Dropped head syndrome as initial and predominant manifestation of inflammatory myopathy.

Dropped head syndrome (DHS) is an uncommon clinical syndrome, which requires complex diagnostic evaluation. A variety of neuromuscular and neurodegenerative disease can produce weakness of head extensor muscles and consequently lead to head drop. Inflammatory myopathy has been described as a cause of DHS, however head drop has only exceptionally been reported as being the presenting symptom of this disorder. We describe an original case of DHS as an initial and predominant manifestation of inflammatory myopathy with histopathological features of polymyositis, with an excellent response to immunosuppressive treatment.

Correction to: iHIVARNA phase IIa, a randomized, placebo-controlled, double-blinded trial to evaluate the safety and immunogenicity of iHIVARNA-01 in chronically HIV-infected patients under stable combined antiretroviral therapy.

Following publication of the original article [1], we have been notified that end note would need to be adjusted.

iHIVARNA phase IIa, a randomized, placebo-controlled, double-blinded trial to evaluate the safety and immunogenicity of iHIVARNA-01 in chronically HIV-infected patients under stable combined antiretroviral therapy.

BACKGROUND: HIV therapeutic vaccination aims to improve the immune responses against HIV in order to control viral replication without the need for combined antiretroviral therapy (cART). iHIVARNA-01 is a novel vaccine combining mRNA delivery and T-cell immunogen (HTI) based on conserved targets of effective antiviral T-cell responses. In addition, it holds adequate stimuli required for activating antigen presenting cells (APC)s and co-activating specific T-cells (TriMix), including human CD40L, constitutively active TLR4 (caTLR4) and CD70. We propose that in-vivo targeting of dendritic cells (DCs) by direct administration of a HIV mRNA encoding these immune modulating proteins might be an attractive alternative to target DCs in vitro. METHODS/DESIGN: This is a phase-IIa, randomized, double-blinded, placebo-controlled, multicenter study in chronically HIV-1 infected patients under stable cART. One of the three study arms is randomly allocated to subjects. Three vaccinations with either HIVACAT T-cell immunogen (HTI)-TriMix (iHIVARNA-01), TriMix or water for injection (WFI) (weeks 0, 2 and 4) are administered by intranodal injection in the inguinal region. Two weeks after the last immunization (week 6) cART is stopped for 12 weeks. The two primary endpoints are: (1) safety and tolerability of intranodal iHIVARNA-01 vaccination compared with TriMix or WFI and (2) induced immunogenicity, i.e., increase in the frequency of HIV-specific T-cell responses between baseline, week 6 and 12 weeks after treatment interruption in iHIVARNA-01-treated patients as compared to the control groups, immunized with TriMix-mRNA or WFI measured by an IFNγ ELISPOT assay. Secondary endpoints include the evaluation of time to viral rebound, plasma viral load (pVL) at w18, the proportion of patients with control of viral load, induction of T-cell responses to new HIV epitopes, polyfunctionality of HIV-specific T-cells, CD8+ T-cell in-vitro HIV suppressive capacity, the effect on viral reservoir (measured by proviral DNA and cell-associated RNA), assessment of viral immune escape by mutation and mRNA expression profiles of host immune genes. DISCUSSION: This trial aims to direct target DC in situ with mRNA encoding HTI and TriMix for co-stimulation. Intranodal injection circumvents laborious DC isolation and handling in the laboratory. The trial extends on the safety results of a phase-I dose-escalating trial. This candidate vaccine could complement or even replace cART for chronic HIV infection and could be applicable to improve the care and cost of HIV infection. TRIAL REGISTRATION: EudraCT 2016-002724-83 (22 September 2016); ClinicalTrials.gov, ID: NCT02888756 . Registered on 23 August 2016.

The frequency-following response (FFR) to speech stimuli: A normative dataset in healthy newborns.

The Frequency-Following Response (FFR) is a neurophonic auditory evoked potential that reflects the efficient encoding of speech sounds and is disrupted in a range of speech and language disorders. This raises the possibility to use it as a potential biomarker for literacy impairment. However, reference values for comparison with the normal population are not yet established. The present study pursues the collection of a normative database depicting the standard variability of the newborn FFR. FFRs were recorded to /da/ and /ga/ syllables in 46 neonates born at term. Seven parameters were retrieved in the time and frequency domains, and analyzed for normality and differences between stimuli. A comprehensive normative database of the newborn FFR is offered, with most parameters showing normal distributions and similar robust responses for /da/ and /ga/ stimuli. This is the first normative database of the FFR to characterize normal speech sound processing during the immediate postnatal days, and corroborates the possibility to record the FFRs in neonates at the maternity hospital room. This normative database constitutes the first step towards the detection of early FFR abnormalities in newborns that would announce later language impairment, allowing early preventive measures from the first days of life.

CTL responses of high functional avidity and broad variant cross-reactivity are associated with HIV control.

