A high HIV DNA level in PBMCs at antiretroviral treatment interruption predicts a shorter time to treatment resumption,independently of the CD4 nadir

This study aimed to evaluate the safety of antiretroviral treatment interruption (TI) in HIV‐infected patients who started treatment based on earlier guidelines, and to identify baseline factors predictive of the time to reach fixed criteria for treatment resumption. Prospective, open‐label, multicenter trial. Patients were eligible if they had a CD4 cell count >350/mm³ and plasma HIV RNA <50,000 copies/ml when they first started antiretroviral therapy (ART); and if they had a CD4 count >450/mm³ and stable plasma HIV RNA <5,000 copies/ml for at least 6 months prior to enrolment. The criteria for ART resumption were a CD4 cell count <300/mm³ and/or a CDC stage B or C event. 116 patients had received ART for a median of 5.3 years. The median CD4 cell count and plasma HIV RNA values at inclusion were 809/mm³ and 2.6 log copies/ml, respectively. Median HIV DNA load at inclusion was 2.3 log copies/10⁶ peripheral blood mononuclear cells (PBMCs). Thirty‐six months after TI, 63.9% of the patients had not yet reached the criteria for ART resumption, and 55.9% of patients had not resumed ART. In Cox multivariable analysis, a high HIV DNA level at TI, a low CD4 nadir, and pre‐existing AIDS status were the only significant risk factors for reaching the criteria for ART resumption (hazards ratio: 2.15 (1.02–4.53), 4.59 (1.22–17.24), and 5.74 (1.60–20.56), respectively). Patients who started ART with a CD4 cell count above 350/mm³ were able to interrupt treatment for long periods without a high absolute risk of either AIDS or severe non‐AIDS morbidity/mortality. A high PBMC HIV DNA level at TI was a strong predictor for more rapid treatment resumption. J. Med. Virol. 82:1819–1828, 2010. © 2010 Wiley‐Liss, Inc.     

Therapeutic potential of self-antigen-specific CD4+ CD25+ regulatory T cells selected in vitro from a polyclonal repertoire

CD4+ CD25+ regulatory T cells (Treg) play a major role in the prevention of autoimmune diseases. Converging evidence indicates that Treg specific for self-antigens expressed by target tissues have a greater therapeutic potential than polyclonal Treg. Therefore, the selective expansion of rare self-antigen-specific T(reg) naturally present in a polyclonal repertoire of Treg is of major importance. In this work, we investigated the potential of different dendritic cell (DC) subsets to expand antigen-specific Treg in mice. The in vitro selective expansion of rare islet-specific Treg from polyclonal Treg could only be achieved efficiently by stimulation with CD8+ splenic DC presenting islet antigens. These islet-specific Treg exerted potent bystander suppression on diabetogenic T cells and prevented type 1 diabetes. This approach opens new perspectives for cell therapy of autoimmune diseases.     

Influence of ambient humidity on the current delivered by air-vented ionization chambers revisited

The influence of ambient humidity on the current delivered by a vented ionization chamber has been re-investigated. A Nucletron 077.091 well-type chamber together with a (192)Ir HDR brachytherapy source was enclosed in a climatic test chamber and the current was recorded for various humidity values. Great care has been taken for the design of the experimental setup in order to obtain reliable measurements of currents and humidity values inside the chamber active volume. A +/-0.35% linear variation of the measured currents has been observed over a common range of humidities. This result is larger than the expected variation. No formal explanation of such a discrepancy has been found yet, however the present results could lead to a set of recommendations.     

One-step surgical removal of cutaneous melanoma with surgical margins based on preoperative ultrasound measurement of the thickness of the melanoma

Background

Surgical margins of melanoma vary from 5 mm to 1 or 2 cm depending on histology thickness (Breslow). This approach usually requires two surgical steps: excisional biopsy and further reexcision according to histology thickness. A previous systematic review showed that measuring melanoma thickness with high-resolution ultrasound imaging equipment correlates well with histological measurement of melanoma thickness. Therefore, we routinely determined tumour sonographic thickness in order to perform surgery as a single step.

