Association of differentiation state of CD4+ T cells and disease progression in HIV-1 perinatally infected children

Background

In the USA, most HIV-1 infected children are on antiretroviral drug regimens, with many individuals surviving through adolescence and into adulthood. The course of HIV-1 infection in these children is variable, and understudied.

Methodology/Principal Findings

We determined whether qualitative differences in immune cell subsets could explain a slower disease course in long term survivors with no evidence of immune suppression (LTS-NS; CD4%≥25%) compared to those with severe immune suppression (LTS-SS; CD4%≤15%). Subjects in the LTS-NS group had significantly higher frequencies of naïve (CCR7+CD45RA+) and central memory (CCR7+CD45RA−) CD4+ T cells compared to LTS-SS subjects (p = 0.0005 and <0.0001, respectively). Subjects in the rapid progressing group had significantly higher levels of CD4+ T_EMRA (CCR7−CD45RA+) cells compared to slow progressing subjects (p<0.0001).

Conclusions/Significance

Rapid disease progression in vertical infection is associated with significantly higher levels of CD4+ T_EMRA (CCR7−CD45RA+) cells.     

Breast feeding, parity and breast cancer subtypes in a Spanish cohort

Background

Differences in the incidence and outcome of breast cancer among Hispanic women compared with white women are well documented and are likely explained by ethnic differences in genetic composition, lifestyle, or environmental exposures.

Methodolgy/Principal Findings

A population-based study was conducted in Galicia, Spain. A total of 510 women diagnosed with operable invasive breast cancer between 1997 and 2010 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics were collected. The different breast cancer tumor subtypes were compared on their clinico-pathological characteristics and risk factor profiles, particularly reproductive variables and breastfeeding. Among the 501 breast cancer patients (with known ER and PR receptors), 85% were ER+/PR+ and 15% were ER-&PR-. Among the 405 breast cancer with known ER, PR and HER2 status, 71% were ER+/PR+/HER2- (luminal A), 14% were ER+/PR+/HER2+ (luminal B), 10% were ER−/PR−/HER2- (triple negative breast cancer, TNBC), and 5% were ER−/PR−/HER2+ (non-luminal). A lifetime breastfeeding period equal to or longer than 7 months was less frequent in case patients with TNBC (OR = 0.25, 95% CI = 0.08–0.68) compared to luminal A breast cancers. Both a low (2 or fewer pregnancies) and a high (3–4 pregnancies) number of pregnancies combined with a long breastfeeding period were associated with reduced odds of TNBC compared with luminal A breast cancer, although the association seemed to be slightly more pronounced among women with a low number of pregnancies (OR = 0.09, 95% CI = 0.005–0.54).

Conclusions/Significance

In case-case analyses with the luminal A cases as the reference group, we observed a lower proportion of TNBC among women who breastfed 7 or more months. The combination of longer breastfeeding duration and lower parity seemed to further reduce the odds of having a TNBC compared to a luminal A breast cancer.     

Evaluation of portable point-of-care CD4 counter with high sensitivity for detecting patients eligible for antiretroviral therapy

Background

Accurate, inexpensive point-of-care CD4+ T cell testing technologies are needed that can deliver CD4+ T cell results at lower level health centers or community outreach voluntary counseling and testing. We sought to evaluate a point-of-care CD4+ T cell counter, the Pima CD4 Test System, a portable, battery-operated bench-top instrument that is designed to use finger stick blood samples suitable for field use in conjunction with rapid HIV testing.

Methods

Duplicate measurements were performed on both capillary and venous samples using Pima CD4 analyzers, compared to the BD FACSCalibur (reference method). The mean bias was estimated by paired Student''s t-test. Bland Altman plots were used to assess agreement.

Results

206 participants were enrolled with a median CD4 count of 396 (range; 18–1500). The finger stick PIMA had a mean bias of −66.3 cells/µL (95%CI −83.4−49.2, P<0.001) compared to the FACSCalibur; the bias was smaller at lower CD4 counts (0–250 cells/µL) with a mean bias of −10.8 (95%CI −27.3−+5.6, P = 0.198), and much greater at higher CD4 cell counts (>500 cells/µL) with a mean bias of −120.6 (95%CI −162.8, −78.4, P<0.001). The sensitivity (95%CI) of the Pima CD4 analyzer was 96.3% (79.1–99.8%) for a <250 cells/ul cut-off with a negative predictive value of 99.2% (95.1–99.9%).

Conclusions

The Pima CD4 finger stick test is an easy-to-use, portable, relatively fast device to test CD4+ T cell counts in the field. Issues of negatively-biased CD4 cell counts especially at higher absolute numbers will limit its utility for longitudinal immunologic response to ART. The high sensitivity and negative predictive value of the test makes it an attractive option for field use to identify patients eligible for ART, thus potentially reducing delays in linkage to care and ART initiation.     

