD under target IOPs of 6, 15, and 24 mmHg, respectively, over 5 years. In contrast, on average, slow progressors would lose 0.8, 2.1, and 4.1 dB MD under the same target IOPs and time frame. When using our tool to quantify the OAG progression dynamics for all 571 patients, we found no statistically significant differences over 5 years between progression for black versus white, male versus female, and CIGTS versus AGIS participants under different target IOPs (P > 0.05 for all). To our knowledge, this is the first clinical decision-making tool that generates personalized forecasts of the trajectory of OAG progression at different target IOP levels. This approach can help clinicians determine appropriate, personalized target IOPs for patients with OAG.

High CXCL10/IP-10 levels are a hallmark in the clinical evolution of the HIV infection

The aim of this study was to investigate the modulation of plasma CXCL10, CCL20, CCL22, CCL2, CCL17 and CCL24 levels in HIV-positive patients grouped according to extreme phenotypes of progression to AIDS, and at different stages of HIV infection. HIV-positive individuals with extreme phenotypes of AIDS progression (n=58) at different clinical stages (chronic individuals, both pre-HAART and under-HAART) and HIV-negative controls (n=20) were evaluated. Additionally, HIV-positive individuals that initiated HAART with >350CD4+T-cells/mm3 were compared with those who initiated treatment with <350CD4+T-cells/mm3. Plasma levels of six chemokines were quantified by a Luminex assay. Higher CXCL10 levels were observed in individuals immediately before their CD4+T-cell levels were indicative for HAART (pre-HAART), independently of their progressor status, i.e. slow (SPs) or rapid progressors (RPs). SPs pre-HAART showed higher CXCL10 levels compared to elite controllers and RPs under HAART (pc=0.009 and pc=0.007, respectively). CXCL10 levels were higher in SPs HAART CD4<350 (initiated HAART with <350 CD4+T-cells) when compared with SPs HAART CD4>350 (initiated HAART with >350 CD4+T-cells) (1096 vs. 360.33pg/mL, p=0.0101). Normalisation of CXCL10 levels seems to depend on the CD4+T-cell nadir at HAART initiation. CCL20 levels were higher in chronic SPs, SPs pre-HAART, SPs HAART and RPs HAART compared with the HIV-negative controls, indicating persistent CCL20 expression. In conclusion, our results indicate that CXCL10 levels are a hallmark in the clinical evolution of HIV infection. However, our results must be verified in a study evaluating a larger number of AIDS progressors.

Fast progressive lower motor neuron disease is an ALS variant: A two-centre tract of interest-based MRI data analysis.

BackgroundThe criteria for assessing upper motor neuron pathology in pure lower motor neuron disease (LMND) still remain a major issue of debate with respect to the clinical classification as an amyotrophic lateral sclerosis (ALS) variant.ObjectiveThe study was designed to investigate white matter damage by a hypothesis-guided tract-of-interest-based approach in patients with LMND compared with healthy controls and ´classical´ ALS patients in order to identify in vivo brain structural changes according to the neuropathologically defined ALS affectation pattern. Data were pooled from two previous studies at two different study sites (Ulm, Germany and Milano, Italy).MethodsDTI-based white matter integrity mapping was performed by voxelwise statistical comparison and by a tractwise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern for 65 LMND patients (clinically differentiated in fast and slow progressors) vs. 92 matched controls and 101 ALS patients with a ‘classical’ phenotype to identify white matter structural alterations.ResultsThe analysis of white matter structural connectivity by regional FA reductions demonstrated the characteristic alteration patterns along the CST and also in frontal and prefrontal brain areas in LMND patients compared to controls and ALS. Fast progressing LMND showed substantial involvement, like in ALS, while slow progressors showed less severe alterations. In the tract-specific analysis according to the ALS-staging pattern, fast progressing LMND showed significant alterations of ALS-related tract systems as compared to slow progressors and controls.ConclusionsThis study showed an affectation pattern for corticoefferent fibers in LMND with fast disease progression as defined for ALS, that way confirming the hypothesis that fast progressing LMND is a phenotypical variant of ALS.