Objectives

To determine the proportion of patients who receive onestep surgery with adequate margins based on sonographic measurement of melanoma thickness and identify the reasons for differences between these two measurements.

Materials & Methods

A retrospective series of patients with melanoma, in which thickness was measured by ultrasound (20 MHz) from April 2007 to December 2015 prior to surgery.

Results

Ninety-nine melanomas were treated, of which 78 were removed in a single step with surgical margins based on sonometric thickness measurements; 71 of these (91%, 95% CI: 82-96) did not require reexcision, five had excessive margins, and two had insufficient margins. The correlation between the histometric and sonometric measurements was good; r=0.88. Significant absolute difference between sonometric and histometric measurementswas associated with thickness, ulceration, and size of tumours, based on bivariate analysis. Thickness remained the only significant factor based on multivariate analysis.

Conclusions

Measuring the thickness of melanoma with high-resolution ultrasound imaging equipment makes it possible to remove the melanoma in a single step with adequate margins in at least 82% of the cases in routine care.

     

Laparoscopic pyloromyotomy for hypertrophic pyloric stenosis: a survey of 407 children

Introduction

Pyloromyotomy is the standard care for hypertrophic pyloric stenosis. The traditional approach for this procedure is a right upper quadrant transverse incision, although other “open” approaches, such as circumumbilical or periumbilical incision have been described. The more recent approach used is laparoscopic pyloromyotomy (LP), but experience feedback is still debated and its benefits remain unproven. The aim of this study was to make a review of all our LP procedures with an objective evaluation according to the literature.

Methods

A retrospective analysis of all the LPs performed in one University Children’s Hospital between 1 January 1996, and 30 December 2015 was realized. Information regarding the patient’s status, intraoperative and postoperative data was analyzed.

Results

407 patients were included in this study. The mean operative time of the overall procedure was 24?±?13 min, which significantly increased with the length of the pyloric muscle (p?=?0.004) and significantly impacted the full feeding time (p?=?0.006). 3.4% required conversion to an open procedure during the LP. We observed a significant correlation between conversion for mucosal perforation and weight loss (p?=?0.04) and between conversion for mucosal perforation and preoperative weight (p?=?0.002). A redo procedure was indicated in 3.7%, for incomplete pyloromyotomy each time. The mean postoperative hospital length of stay for all procedures was 1.6?±?0.8 days. There were no inflammatory scars. None had incisional hernias or wound dehiscence.

Discussion

LP procedure appeared to be as quick as the open procedure. Our results were similar to others series for intraoperative complications. According to operative time, this technique does not have an impact on operative room utilization. Vomiting duration at presentation in HPS does not seem to have a significant impact on postoperative outcomes. LP procedure causes little pain during the postoperative period. No wound complications were registered.

     

The Sociolinguistic Repetition Task: A New Paradigm for Exploring the Cognitive Coherence of Language Varieties

Sociolinguistic studies generally focus on specific sociolinguistic variables. Consequently, they rarely examine whether different sociolinguistic variables have coherent orientation in a specific language variety (a social or a regional dialect) or whether the speakers freely mix sociolinguistic variants. While different attempts have been made to identify coherence and mixing in the production or perception of dialects, our aim is to answer this question at the level of the cognitive representation of varieties. For this purpose, we draw on the phenomenon of sociolinguistic restoration: when they repeat sociolinguistically mixed utterances, people tend to make them homogeneous. The first experiment—a repetition task—reproduced sociolinguistic restoration in an experimental setting. The second experiment—a judgment task—ensured that participants perceived the difference between homogeneous and mixed utterances. We conclude that high-order coherent representations influence the reconstruction of utterances during the repetition task.     

