Recirculating IL-1R2+ Tregs fine-tune intrathymic Treg development under inflammatory conditions

The vast majority of Foxp3⁺ regulatory T cells (Tregs) are generated in the thymus, and several factors, such as cytokines and unique thymic antigen-presenting cells, are known to contribute to the development of these thymus-derived Tregs (tTregs). Here, we report the existence of a specific subset of Foxp3⁺ Tregs within the thymus that is characterized by the expression of IL-1R2, which is a decoy receptor for the inflammatory cytokine IL-1. Detailed flow cytometric analysis of the thymocytes from Foxp3^hCD2xRAG1^GFP reporter mice revealed that the IL-1R2⁺ Tregs are mainly RAG1^GFP– and CCR6⁺CCR7^–, demonstrating that these Tregs are recirculating cells entering the thymus from the periphery and that they have an activated phenotype. In the spleen, the majority of IL-1R2⁺ Tregs express neuropilin-1 (Nrp-1) and Helios, suggesting a thymic origin for these Tregs. Interestingly, among all tissues studied, the highest frequency of IL-1R2⁺ Tregs was observed in the thymus, indicating preferential recruitment of this Treg subset by the thymus. Using fetal thymic organ cultures (FTOCs), we demonstrated that increased concentrations of exogenous IL-1β blocked intrathymic Treg development, resulting in a decreased frequency of CD25⁺Foxp3⁺ tTregs and an accumulation of CD25⁺Foxp3⁻ Treg precursors. Interestingly, the addition of IL-1R2⁺ Tregs, but not IL-1R2⁻ Tregs, to reaggregated thymic organ cultures (RTOCs) abrogated the IL-1β-mediated blockade, demonstrating that these recirculating IL-1R2⁺ Tregs can quench IL-1 signaling in the thymus and thereby maintain thymic Treg development even under inflammatory conditions.     

The rehabilitation of clinical assessment for the diagnosis of pulmonary embolism

Pulmonary angiography is the gold standard for diagnosis of segmental pulmonary embolism, but no longer for subsegmental pulmonary embolism because the inter-observer agreement for angiographically documented subsegmental pulmonary embolism is only 60%. A normal rapid ELISA VIDAS D-dimer test result and a normal perfusion scan exclude pulmonary embolism with a negative predictive value of >99%, irrespective of clinical score. The positive predictive value for pulmonary embolism of a high probability VP-scan compared to pulmonary angiography is 87% indicating that 13% of patients with a high probability VP-scan do not have pulmonary embolism. The combination of a negative CUS, a low clinical score, and a non-diagnostic VP-scan safely excludes pulmonary embolism. Patients with a non-diagnostic VP-scan, a negative CUS, but a moderate to high clinical score are candidates for pulmonary angiography. The positive predictive value of helical spiral CT is >95 to 99%. The combination of a negative CUS, a low clinical score, and the presence of a clear alternative diagnosis is predicted to safely exclude pulmonary embolism. Helical spiral CT detects all clinical relevant pulmonary emboli and a large number of alternative diagnoses in symptomatic patients with a non-diagnostic or a high-probability VP-scan. The negative predictive value during 3 months followup after a negative spiral CT for pulmonary embolism in 4 retrospective studies and 1 prospective management study was >99%. Only a small group of patients (1-2%) with a non-diagnostic spiral CT are candidates for pulmonary angiography. Therefore, it is predicted that the spiral CT will replace both VP-scanning and pulmonary angiography to safely exclude or diagnose pulmonary emboli in patients with suspected pulmonary embolism.     

HIV Prevalence Among Hospitalized Patients at the Main Psychiatric Referral Hospital in Botswana

We examined HIV prevalence among patients 18–49 year olds admitted to a psychiatric hospital in Botswana in 2011 and 2012. The retrospective study analyzed females (F) and males (M) separately, comparing proportions with Chi square test and continuous variables with Wilcoxon rank-sum test, assessing significance at the 5% level. HIV seroprevalence among hospitalized psychiatric patients was much more common among females (53%) compared with males (19%) (p < 0.001). These women also appeared more vulnerable to infection compared with females in the general population (29%) (p < 0.017). Among both women and men, HIV-infection appeared most common among patients with organic mental disorders (F:68%, M:41%) and neurotic, stress related and somatoform disorders (F:68%, M:42%). The largest proportion of HIV infections co-occurred among patients diagnosed with schizophrenia, schizotypal and other psychotic disorders (F:48%; M:55%), mood (affective) disorders (F:21%; M:16%) and neurotic, stress-related and somatoform disorders (F:16%; M:20%). Interventions addressing both mental health and HIV among women and men require development.     