Cutoff values of disease activity markers to distinguish rapid vs slow progression in patients with HTLV-1-associated myelopathy (HAM/TSP)

Background: Since the disease course of HTLV-1-associated myelopathy (HAM/TSP) varies among patients that enables to divide patients into groups such as rapid and slow progressors, there is a dire need for biomarkers capable of discriminating these groups.

FV 9 Diffusion tensor imaging in pure lower motor neuron disease

Criteria for assessing upper motor neuron pathology in lower motor neuron disease (LMND) still remain a major issue in clinical diagnosis. This study was designed to investigate patients with the clinical diagnosis of adult pure LMND by use of whole-brain based diffusion tensor imaging (DTI) in order to delineate alterations of corticoefferent pathways in vivo. Comparison of fractional anisotropy (FA) maps was performed by whole brain-based spatial statistics for 37 LMND patients vs. 53 matched controls to detect white matter structural alterations. LMND patients were clinically differentiated in fast and slow progressors. Tract specific alterations were investigated by fiber tracking techniques according to the staging hypothesis for amyotrophic lateral sclerosis (ALS). The analysis of white matter structural connectivity demonstrated widespread and characteristic patterns of alterations in patients with LMND, predominantly along the corticospinal tract (CST), with multiple clusters of regional FA reductions in the motor system at p < 0.05 (corrected for multiple comparisons). Fast progressing LMND showed substantial CST involvement, while slow progressors showed less CST alterations. In the tract-specific analysis according to the ALS-staging pattern (Kassubek et al., 2014), fast progressing LMND showed significant alterations of ALS-related tract systems (Müller et al., xxxx) beyond the CST compared to slow progressors and controls. In clinically pure LMND patients, the involvement of corticoefferent tracts was demonstrated, in particular along the CST, supporting the hypothesis that LMND is a phenotypical variant of ALS. This finding suggests to treat these patients like ALS, including the opportunity to participate in clinical trials.

Predict disease progression from T-cell phenotypes in northern pig-tailed macaques (Macaca leonina) during SIVmac239 infection.

Macaca leonina (northern pig-tailed macaques, NPMs) have variable disease progression during SIVmac239 infection. In the present study, we analysed, for the first time, the correlations between T-cell phenotypes and disease progression in NPMs during SIVmac239 infection. In comparison to normal progressors (NPs), slow progressors (SPs) had lower chronic T-cell activation and exhaustion levels. In addition, SPs showed higher peripheral CD4+ T-cell count and CD4:CD8 ratio, and lower plasma viral load than NPs. CD4+ T-cell count and CD4:CD8 ratio decreased more sharply in NPs than in SPs. Furthermore, T cells in NPs were more highly differentiated, at least in acute infection, than in SPs. These results indicated that T-cell phenotypes were correlated with disease progression in SIVmac239-infected NPMs and these correlations may provide valuable guidance for the improvement of therapeutic strategies tested in NPMs.

Comparative evaluation of microbial translocation products (LPS, sCD14, IgM Endocab) in HIV-1 infected Indian individuals

BackgroundMicrobial translocation of lipopolysaccharides (LPS), soluble CD14 (sCD14) and IgM Endocab levels have been reported to be associated with disease progression in HIV-1 infection. In this longitudinal study, plasma levels of different microbially translocated products (LPS, sCD14, Endocab) was investigated in HIV-1 infected Indian Individuals stratified as Rapid (R), Viremic slow (VS), Slow progressors (S) and healthy controls. MethodTen healthy and twenty HIV-1 infected individuals were enrolled. Plasma levels of LPS, sCD14, Endocab was examined using commercially available Limulus Amebocyte assay and enzyme-linked immunosorbent assay (ELISA) enzyme linked immunosorbant assay. ResultsElevated levels of sCD14, IgM EndoCab and LPS were observed during HIV-1 infection compared to healthy controls. Rapid progressors had higher levels of sCD14, IgM EndoCab, LPS (median% 1553, 3596, 202.2) compared to viremic slow, slow progressors and healthy controls both at baseline and follow up visits. At baseline, LPS correlated positively with IgM Endocab and negatively with sCD14 levels while at follow-up, significant positive correlation was observed between IgM Endocab and sCD14 (IgM EndoCab r = 0.490, p = 0.05; sCD14 r = 0.051, p = 0.830). Plasma levels of sCD14 correlated positively with viral load in rapid, viremic slow and slow progressors while CD + T cell count correlated positively with sCD14 and IgM EndoCab levels in viremic slow and slow progressors. ConclusionOur findings indicate that elevated levels of sCD14, IgM EndoCab and LPS in HIV-1 infected individuals are strong predictors of disease progression and could be considered as candidate biomarkers for disease monitoring.

