CD4 T-cell count and HIV-1 infection in adults with uncomplicated malaria

BACKGROUND: HIV-1-negative children with malaria have reversible lymphocyte and CD4 count decreases. We assessed the impact of malaria parasitemia on the absolute CD4 count in both HIV-1-infected and non-HIV-infected adults. METHODS: In Ndola, Zambia, at the health-center level, we treated 327 nonpregnant adults for confirmed, uncomplicated, clinical malaria. We assessed HIV-1 status, CD4 count, and HIV-1 viral load (if HIV-1-infected) at enrollment and at 28 and 45 days after treatment. RESULTS: After successful antimalarial treatment, the median CD4 count at day 28 of follow-up increased from 468 to 811 cells/microL in HIV-1-negative and from 297 to 447 cells/microL in HIV-1-positive patients (paired t test, P < 0.001 for both). CD4 count increment was inversely correlated with CD4 count at day 0 in both HIV-1-negative (P < 0.001) and HIV-1-positive patients (P = 0.03). After successful treatment, the proportion of patients with CD4 count <200/microL at day 45 decreased from 9.6% to 0% in HIV-1-negative and from 28.7% to 13.2% in HIV-1-positive malaria patients (P < 0.001 for both). In patients with detectable but mostly asymptomatic parasitemia, CD4 count and, if HIV-1-infected, viral load at day 45 of follow-up were similar to those observed at enrollment. CONCLUSION: Interpretation of absolute CD4 count might be biased during or just after a clinical malaria episode. Therefore, in malaria-endemic areas, before taking any decision on the management of HIV-1-positive individuals, their malaria status should be assessed.     

Inhibition of histone deacetylases by chlamydocin induces apoptosis and proteasome-mediated degradation of survivin

The naturally occurring cyclic tetrapeptide chlamydocin is a very potent inhibitor of cell proliferation. Here we show that chlamydocin is a highly potent histone deacetylase (HDAC) inhibitor, inhibiting HDAC activity in vitro with an IC(50) of 1.3 nM. Like other HDAC inhibitors, chlamydocin induces the accumulation of hyperacetylated histones H3 and H4 in A2780 ovarian cancer cells, increases the expression of p21(cip1/waf1), and causes an accumulation of cells in G(2)/M phase of the cell cycle. In addition, chlamydocin induces apoptosis by activating caspase-3, which in turn leads to the cleavage of p21(cip1/waf1) into a 15-kDa breakdown product and drives cells from growth arrest into apoptosis. Concomitant with the activation of caspase-3 and cleavage of p21(cip1/waf1), chlamydocin decreases the protein level of survivin, a member of the inhibitor of apoptosis protein family that is selectively expressed in tumors. Although our data indicate a potential link between degradation of survivin and activation of the apoptotic pathway induced by HDAC inhibitors, stable overexpression of survivin does not suppress the activation of caspase-3 or cleavage of p21(cip1/waf1) induced by chlamydocin treatment. The decrease of survivin protein level is mediated by degradation via proteasomes since it can be inhibited by specific proteasome inhibitors. Taken together, our results show that induction of apoptosis by chlamydocin involves caspase-dependent cleavage of p21(cip1/waf1), which is strikingly associated with proteasome-mediated degradation of survivin.     

Multifunctional cells in human pituitary adenomas: implications for paradoxical secretion and tumorigenesis

Pituitary adenomas are very common in humans. They are of monoclonal origin, very heterogeneous, and produce frequently paradoxical secretion. The normal anterior pituitary (AP) contains some unorthodox multifunctional cells able to store more than one AP hormone (polyhormonal) and/or to express multiple hypothalamic-releasing hormone receptors (multiresponsive). Multifunctional AP cells seem to be involved in plasticity processes such as transdifferentiation or paradoxical secretion. Here, we have characterized the single-cell phenotypes of 15 human pituitary tumors, including prolactinomas, nonfunctioning adenomas, and adenomas from multiple endocrine neoplasia type I (MEN-I) and pituitary Cushing's disease patients. Individual tumor cells were typed according to expression of AP hormones and hypothalamic-releasing hormone receptors by combination of calcium imaging and multiple sequential immunocytochemistry in the same cells. We found a large heterogeneity among the different tumors. In eight of the 15 tumors studied, more than 80% of the cells presented a multifunctional phenotype. This may explain the occurrence of paradoxical secretion. In addition, our results suggest that human pituitary adenomas might derive from multifunctional cells. This is consistent with the existence of a link between pituitary plasticity and tumorigenesis.     

