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A dilute ensemble of randomly oriented non-interacting spherical nanomagnets is considered, and its magnetization structure and ensuing neutron scattering response are investigated by numerically solving the Landau–Lifshitz equation. Taking into account the isotropic exchange interaction, an external magnetic field, a uniaxial magnetic anisotropy for the particle core, and in particular the Néel surface anisotropy, the magnetic small-angle neutron scattering cross section and pair-distance distribution function are calculated from the obtained equilibrium spin structures. The numerical results are compared with the well known analytical expressions for uniformly magnetized particles and provide guidance to the experimentalist. In addition, the effect of a particle-size distribution function is modelled.

PURPOSE OF REVIEW: To summarize the current status and highlight recent findings on predictive biomarkers for posttreatment HIV control (PTC) and virological remission. While historically, many studies focused on virological markers, there is an increasing tendency to enter immune and metabolic factors into the equation. RECENT FINDINGS: On the virological side, several groups reported that cell-associated HIV RNA could predict time to viral rebound. Recent data hints at the possible importance of the genic location and chromatin context of the integrated provirus, although these factors still need to be assessed in relation to PTC and virological remission. Evidence from immunological studies highlighted innate and humoral immunity as important factors for prolonged HIV remission. Interestingly, novel metabolic markers have emerged, which offer additional angles to our understanding of latency and viral rebound. SUMMARY: Facilitating PTC and virological remission remain top priorities for the HIV cure research. We advocate for clear and precise definitions for both phenomena in order to avoid misconceptions and to strengthen the conclusions that can be drawn. As no one-size-fits-all marker has emerged yet, more biomarkers are on the horizon, and viral rebound is a complex and heterogeneous process, it is likely that a combination of various biomarkers in cohesion will be necessary for a more accurate prediction of antiretroviral therapy-free HIV remission.

BackgroundHIV-1 infection results in the activation of inflammasome involving NLRP3, IFI16, caspase-1 and release of IL-1 β and IL-18. Early inflammasome activation may facilitate viral spread and establishment of the viral reservoir. We evaluated the effect of the caspase-1 inhibitor VX-765 on virological and immunological parameters after HIV-1 infection in humanized mice.MethodsNSG mice were engrafted with human CD34+hematopoietic stem cells and were infected with HIV-1 JRCSF. 15 mice were first sacrificed serially to investigate kinetics of the HIV-1 related inflammasome activation. Infected mice (n=24) were then treated with VX-765 or vehicle from day 1 post infection for 21 days. Blood and organs were collected at different time points, and analysed for inflammasome genes expression, cytokines levels, viral load, CD4 cell count, and total HIV-1 DNA.ResultsExpression of caspase-1, NLRP3 and IL1-β was increased in lymph nodes and bone marrow on day 1 and 3 post infection (mean fold change (FC) of 2.08, 3.23, and 6.05, p< 0.001 respectively between day 1 and 3). IFI16 expression peaked at D24 in lymph node and bone marrow (FC 1.49 and 1.64, p+T cells percentage in blood (p+T cells (44.3% vs 36,7%, p=0.01) and the CD4/CD8 ratio (0.92 vs 0.67, p=0.005) in plasma. Importantly, viral load (4.26 vs. 4.89 log 10 copies/ml, p=0.027) and total HIV-1 DNA (1 054 vs. 2 889 copies /106cells, p=0.029) were decreased in VX-765-treated mice as compared to vehicle-treated mice.Discussionwe report here an early inflammasome activation before detectable viral dissemination in humanized mice. We demonstrated that targeting inflammasome activation early after HIV-1 infection may represent a potential therapeutic strategy to prevent CD4+T cell depletion as well as to reduce immune activation, viral load and the HIV-1 reservoir formation.

The magnetization profile and the related magnetic small-angle neutron scattering cross section of a single spherical nanoparticle with Néel surface anisotropy are analytically investigated. A Hamiltonian is employed that comprises the isotropic exchange interaction, an external magnetic field, a uniaxial magnetocrystalline anisotropy in the core of the particle and the Néel anisotropy at the surface. Using a perturbation approach, the determination of the magnetization profile can be reduced to a Helmholtz equation with Neumann boundary condition, whose solution is represented by an infinite series in terms of spherical harmonics and spherical Bessel functions. From the resulting infinite series expansion, the Fourier transform, which is algebraically related to the magnetic small-angle neutron scattering cross section, is analytically calculated. The approximate analytical solution for the spin structure is compared with the numerical solution using the Landau–Lifshitz equation, which accounts for the full nonlinearity of the problem. The signature of the Néel surface anisotropy can be identified in the magnetic neutron scattering observables, but its effect is relatively small, even for large values of the surface anisotropy constant.