Fast Versus Slow Progressors of Infarct Growth in Large Vessel Occlusion Stroke

Approximately 40% of acute ischemic strokes are caused by proximal intracranial large vessel occlusion (LVO) and are associated with the worst clinical outcomes.1 Early reperfusion with IV tPA (tissue-type plasminogen activator) and intra-arterial thrombectomy leads to reduced final infarct volumes, lower disability rates, and improved cognitive function after anterior circulation LVO.2–6 However, most stroke patients with LVO remain untreated because they present beyond the conventional time windows for acute reperfusion therapies.7,8 Therefore, a growing paradigm has been to transition to a therapeutic window that is tailored to each patient’s individual pathophysiology or brain tissue window rather than a standardized time window.9,10 The principle of pathophysiology-based reperfusion therapy is built on the fundamental concept of a dynamic interrelation between the ischemic core (tissue that is already infarcted) and the ischemic penumbra (physiologically impaired but potentially salvageable tissue).11–13 After arterial occlusion, there can be temporal growth of the ischemic core into the penumbral area that is modulated by collateral blood flow, the key element setting the pace of the ischemic process.14 Infarct growth is thought to progress at different speeds across individuals because patients with occlusion of the proximal middle cerebral artery (MCA) or internal carotid artery (ICA) terminus present with widely variable stroke volumes independently of time after symptom onset.15–18 We refer to patients with LVO who experience rapid infarct growth as fast progressors. These patients have failing collaterals and a large ischemic core despite presenting early within 6 hours of stroke onset. Conversely, a significant number of patients maintain a small ischemic core and significant salvageable tissue beyond 6 hours and up to several days after persistent LVO.17,19 The latter patients are slow progressors because they maintain good collaterals and …

Exploring the diagnosis delay and ALS functional impairment at diagnosis as relevant criteria for clinical trial enrolment*

Objectives were: i) to describe the phenotypic heterogeneity of incident amyotrophic lateral sclerosis (ALS) patients diagnosed in 2012 in French ALS centres; ii) to look at the associations between ALSFRS-R score and ALSFRS-R slope (ΔFS) at time of diagnosis with diagnosis delay, ALS phenotypes and Airlie House diagnosis criteria (AHDC); iii) to describe the rate of progression on ΔFS, according to diagnosis delay. Methods: Incident ALS cases diagnosed in French ALS centres were included. The rate of progression was evaluated as follows: ΔFS = (48 – ALSFRS-R at time of diagnosis)/duration from onset to diagnosis (months). Fast and slow progressors were defined by ΔFS >1 and <0.5, respectively. Results: At time of diagnosis, 476 patients were classified into eight phenotypes: bulbar (33.0%), spinal lumbar (28.2%), spinal cervical (23.1%), flail leg (4.4%), ALS/FTD (4.2%), possible flail arm (4.0%), respiratory (2.1%), dropped-head (1.0%). Median ΔFS (n = 358/476) was 1.0 [0.5–2.0]. ΔFS was associated with AHDC (p = 0.009), but not with clinical phenotype (p = 0.902). Stratification on diagnosis delay (<12 months or ≥18 months) allowed to differentiate fast progressors from slow progressors. Conclusion: At time of inclusion in therapeutic trial closed to diagnosis, ΔFS or diagnosis delay may discriminate the rate of progression.