Fecal incontinence in females with a past history of vaginal delivery: significance of anal sphincter defects detected by ultrasound

PURPOSE: The aim of this study was to determine the significance of anal sphincter defects detected by ultrasonography, in a population of fecal incontinent parous females without previous anoperineal surgery. METHODS: From 100 consecutive incontinent patients, 61 females with at least one previous vaginal delivery and no past anoperineal surgery were studied. The severity of fecal incontinence was assessed by the Cleveland Clinic questionnaire score. Lesions of the internal or external anal sphincters, and the radial size of these defects were assessed by ultrasonography. Anal vector manometry was performed to measure anal pressures at rest and during voluntary squeeze, and the anal asymmetry index. RESULTS: Twenty-three had a normal sphincter (38 percent), and 38 (62 percent) had a defect detected by ultrasonography: 20 isolated defects of the external sphincter and 18 combined defects of the internal and external sphincters. Combined defects were significantly larger. The radial size of the defects was positively correlated with the severity of clinical symptoms. Anal pressure asymmetry index was significantly increased in the group with combined defects compared with the two other groups. An index of 25 percent or greater had a very high (100 percent) negative predictive value for the presence of a defect larger than 90 degrees. CONCLUSIONS: This study confirms the high prevalence of anal sphincter defects detected by ultrasonography in a population of incontinent parous females without previous proctologic surgery. The clinical symptoms are related to the size of these defects. Anal vector manometry may be a useful tool to confirm the relation between echographic anal sphincter lesions and fecal incontinence.     

Idiopathic CD4 Lymphocytopenia: Clinical and Immunologic Characteristics and Follow-Up of 40 Patients

Idiopathic CD4 T lymphocytopenia (ICL) is a rare and severe condition with limited available data. We conducted a French multicenter study to analyze the clinical and immunologic characteristics of a cohort of patients with ICL according to the Centers for Disease Control criteria.We recruited 40 patients (24 female) of mean age 44.2 ± 12.2 (19–70) years. Patients underwent T-lymphocyte phenotyping and lymphoproliferation assay at diagnosis, and experiments related to thymic function and interferon (IFN)-γ release by natural killer (NK) cell were performed. Mean follow-up was 6.9 ± 6.7 (0.14–24.3) years. Infectious, autoimmune, and neoplastic events were recorded, as were outcomes of interleukin 2 therapy.In all, 25 patients had opportunistic infections (12 with human papillomavirus infection), 14 had autoimmune symptoms, 5 had malignancies, and 8 had mild or no symptoms. At the time of diagnosis, the mean cell counts were as follows: mean CD4 cell count: 127/mm³ (range, 4–294); mean CD8: 236/mm³ (range, 1–1293); mean CD19: 113/mm³ (range, 3–547); and mean NK cell count: 122/mm³ (range, 5–416). Most patients had deficiency in CD8, CD19, and/or NK cells. Cytotoxic function of NK cells was normal, and patients with infections had a significantly lower NK cell count than those without (p = 0.01). Patients with autoimmune manifestations had increased CD8 T-cell count. Proliferation of thymic precursors, as assessed by T-cell rearrangement excision circles, was increased. Six patients died (15%). CD4 T-cell count <150/mm³ and NK cell count <100/mm³ were predictors of death.In conclusion, ICL is a heterogeneous disorder often associated with deficiencies in CD8, CD19, and/or NK cells. Long-term prognosis may be related to initial CD4 and NK cell deficiency.Abbreviations: AIHA = autoimmune hemolytic anemia, CDC = Centers for Disease Control, CMV = cytomegalovirus, cpm = count per minute, CVID = common variable immunodeficiency, CXCR4 = C-X-C chemokine receptor type 4, HIV = human immunodeficiency virus, HLA = human leukocyte antigen, HPV = human papillomavirus, HTLV-1/2 = human T-cell lymphotropic 1/2, ICL = idiopathic CD4 T lymphocytopenia, IFN-γ = interferon-γ, IL = interleukin, JC virus = John Cunningham virus, LPA = lymphocyte proliferation assay, NK = natural killer, P = patient, PBMC = peripheral blood mononuclear cell, Pwd = pokeweed, SI = stimulation index, sj = signal joint, TREC = T-cell rearrangement excision circle     

Volcano-induced regime shifts in millennial tree-ring chronologies from northeastern North America