CD32 has raised conflicting results as a putative marker of the HIV-1 reservoir. We measured CD32 expression in tissues from viremic and virally suppressed humanized mice treated relatively early or late after HIV-1 infection with combined antiretroviral therapy. CD32 was expressed in a small fraction of the memory CD4(+) T-cell subsets from different tissues in viremic and aviremic mice, regardless of treatment initiation time. CD32(+) memory CD4(+) T cells were enriched in cell associated (CA) HIV-1 DNA but not in CA HIV-1 RNA as compared to the CD32(-) CD4(+) fraction. Using multidimensional reduction analysis, several memory CD4(+)CD32(+) T-cell clusters were identified expressing HLA-DR, TIGIT, or PD-1. Importantly, although tissue-resident CD32(+)CD4(+) memory cells were enriched with translation-competent reservoirs, most of it was detected in memory CD32-CD4(+) T cells. Our findings support that CD32 labels highly activated/exhausted memory CD4(+) T-cell subsets that contain only a small proportion of the translation-competent reservoir.

Antiretroviral therapy (ART) is not curative as HIV-1 persists in long-lived viral reservoirs. Consequently, patients are dependent on life-long drug adherence with possible side effects. To overcome these limitations strategies of a functional cure aim at ART free viral remission. In this study, we sought to identify detailed subsets of anti-viral CD8+ T cell immunity linked to natural long-term control of HIV-1 infection. Here, we analyzed HIV controllers and ART suppressed progressors for in vitro viral suppressive capacity (VSC) at baseline and after peptide stimulation. Functional properties and phenotypes of CD8+ T cells were assessed by IFN-γ ELISPOT and 18 color flow cytometry. HIV controllers showed significantly increased suppression at baseline as well as after peptide stimulation. IFN-γ secretion and the proliferation marker Ki67 positively correlated with VSC. Moreover, the detailed phenotype of three distinct multifunctional memory CD8+ T cell subsets were specific traits of HIV controllers of which two correlated convincingly with VSC. Our results underline the importance of multifunctional CD8+ T cell responses during natural control. Especially the role of CXCR5 expressing cytotoxic subsets emphasizes potential surveillance in sites of reservoir persistence and demand further study.

Summary CD32 has raised conflicting results as a putative marker of the HIV-1 reservoir. We measured CD32 expression in tissues from viremic and virally suppressed humanized mice treated relatively early or late after HIV-1 infection with combined antiretroviral therapy. CD32 was expressed in a small fraction of the memory CD4+ T-cell subsets from different tissues in viremic and aviremic mice, regardless of treatment initiation time. CD32+ memory CD4+ T cells were enriched in cell-associated (CA) HIV-1 DNA but not in CA HIV-1 RNA as compared to the CD32−CD4+ fraction. Using multidimensional reduction analysis, several memory CD4+CD32+ T-cell clusters were identified expressing HLA-DR, TIGIT, or PD-1. Importantly, although tissue-resident CD32+CD4+ memory cells were enriched with translation-competent reservoirs, most of it was detected in memory CD32-CD4+ T cells. Our findings support that CD32 labels highly activated/exhausted memory CD4+ T-cell subsets that contain only a small proportion of the translation-competent reservoir., Graphical abstract, Highlights • CD32 is rarely expressed in memory CD4+T cells in humanized mice infected with HIV-1 • Tissue-resident CD32+CD4+ memory T cells are enriched for HIV-1 DNA but not for RNA • CD32+CD4+ memory cells are enriched for translation-competent reservoirs • CD32 labels highly activated/exhausted memory T-cell subsets in tissues, Molecular Biology; Immunology ; Virology; Cell Biology

Objective: To determine whether viral suppressive capacity (VSC) of CD8(+) T cells can be boosted by stimulation with HIV-1 peptides and whether the ability to control HIV-1 replication correlates with immunological (cytokine production and CD8(+) T-cell phenotype) and viral reservoir measures (total HIV-1 DNA and cell-associated RNA) in well treated HIV-infected chronic progressors. Design: We compared VSC of peripheral CD8(+) T cells to cytokine production profile in response to peptide stimulation, detailed phenotype (17-color flow-cytometry), reservoir size (total HIV-1 DNA), basal viral transcription (unspliced cell-associated RNA) and inducible viral transcription (tat/rev induced limiting dilution assay) in 36 HIV+patients on cART and six healthy donors. Results: We found that the VSC of CD8(+) T cells can be increased by prior stimulation with a pool of consensus HIV-1 gag peptides in a significant proportion of progressor patients. We also found that VSC after peptide stimulation was correlated with higher expression of immune checkpoint markers on subsets of terminally differentiated effector memory (TEMRA) CD8(+) T cells as well as with production of IFN-gamma, TNF-alpha and IL-10. We did not find a correlation between VSC and viral reservoir measures. Conclusion: These results add to a small body of evidence that the capacity of CD8(+) T cells to suppress viral replication is increased after stimulation with HIV-1 peptides. Interestingly, this VSC was correlated with expression of immune checkpoint markers, which are generally considered to be markers of exhaustion. Our findings may guide further investigations into immune phenotypes correlated with viral suppression. Copyright (C) 2018 Wolters Kluwer Health, Inc. All rights reserved.