A Classification Model to Predict the Rate of Decline of Kidney Function.

The African American Study of Kidney Disease and Hypertension (AASK), a randomized double-blinded treatment trial, was motivated by the high rate of hypertension-related renal disease in the African-American population and the scarcity of effective therapies. This study describes a pattern-based classification approach to predict the rate of decline of kidney function using surface-enhanced laser desorption ionization/time of flight proteomic data from rapid and slow progressors classified by rate of change in glomerular filtration rate. An accurate classification model consisting of 7 out of 5,751 serum proteomic features is constructed by applying the logical analysis of data (LAD) methodology. On cross-validation by 10-folding, the model was shown to have an accuracy of 80.6 ± 0.11%, sensitivity of 78.4 ± 0.17%, and specificity of 78.5 ± 0.16%. The LAD discriminant is used to identify the patients in different risk groups. The LAD risk scores assigned to 116 AASK patients generated a receiver operating curves curve with AUC 0.899 (CI 0.845–0.953) and outperforms the risk scores assigned by proteinuria, one of the best predictors of chronic kidney disease progression.

Quality of Life, Risk Factors and Mortality in Children with HIV/AIDS on 2nd Line Treatment, Slow Progressors and Late Presenters in Cambodian Orphanage

Quality of Life, Risk Factors and Mortality in Children with HIV/AIDS on 2nd Line Treatment, Slow Progressors and Late Presenters in Cambodian Orphanage

HIV Progression Depends on Codon and Amino Acid Usage Profile of Envelope Protein and Associated Host-Genetic Influence.

Acquired immune deficiency syndrome (AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV). Two types of HIV have been characterized: HIV-1 and HIV-2. The present study investigated whether evolutionary selection pressure differs between rapid progressor (RP), slow progressor (SP), and long-term non-progressor (LTNP) of HIV-I infected individuals. An unexpected association between the evolutionary rate of substitution in envelope (env) gene and disease progression is observed. Our present study suggests that env genes of LTNP are subject to unusually strong functional constraint with respect to RP. We also observed that the three categories of env genes i.e., RP, SP, and LTNP, had their own characteristic pattern of amino acid usage and SP and LTNP sequences shared similar patterns of amino acid usage different from RP sequences and evolutionary rate significantly influenced the amino acid usage pattern of the three different types of env gene sequences. It was also noted that the evolutionary rate for the glycosylation sites of LTNP and SP sequences were even significantly less than the RP sequences. Comparative analysis on the influence of human host on the three categories of env genes are well correlated with the rates of disease progression suggesting the adaptive strategies of the viruses for successful residence and infection. Host associated selective constraints appeared most relaxed on the RP sequences and strongest in LTNP sequences. The present study clearly portrays how evolutionary selection pressure differs between three categories of env genes i.e., RP, SP, and LTNP. The env genes, coding for the env glycoproteins, experience severe selection constraints from the host due to their constant exposure to the host immune system. In this perspective it might be suggested that env gene evolution occurs mainly by negative selection with the occurrence of mutation that might not reach fixation in the viral population. This work also confers a deeper insight into the crucial effects of host factors that govern the overall progression of HIV infection.

Neurofilament markers for ALS correlate with extent of upper and lower motor neuron disease.

To determine the diagnostic performance and prognostic value of phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) in CSF as possible biomarkers for amyotrophic lateral sclerosis (ALS) at the diagnostic phase. We measured CSF pNfH and NfL concentrations in 220 patients with ALS, 316 neurologic disease controls (DC), and 50 genuine disease mimics (DM) to determine and assess the accuracy of the diagnostic cutoff value for pNfH and NfL and to correlate with other clinical parameters. pNfH was most specific for motor neuron disease (specificity 88.2% [confidence interval (CI) 83.0%-92.3%]). pNfH had the best performance to differentially diagnose patients with ALS from DM with a sensitivity of 90.7% (CI 84.9%-94.8%), a specificity of 88.0% (CI 75.7%-95.5%) and a likelihood ratio of 7.6 (CI 3.6-16.0) at a cutoff of 768 pg/mL. CSF pNfH and NfL levels were significantly lower in slow disease progressors, however, with a poor prognostic performance with respect to the disease progression rate. CSF pNfH and NfL levels increased significantly as function of the number of regions with both upper and lower motor involvement. In particular, CSF pNfH concentrations show an added value as diagnostic biomarkers for ALS, whereas the prognostic value of pNfH and NfL warrants further investigation. Both pNfH and NfL correlated with the extent of motor neuron degeneration. This study provides Class II evidence that elevated concentrations of CSF pNfH and NfL can accurately identify patients with ALS.