Langerhans cell (LC) proliferation mediates neonatal development,homeostasis, and inflammation-associated expansion of the epidermal LC network

Most tissues develop from stem cells and precursors that undergo differentiation as their proliferative potential decreases. Mature differentiated cells rarely proliferate and are replaced at the end of their life by new cells derived from precursors. Langerhans cells (LCs) of the epidermis, although of myeloid origin, were shown to renew in tissues independently from the bone marrow, suggesting the existence of a dermal or epidermal progenitor. We investigated the mechanisms involved in LC development and homeostasis. We observed that a single wave of LC precursors was recruited in the epidermis of mice around embryonic day 18 and acquired a dendritic morphology, major histocompatibility complex II, CD11c, and langerin expression immediately after birth. Langerin⁺ cells then undergo a massive burst of proliferation between postnatal day 2 (P2) and P7, expanding their numbers by 10–20-fold. After the first week of life, we observed low-level proliferation of langerin⁺ cells within the epidermis. However, in a mouse model of atopic dermatitis (AD), a keratinocyte signal triggered increased epidermal LC proliferation. Similar findings were observed in epidermis from human patients with AD. Therefore, proliferation of differentiated resident cells represents an alternative pathway for development in the newborn, homeostasis, and expansion in adults of selected myeloid cell populations such as LCs. This mechanism may be relevant in locations where leukocyte trafficking is limited.Current data indicate that many macrophage subsets and most DCs in nonlymphoid tissues and in the secondary lymphoid organs of mice originate and are renewed from bone-marrow hematopoietic stem cell–derived progenitors with myeloid-restricted differentiation potential (Fogg et al., 2006; Liu et al., 2009). However, exceptions must exist to this major pathway of macrophage and DC generation, because Langerhans cells (LCs) and microglia remain of host origin after syngeneic bone marrow transplant (Merad et al., 2002; Ajami et al., 2007; Mildner et al., 2007), and LCs remain of donor origin after a limb graft (Kanitakis et al., 2004). Epidermal LCs have been shown to be a cycling population (Giacometti and Montagna, 1967; Czernielewski et al., 1985; Czernielewski and Demarchez, 1987). LC precursors were proposed to reside in the dermis (Larregina et al., 2001) or in the hair follicle (Gilliam et al., 1998), and cells with features of proliferating LC precursors have been found in fetal and newborn skin (Elbe et al., 1989; Chang-Rodriguez et al., 2005). On the other hand, monocytes can give rise to LC-like cells in vitro (Geissmann et al., 1998; Mohamadzadeh et al., 2001), and LCs can be replaced by bone marrow–derived cells in a selected experimental setting, i.e., after allogeneic bone marrow transplant, UV light irradiation, and conditional genetic ablation (Katz et al., 1979; Frelinger and Frelinger, 1980; Merad et al., 2002; Bennett et al., 2005). The nature of the endogenous LC precursor is thus unclear.LC development is controlled by M-CSF receptor and TGF-β1 (Borkowski et al., 1996; Ginhoux et al., 2006; Kaplan et al., 2007), but the LC precursor is particularly enigmatic because, in contrast to most organs, migration of leukocytes into the epidermis, as well as the brain, is rarely observed in a steady state; when such migration is observed, it is typically associated with inflammation. The mechanisms by which LCs develop and are renewed may differ from those involved in organs where hematopoietic cells circulate constantly, such as the spleen, liver, or lung. Although the roles of epidermal LCs remain controversial, recent evidence indicates a role as scavengers for viruses such as HIV-1 (de Witte et al., 2007) and possibly for carcinogens (Strid et al., 2008), as well as their role in promoting and regulating T cell–mediated immune responses (Bennett et al., 2007; Stoitzner et al., 2008; Elentner et al., 2009; Vesely et al., 2009). Understanding the mechanisms that control the development and homeostasis of DCs and macrophages in the skin or brain is thus of importance in understanding the pathophysiology of inflammation in these organs. In this study, we investigated the development of the LC network of the epidermis, and how it is maintained in a steady state and during epidermal inflammation.