Aims Occurrence of late gadolinium enhancement (LGE) as assessed by cardiac magnetic resonance (CMR) imaging has been attributed to various myocardial injuries. We hypothesized that LGE is associated with left ventricular (LV) wall stress. Methods and results We examined 300 patients with suspected non-ischaemic dilated cardiomyopathy. Cardiac magnetic resonance was used to assess LV volume, mass, wall stress, and LGE. Increased LV end-diastolic wall stress (> 4 kPa) was found in 112 patients (37 %), and increased end-systolic wall stress (>18 kPa) in 121 patients (40%). Presence of LGE was observed in 93 patients (31%). End-diastolic (94 ± 43 vs. 79 ± 42 ml/m², P = 0.006) and end-systolic LV volumes (62 ± 44 vs. 44 ± 37 ml/m², P < 0.001) and LV mass (95 ± 34 vs. 78 ± 31 g/m², P < 0.001) were increased in patients exhibiting LGE. In particular, LV end-diastolic and end-systolic wall stress were increased (4.5 ± 2.8 vs. 3.6 ± 3.0 kPa, P = 0.025; 19.6 ± 9.1 vs. 17.5 ± 8.2 kPa, P = 0.045). Late gadolinium enhancement was observed more frequently than would be expected from random occurrence in patients with increased end-diastolic (39 vs. 26%, P = 0.020) and end-systolic wall stress (41 vs. 24%, P = 0.002). Both normal end-diastolic and end-systolic wall stress had a high negative predictive value for LGE (75 and 76%). Conclusions The present study shows that occurrence of LGE in cardiomyopathy is associated with increased LV wall stress and mass. Suspected causes are an increased capillary leakage by stretch, impaired contrast agent redistribution, or increased diffusion distances. It is proposed that LGE should be considered as a potential prognostic determinant of heart failure and severe arrhythmias.

The current resuscitation guidelines of the European Resuscitation Council do not include automatic chest compression devices (ACDs) as standard equipment to support cardiopulmonary resuscitation attempts. One possible reason could be the lack of a list of indications and contraindications for the use of ACD systems. This review should give a summary of current studies and developments according to ACD systems and deliver a list of possible applications. Furthermore, we discuss some ethical problems with cardiopulmonary resuscitation attempts and, in particular, with ACD systems. The use of ACDs occurs instead of manual chest compression. Because of this, there is no reason for changing the current guidelines, especially termination recommendations while using ACD systems. From our point of view, ACDs are a very good supplement to the current standard of resuscitation according to the European Resuscitation Council guidelines.

Background Although B-type natriuretic peptide (BNP) is used as complimentary diagnostic tool in patients with unknown thoracic disorders, many other factors appear to trigger its release. In particular, it remains unresolved to what extent cellular stretch or wall stress of the whole heart contributes to enhanced serum BNP concentration. Wall stress cannot be determined directly, but has to be calculated from wall volume, cavity volume and intraventricular pressure of the heart. The hypothesis was, therefore, addressed that wall stress as determined by cardiac magnetic resonance imaging (CMR) is the major determinant of serum BNP in patients with a varying degree of left ventricular dilatation or dysfunction (LVD). Methods A thick-walled sphere model based on volumetric analysis of the LV using CMR was compared with an echocardiography-based approach to calculate LV wall stress in 39 patients with LVD and 21 controls. Serum BNP was used as in vivo marker of a putatively raised wall stress. Nomograms of isostress lines were established to assess the extent of load reduction that is necessary to restore normal wall stress and related biochemical events. Results Both enddiastolic and endsystolic LV wall stress were correlated with the enddiastolic LV volume (r = 0.54, P0.001; r = 0.81, P0.001). LV enddiastolic wall stress was related to pulmonary pressure (capillary: r = 0.69, P0.001; artery: r = 0.67, P0.001). Although LV growth was correlated with the enddiastolic and endsystolic volume (r = 0.73, P0.001; r = 0.70, P0.001), patients with LVD exhibited increased LV wall stress indicating an inadequately enhanced LV growth. Both enddiastolic (P0.05) and endsystolic (P0.01) wall stress were increased in patients with increased BNP. In turn, BNP concentration was elevated in individuals with increased enddiastolic wall stress (8 kPa: 587 +/- 648 pg/ml, P0.05;12 kPa: 715 +/- 661 pg/ml, P0.001; normalor =4 kPa: 124 +/- 203 pg/ml). Analysis of variance revealed LV enddiastolic wall stress as the only independent hemodynamic parameter influencing BNP (P0.01). Using nomograms with "isostress" curves, the extent of load reduction required for restoring normal LV wall stress was assessed. Compared with the CMR-based volumetric analysis for wall stress calculation, the echocardiography based approach underestimated LV wall stress particularly of dilated hearts. Conclusions In patients with LVD, serum BNP was increased over the whole range of stress values which were the only hemodynamic predictors. Cellular stretch appears to be a major trigger for BNP release. Biochemical mechanisms need to be explored which appear to operate over this wide range of wall stress values. It is concluded that the diagnostic use of BNP should primarily be directed to assess ventricular wall stress rather than the extent of functional ventricular impairment in LVD.