Emergence of CXCR4-tropic HIV-1 variants followed by rapid disease progression in hemophiliac slow progressors.

ObjectiveThe association between emergence of CXCR4-tropic HIV-1 variants (X4 variants) and disease progression of HIV-1 infection has been reported. However, it is not known whether the emergence of X4 variants is the cause or result of HIV-1 disease progression. We tried to answer this question.DesignHIV-1 env sequences around the V3 region were analyzed in serially stocked samples in order to determine whether X4 variants emerged before or after the fall in CD4+ T-cell count.MethodsThe study subjects were five HIV-1-infected hemophiliac slow progressors. Deep sequencing around the HIV-1 env V3 region was conducted in duplicate. Tropism was predicted by geno2pheno [coreceptor] 2.5 with cutoff value of false positive ratio at <5%. When X4 variant was identified in the latest stocked sample before the introduction of antiretroviral therapy, we checked viral genotype in previously stocked samples to determine the time of emergence of X4 variants.ResultsEmergence of X4 variants was noted in two of the five patients when their CD4+ T-cell counts were still high. The rate of decrease of CD4+ T-cell count or of rise of HIV-1 load accelerated significantly after the emergence of X4 variants in these two cases. Phylogenetic analysis showed that these X4 variants emerged from CCR5-tropic HIV-1 viruses with several amino acid changes in the V3 region.ConclusionsThe emergence of X4 variants preceded HIV-1 disease progression in two hemophiliac slow progressors.

Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility.

In this study, we aimed to characterise rapid progressors to type 1 diabetes among children recruited from the general population, on the basis of HLA-conferred disease susceptibility. We monitored 7410 HLA-predisposed children participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study for the development of beta cell autoimmunity and type 1 diabetes from birth over a median follow-up time of 16.2years (range 0.9-21.1years). Islet cell antibodies (ICA) and autoantibodies to insulin (IAA), GAD (GADA) and islet antigen 2 (IA-2A) were assessed as markers of beta cell autoimmunity. Rapid progression was defined as progression to clinical type 1 diabetes within 1.5years of autoantibody seroconversion. We analysed the association between rapid progression and demographic and autoantibody characteristics as well as genetic markers, including 25 non-HLA SNPs predisposing to type 1 diabetes. Altogether, 1550 children (21%) tested positive for at least one diabetes-associated autoantibody in at least two samples, and 248 (16%) of seroconverters progressed to type 1 diabetes by the end of 2015. The median time from seroconversion to diagnosis was 0.51years in rapid progressors (n=42, 17%) and 5.4years in slower progressors. Rapid progression was observed both among young (<5years) and early pubertal children (>7years), resulting in a double-peak distribution of seroconversion age. Compared with slower progressors, rapid progressors had a higher frequency of positivity for multiple (≥2) autoantibodies and had higher titres of ICA, IAA and IA-2A at seroconversion, and there was a higher prevalence of the secretor genotype in the FUT2 gene among those carrying the high-risk HLA genotype. Compared with autoantibody-positive non-progressors, rapid progressors were younger, were more likely to carry the high-risk HLA genotype and a predisposing SNP in the PTPN22 gene, had higher frequency of ICA, IAA, GADA and IA-2A positivity and multipositivity, and had higher titres of all four autoantibodies at seroconversion. At seroconversion, individuals with rapid progression to type 1 diabetes were characterised by a younger age, higher autoantibody titres, positivity for multiple autoantibodies and higher prevalence of a FUT2 SNP. The double-peak profile for seroconversion age among the rapid progressors demonstrates for the first time that rapid progression may take place not only in young children but also in children in early puberty. Rapid progressors might benefit from careful clinical follow-up and early preventive measures.