Musashi2 sustains the mixed-lineage leukemia–driven stem cell regulatory program

Leukemia stem cells (LSCs) are found in most aggressive myeloid diseases and contribute to therapeutic resistance. Leukemia cells exhibit a dysregulated developmental program as the result of genetic and epigenetic alterations. Overexpression of the RNA-binding protein Musashi2 (MSI2) has been previously shown to predict poor survival in leukemia. Here, we demonstrated that conditional deletion of Msi2 in the hematopoietic compartment results in delayed leukemogenesis, reduced disease burden, and a loss of LSC function in a murine leukemia model. Gene expression profiling of these Msi2-deficient animals revealed a loss of the hematopoietic/leukemic stem cell self-renewal program and an increase in the differentiation program. In acute myeloid leukemia patients, the presence of a gene signature that was similar to that observed in Msi2-deficent murine LSCs correlated with improved survival. We determined that MSI2 directly maintains the mixed-lineage leukemia (MLL) self-renewal program by interacting with and retaining efficient translation of Hoxa9, Myc, and Ikzf2 mRNAs. Moreover, depletion of MLL target Ikzf2 in LSCs reduced colony formation, decreased proliferation, and increased apoptosis. Our data provide evidence that MSI2 controls efficient translation of the oncogenic LSC self-renewal program and suggest MSI2 as a potential therapeutic target for myeloid leukemia.     

Well‐Being and Personal Growth in Mothers of Full‐Term and Pre‐Term Singletons and Twins

The present study examined well‐being and personal growth in mothers (n = 414) 1 year after childbirth. We examined the contribution of the event characteristics (birth of singletons or twins, full‐ or pre‐term babies, first or non‐first child, spontaneous pregnancy or fertility treatments and infant temperament), internal resources (attachment anxiety and avoidance) and external resources (marital quality and maternal grandmother's support). Regressions indicated that having a first child, child's easier temperament, lower attachment anxiety and avoidance, grandmother's emotional support and some aspects of the spousal relationships contributed to well‐being. Personal growth was found to be related to the birth of a pre‐term baby or babies, positively associated with maternal grandmother's support, and the marital quality of parenthood, and negatively with mothers' education. Beyond the findings that well‐being and personal growth are related to the availability of certain resources, the current study demonstrates that the two outcomes are separate phenomena that reveal different patterns of associations with other variables. Several explanations for the findings are proposed, and practical implications are discussed. Copyright © 2014 John Wiley & Sons, Ltd.     

Distinct Haplotype in Non-Ashkenazi Gaucher Patients with N370S Mutation

ABSTRACT: A new polymorphism, in intron 7 of glucocerebrosidase gene, has been identified in Gaucher Disease patients. It seems to appear only in Pv1.1^-alleles bearing the N370S mutation. This new sub-haplotype was only identified in Portuguese patients, of origins spanning all of the Portuguese continental territory. This finding indicates that, in the Portuguese, mutation N370S has existed in the context of two slightly different haplotypes and thus must be relatively ancient.     

Insulin sensitivity and beta-cell function in protease inhibitor-treated and -naive human immunodeficiency virus-infected children

Previous pediatric studies have failed to demonstrate a clear association between protease inhibitor (PI) therapy and abnormal glucose homeostasis in HIV-infected children. To define more precisely the impact of PI therapy on glucose homeostasis in this population, we performed the insulin-modified frequent-sampling iv glucose tolerance test on 33 PI-treated and 15 PI-naive HIV-infected children. Other investigations included fasting serum lipids; glucose, insulin, and C-peptide; single-slice abdominal computed tomography; and, in a subset of PI-treated children, an oral glucose tolerance test.There were no differences between the two groups with respect to fasting serum insulin or C-peptide, homeostatic model assessment insulin resistance, or quantitative insulin sensitivity check index. The mean insulin sensitivity index of PI-treated and PI-naive children was 6.93 +/- 6.37 and 10.58 +/- 12.93 x 10(-4)min(-1) [microU/ml](-1), respectively (P = 0.17). The mean disposition index for the two groups was 1840 +/- 1575 and 3708 +/- 3005 x 10(-4)min(-1) (P = 0.013), respectively. After adjusting for potential confounding variables using multiple regression analysis, the insulin sensitivity index and disposition index of PI-treated children were significantly lower than that of PI-naive children (P = 0.01 for both). In PI-treated but not PI-naive children, insulin sensitivity correlated inversely with visceral adipose tissue area (r = -0.43, P = 0.01) and visceral to sc adipose tissue ratio (r = -0.49, P = 0.004). Mildly impaired glucose tolerance was noted in four of 21 PI-treated subjects tested.Our results demonstrate not only that PI therapy reduces insulin sensitivity in HIV-infected children but also that it impairs the beta-cell response to this reduction in insulin sensitivity and, in a subset of children, leads to the development of impaired glucose tolerance. The presence of insulin resistance, dyslipidemia, and the significant correlation of reduced insulin sensitivity with increased visceral adipose tissue content suggest that PI-containing highly active antiretroviral therapy is associated with the emergence of early features of a metabolic syndrome-like phenotype.