Dated records of ice-cap growth from Arctic Canada recently suggested that a succession of strong volcanic eruptions forced an abrupt onset of the Little Ice Age between A.D. 1275 and 1300 [Miller GH, et al. (2012) Geophys Res Lett 39(2):L02708, 10.1029/2011GL050168]. Although this idea is supported by simulation experiments with general circulation models, additional support from field data are limited. In particular, the Northern Hemisphere network of temperature-sensitive millennial tree-ring chronologies, which principally comprises Eurasian sites, suggests that the strongest eruptions only caused cooling episodes lasting less than about 10 y. Here we present a new network of millennial tree-ring chronologies from the taiga of northeastern North America, which fills a wide gap in the network of the Northern Hemisphere''s chronologies suitable for temperature reconstructions and supports the hypothesis that volcanoes triggered both the onset and the coldest episode of the Little Ice Age. Following the well-expressed Medieval Climate Anomaly (approximately A.D. 910–1257), which comprised the warmest decades of the last millennium, our tree-ring-based temperature reconstruction displays an abrupt regime shift toward lower average summer temperatures precisely coinciding with a series of 13th century eruptions centered around the 1257 Samalas event and closely preceding ice-cap expansion in Arctic Canada. Furthermore, the successive 1809 (unknown volcano) and 1815 (Tambora) eruptions triggered a subsequent shift to the coldest 40-y period of the last 1100 y. These results confirm that series of large eruptions may cause region-specific regime shifts in the climate system and that the climate of northeastern North America is especially sensitive to volcanic forcing.Tree-ring chronologies are the type of proxy record most used to develop climate reconstructions covering the last millennium (1). These chronologies have been integrated into large-scale networks, often with additional proxies, to document the amplitude, duration, and forcing mechanisms of the Medieval Climate Anomaly, the Little Ice Age, and the recent warming trend. However, the spatial coverage of long tree-ring records must be improved to allow a better understanding of regional variations in past climate (1, 2). For example, in eastern North America, millennial climate reconstructions have been constructed from tree species and sites sensitive to drought and precipitation (3), whereas temperatures were inferred solely from low-resolution proxies, such as pollen data (4, 5). Furthermore, only tree-ring-based climate reconstructions shorter than a millennium or using chronologies poorly replicated before A.D. 1500 have been published for the entire North American boreal forest (6, 7), whereas several millennial, highly replicated, temperature-sensitive tree-ring records have been developed across the Eurasian boreal zone. This lack of data is an important issue that causes the poor representation of North America in long-term, large-scale temperature reconstructions (1, 4).The feasibility of reconstructing volcanic forcing from tree-ring data has been debated, especially in regards to large and successive eruptions. Two of the largest eruptions of the last millennium, the A.D. 1257 Samalas and A.D. 1815 Tambora events, were both closely followed and preceded by additional large eruptions in 1227, 1275, 1284, 1809, and 1835 (8−11). Whereas general circulation model experiments suggest that the impacts of large and successive eruptions might have influenced climate systems for periods ranging from 20 y to several decades, or even centuries (12–16), Northern Hemisphere tree-ring-based temperature reconstructions only display negative temperature anomalies lasting between 2 and 10 y (17–20). Region-specific responses of the climate system to volcanic forcing may in part explain this discrepancy (17). For example, large and successive eruptions may have had stronger impacts on summer temperatures in northeastern North America (hereafter NENA) than elsewhere. An extensive Northern Hemisphere network of tree-ring density chronologies supports this idea, showing that the coldest 1816 temperature anomalies occurred over the Quebec-Labrador Peninsula (21), where they may have persisted for several decades (7). The idea is also supported by the abrupt acceleration of ice-cap growth in the Eastern Canadian Arctic during A.D. 1275–1300, at the onset of the Little Ice Age, as a consequence of a series of eruptions (22). However, the lack of millennial, well-replicated, and temperature-sensitive tree-ring chronologies in the NENA sector precludes the examination of the volcano−temperature relationship in a long-term context with an annual resolution.In this study, we have built a network of six highly replicated millennial tree-ring chronologies from large stocks of black spruce [Picea mariana (Mill.) B.S.P.] subfossil trees preserved in lakes of the NENA taiga from which we developed a millennial reconstruction (A.D. 910–2011) of regional July−August temperatures. For this purpose, we selected homogeneous sites with infrequent and well-documented ecological disturbances (23), and sampled homogeneous subfossil and living samples to maximize the robustness of our reconstruction. We then used a Bayesian mixture of probability distributions with dependence (also referred to as hidden Markov models or Markov switching models; see refs. 24 and 25) to detect possible regime shifts in summer temperatures triggered by series of large eruptions and to provide new insights concerning the climate history of NENA during the last 1,100 y.     

Incidence and consequences of systemic arterial thrombotic events in COVID-19 patients

Journal of Thrombosis and Thrombolysis - A high incidence of thrombotic events, particularly deep vein thrombosis and pulmonary embolism, has been clearly documented in COVID-19 patients. In...