Uremic Solutes in Chronic Kidney Disease and Their Role in Progression.

BackgroundTo date, over 150 possible uremic solutes have been listed, but their role in the progression of CKD is largely unknown. Here, the association between a selected panel of uremic solutes and progression in CKD patients was investigated.MethodsPatients from the MASTERPLAN study, a randomized controlled trial in CKD patients with a creatinine clearance between 20 and 70 ml/min per 1.73m2, were selected based on their rate of eGFR decline during the first five years of follow-up. They were categorized as rapid (decline >5 ml/min per year) or slow progressors. Concentrations of eleven uremic solutes were obtained at baseline and after one year of follow-up. Logistic regression was used to compare the odds for rapid to slow progression by uremic solute concentrations at baseline. Variability in uremic solute levels was assessed using scatter plots, and limits of variability were calculated.ResultsIn total, 40 rapidly and 40 slowly progressing patients were included. Uremic solutes were elevated in all patients compared to reference values for healthy persons. The serum levels of uremic solutes were not associated with rapid progression. Moreover, we observed substantial variability in solute levels over time.ConclusionsElevated concentrations of uremic solutes measured in this study did not explain differences in rate of eGFR decline in CKD patients, possibly due to lack of power as a result of the small sample size, substantial between patient variability, and variability in solute concentrations over time. The etiology of intra-individual variation in uremic solute levels remains to be elucidated.

Exogenous re-infection does not always cause backward bifurcation in TB transmission dynamics

Models for the transmission dynamics of mycobacterium tuberculosis (TB) that incorporate exogenous re-infection are known to induce the phenomenon of backward bifurcation, a dynamic phenomenon associated with the existence of two stable attractors when the reproduction number of the model is less than unity. This study shows, by way of a counter example, that exogenous re-infection does not always cause backward bifurcation in TB transmission dynamics. In particular, it is shown that it is the transmission ability of the re-infected individuals, and not just the re-infection process, that causes the backward bifurcation phenomenon. When re-infected individuals do not transmit infection, the disease-free equilibrium of the model is shown to be globally-asymptotically stable (GAS) when the associated reproduction number is less than unity. The model has a unique endemic equilibrium whenever the reproduction threshold exceeds unity. It is shown, using a Lyapunov function, that the unique endemic equilibrium is GAS for the special case with no disease-induced mortality and no transmission by re-infected individuals. It is further shown that even if re-infected individuals do transmit infection, backward bifurcation only occurs if their transmissibility exceeds a certain threshold. Sensitivity analyses, with respect to the derived backward bifurcation threshold, show that the phenomenon of backward bifurcation is more likely to occur if the rates of re-infection and transmissibility of re-infected individuals are sufficiently high. Furthermore, it is likely to occur if the fraction of slow progressors (to active TB) is increased or if the rates of treatment (of symptomatic cases) and disease-induced mortality are increased. On the other hand, backward bifurcation is less likely to occur for increasing rates of endogenous re-activation of latent TB cases.

Cytokine cascade and networks among MSM HIV seroconverters: implications for early immunotherapy.

The timing, intensity and duration of the cytokine cascade and reorganized interrelations in cytokine networks are not fully understood during acute HIV-1 infection (AHI). Using sequential plasma samples collected over three years post-infection in a cohort of MSM HIV-1 seroconvertors, we determined the early kinetics of cytokine levels during FiebigI-IV stages using Luminex-based multiplex assays. Cytokines were quantified and relationships between cytokines were assessed by Spearman correlation. Compared with HIV-negative MSM, HIV-infected individuals had significantly increased multiple plasma cytokines, including GM-CSF, IFN-α2, IL-12p70, IP-10 and VEGF, during both acute and chronic stages of infection. Furthermore, rapid disease progressors (RDPs) had earlier and more robust cytokine storms, compared with slow disease progressors (SDPs) (49.6 days vs. 74.9 days, respectively; 6.7-fold vs. 3.7-fold change of cytokines, respectively), suggesting the faster and stronger cytokine storm during AHI could promote disease progression. On the other hand, HIV-1 infection induced more interlocked cytokines network, establishing new strong correlations and imposing a higher rigidity. There were, respectively, 146 (44.9%) statistically significant correlations of cytokines in RDPs and 241 (74.2%) in SDPs (p < 0.001). This study suggests that immunomodulatory interventions aimed at controlling cytokine storm in AHI may be beneficial to slow eventual disease progression.