Cytotoxic T lymphocyte (CTL) responses targeting specific HIV proteins, in particular Gag, have been associated with relative control of viral replication in vivo. However, Gag-specific CTL can also be detected in individuals who do not control the virus and it remains thus unclear how Gag-specific CTL may mediate the beneficial effects in some individuals but not in others. Here, we used a 10mer peptide set spanning HIV Gag-p24 to determine immunogen-specific T-cell responses and to assess functional properties including functional avidity and cross-reactivity in 25 HIV-1 controllers and 25 non-controllers without protective HLA class I alleles. Our data challenge the common belief that Gag-specific T cell responses dominate the virus-specific immunity exclusively in HIV-1 controllers as both groups mounted responses of comparable breadths and magnitudes against the p24 sequence. However, responses in controllers reacted to lower antigen concentrations and recognized more epitope variants than responses in non-controllers. These cross-sectional data, largely independent of particular HLA genetics and generated using direct ex-vivo samples thus identify T cell responses of high functional avidity and with broad variant reactivity as potential functional immune correlates of relative HIV control.

Non-myeloablative hematopoietic stem cell transplantation in the treatment of severe idiopathic CD4+ lymphocytopenia.

A 40-year-old man with severe chronic idiopathic CD4+ lymphocytopenia complicated with opportunistic infections was successfully treated with non-myeloablative allogeneic hematopoietic stem cell transplantation. After conditioning with fludarabine plus low dose of total-body irradiation, CD34+ peripheral blood stem cells obtained by leukapheresis from his HLA-identical sister were infused. T cell and myeloid complete chimerism was achieved at day +28 and remained stable during the follow-up period. The patient did not develop infectious complications during the procedure. At 35 months of follow-up, his CD4+ T cell count was 1019 cells per microliter. Non-myeloablative allogeneic hematopoietic stem cell transplantation should be considered a treatment option for patients with severe forms of idiopathic CD4+ lymphocytopenia.

Redistribution of FOXP3-positive regulatory T cells from lymphoid tissues to peripheral blood in HIV-infected patients.

OBJECTIVE: Regulatory T (Treg) cells are altered during HIV replication, but their role in chronic infection is controversial and lacks reproducibility between series. FOXP3 is a specific marker of Treg cells. We study for the first time FOXP3 expression in a unique series of paired samples at different time points of HIV infection. DESIGN: Paired samples from lymphoid tissue and peripheral blood were simultaneously obtained from 27 HIV-infected patients (before and after highly active antiretroviral therapy [HAART]) and 6 controls. METHODS: We analyzed FOXP3 expression by TaqMan (Universal PCR Master Mix; Applied Biosystems, Foster City, CA) reverse transcriptase polymerase chain reaction in lymphoid tissue and peripheral blood. Treg cells were assessed in lymphoid tissue by immunohistochemistry/computer image analysis and in peripheral blood by flow cytometry. CD4 cell counts and viral loads were obtained. RESULTS: HIV-infected patients had a low FOXP3 copy number and Treg cell frequencies in lymphoid tissue but a high number of Treg cells in peripheral blood. Lymphoid tissue FOXP3 expression decreased after HAART, and it correlated to lymphoid tissue viral load. Patients treated with nonnucleoside HAART had the lowest lymphoid tissue FOXP3 expression. CONCLUSIONS: HIV-infected patients had low FOXP3 expression in lymphoid tissue and redistributed Treg to peripheral blood. HAART reduced even more the proportion of lymphoid tissue Treg in association with the immunologic recovery observed after treatment. The type of HAART may have an impact on the distribution of Treg cells.

Immunoarchitecture of lymphoid tissue in HIV-infection during antiretroviral therapy correlates with viral persistence.

Plasma viral load and T-cell subset determinations in blood are the markers used for monitoring HIV-1 infection. However, key pathogenesis events, viral replication and most immunologic changes occur in the lymphoid tissues. We have studied the tonsillar biopsies of 30 patients in the early stages of the disease, before initiating treatment and after 12 and 36 months of fully effective highly active antiretroviral therapy. We have investigated the HIV RNA by polymerase chain reaction (lymphoid tissue viral load), the immunohistochemical HIV-p24 antigen expression, as well as the lymphoid tissue architecture and lymphoid cell subsets using morphometry. The lymphoid tissue viral load and the immunoexpression of p24, which was found to be mainly associated with follicular dendritic cells, decreased significantly after treatment, but did not disappear in all cases, even after 36 months of treatment. A significant improvement of the lymphoid tissue architecture was also observed after treatment, with recovery of follicular structures. These histological changes correlated with the lymphoid tissue viral load. Moreover, the counts of CD4+ increased whereas CD8+ and cytotoxic lymphocytes (CD8+ granzyme B+) decreased significantly, the latter in both interfollicular and intrafollicular areas. However, these cellular counts after treatment did not reach those of lymphoid tissue of non-HIV-infected patients used as control cases. Naive (CD45RA+) and memory (CD45RO+) cells also improved significantly after treatment. In conclusion, in HIV-infection the impact of treatment can only be assessed completely in the lymphoid tissue reservoir, where most of the virus is stored and associated with follicular dendritic cells. Highly active antiretroviral therapy produces a significant recovery of lymphoid tissue architecture and lymphoid cell subsets, which are associated with the decrease of lymphoid tissue viral load. However, these parameters studied in lymphoid tissue are not re-established completely, even after 36 months of highly active antiretroviral therapy.