Immune response in peripheral axons delays disease progression in SOD1G93A mice.

BackgroundIncreasing evidence suggests that the immune system has a beneficial role in the progression of amyotrophic lateral sclerosis (ALS) although the mechanism remains unclear. Recently, we demonstrated that motor neurons (MNs) of C57SOD1G93A mice with slow disease progression activate molecules classically involved in the cross-talk with the immune system. This happens a lot less in 129SvSOD1G93A mice which, while expressing the same amount of transgene, had faster disease progression and earlier axonal damage. The present study investigated whether and how the immune response is involved in the preservation of motor axons in the mouse model of familial ALS with a more benign disease course.MethodsFirst, the extent of axonal damage, Schwann cell proliferation, and neuromuscular junction (NMJ) denervation were compared between the two ALS mouse models at the disease onset. Then, we compared the expression levels of different immune molecules, the morphology of myelin sheaths, and the presence of blood-derived immune cell infiltrates in the sciatic nerve of the two SOD1G93A mouse strains using immunohistochemical, immunoblot, quantitative reverse transcription PCR, and rotating-polarization Coherent Anti-Stokes Raman Scattering techniques.ResultsMuscle denervation, axonal dysregulation, and myelin disruption together with reduced Schwann cell proliferation are prominent in 129SvSOD1G93A compared to C57SOD1G93A mice at the disease onset, and this correlates with a faster disease progression in the first strain. On the contrary, a striking increase of immune molecules such as CCL2, MHCI, and C3 was seen in sciatic nerves of slow progressor C57SOD1G93A mice and this was accompanied by heavy infiltration of CD8+ T lymphocytes and macrophages. These phenomena were not detectable in the peripheral nervous system of fast-progressing mice.ConclusionsThese data show for the first time that damaged MNs in SOD1-related ALS actively recruit immune cells in the peripheral nervous system to delay muscle denervation and prolong the lifespan. On the contrary, the lack of this response has a negative impact on the disease course.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0732-2) contains supplementary material, which is available to authorized users.

Dinámica de la Leucosis Bovina en el ganado criollo Hartón del Valle en infección natural

Los bovinos criollos presentan características adaptativas de importancia. Se ha propuesto que el desarrollo y/o progresión de la leucosis bovina tiene bases genéticas. En el presente trabajo se estudió la dinámica del virus de la leucosis bovina en el ganado criollo Hartón del Valle en condiciones de infección natural. En 93 animales Hartón del Valle (HV), 30 Lucerna (LUC) y 30 Holstein (HOL) se evaluó la presencia del VLB por PCR-anidada, el desarrollo de linfocitosis por extendido en placa, los títulos de anticuerpos usando ELISA y la carga proviral mediante PCR en tiempo real, en tres muestreos durante un año. Se estimaron los porcentajes de animales infectados y se realizaron pruebas de independencia entre las variables evaluadas. Se encontró un efecto racial significativo sobre el desarrollo de la leucosis bovina, los animales de la raza Hartón presentaron menor tasa de infección del VLB (38,3%), desarrollaron menos linfocitosis persistente (15%), tuvieron mayores títulos de anticuerpos contra el virus (97,6) y mantuvieron la carga proviral más baja (663828 copias/ng de ADN) que las razas Lucerna y Holstein. Los datos aquí presentados pueden ser utilizados en programas de erradicación y control de la enfermedad. Se concluye que el ganado criollo Hartón del Valle puede ser considerado un progresor lento de la leucosis bovina.