Biomarkers for clinical and incipient tuberculosis: performance in a TB-endemic country

Background

Simple biomarkers are required to identify TB in both HIV⁻TB⁺ and HIV⁺TB⁺ patients. Earlier studies have identified the M. tuberculosis Malate Synthase (MS) and MPT51 as immunodominant antigens in TB patients. One goal of these investigations was to evaluate the sensitivity and specificity of anti-MS and –MPT51 antibodies as biomarkers for TB in HIV⁻TB⁺ and HIV⁺TB⁺ patients from a TB-endemic setting. Earlier studies also demonstrated the presence of these biomarkers during incipient subclinical TB. If these biomarkers correlate with incipient TB, their prevalence should be higher in asymptomatic HIV⁺ subjects who are at a high-risk for TB. The second goal was to compare the prevalence of these biomarkers in asymptomatic, CD4⁺ T cell-matched HIV⁺TB⁻ subjects from India who are at high-risk for TB with similar subjects from US who are at low-risk for TB.

Methods and Results

Anti-MS and -MPT51 antibodies were assessed in sera from 480 subjects including PPD⁺ or PPD⁻ healthy subjects, healthy community members, and HIV⁻TB⁺ and HIV⁺TB⁺ patients from India. Results demonstrate high sensitivity (∼80%) of detection of smear-positive HIV⁻TB⁺ and HIV⁺TB⁺ patients, and high specificity (>97%) with PPD⁺ subjects and endemic controls. While ∼45% of the asymptomatic HIV⁺TB⁻ patients at high-risk for TB tested biomarker-positive, >97% of the HIV⁺TB⁻ subjects at low risk for TB tested negative. Although the current studies are hampered by lack of knowledge of the outcome, these results provide strong support for the potential of these biomarkers to detect incipient, subclinical TB in HIV⁺ subjects.

Conclusions

These biomarkers provide high sensitivity and specificity for TB diagnosis in a TB endemic setting. Their performance is not compromised by concurrent HIV infection, site of TB and absence of pulmonary manifestations in HIV⁺TB⁺ patients. Results also demonstrate the potential of these biomarkers for identifying incipient subclinical TB in HIV⁺TB⁻ subjects at high-risk for TB.     

A randomized open-label trial of artesunate- sulfadoxine-pyrimethamine with or without primaquine for elimination of sub-microscopic P. falciparum parasitaemia and gametocyte carriage in eastern Sudan

Background

In areas of seasonal malaria transmission, treatment of asymptomatic carriers of malaria parasites, whose parasitaemia persists at low densities throughout the dry season, could be a useful strategy for malaria control. We carried out a randomized trial to compare two drug regimens for clearance of parasitaemia in order to identify the optimum regimen for use in mass drug administration in the dry season.

Methodology and Principal Findings

A two-arm open-label randomized controlled trial was conducted during the dry season in an area of distinct seasonal malaria in two villages in Gedarif State in eastern Sudan. Participants were asymptomatic adults and children aged over 6 months, with low-density P. falciparum infection detected by PCR. Participants were randomized to receive artesunate/sulfadoxine-pyrimethamine (AS+SP) combination for three days with or without a dose of primaquine (PQ) on the fourth day. Parasitaemia detected by PCR on days 3, 7 and 14 after the start of treatment and gametocytes detected by RT-PCR on days 7 and 14 were then recorded. 104 individuals who had low density parasitaemia at screening were randomized and treated during the dry season. On day 7, 8.3% were positive by PCR in the AS+SP+PQ group and 6.5% in the AS+SP group (risk difference 1.8%, 95%CI −10.3% to +13.8%). At enrolment, 12% (12/100) were carrying gametocytes. This was reduced to 6.4% and 4.4% by day 14 (Risk difference 1.9% (95%CI −9.3% to +13.2%) in AS+SP+PQ and AS+SP groups, respectively.

Conclusion

Addition of primaquine to artemisinin combination treatment did not improve elimination of parasitaemia and prevention of gametocyte carriage in carriers with low-density parasitaemia in the dry season.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00330902","term_id":"NCT00330902"}}NCT00330902     

Family history and breast cancer hormone receptor status in a Spanish cohort

Background

Breast cancer is a heterogenous disease that impacts racial/ethnic groups differently. Differences in genetic composition, lifestyles, reproductive factors, or environmental exposures may contribute to the differential presentation of breast cancer among Hispanic women.

Materials and Methods

A population-based study was conducted in the city of Santiago de Compostela, Spain. A total of 645 women diagnosed with operable invasive breast cancer between 1992 and 2005 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics of the tumors were collected. Hormone receptor negative tumors were compared with hormone receptor postive tumors on their clinico-pathological characteristics as well as risk factor profiles.

Results

Among the 645 breast cancer patients, 78% were estrogen receptor-positive (ER+) or progesterone receptor-positive (PR+), and 22% were ER−&PR−. Women with a family history of breast cancer were more likely to have ER−&PR− tumors than women without a family history (Odds ratio, 1.43; 95% confidence interval, 0.91–2.26). This association was limited to cancers diagnosed before age 50 (Odds ratio, 2.79; 95% confidence interval, 1.34–5.81).

Conclusions

An increased proportion of ER−&PR− breast cancer was observed among younger Spanish women with a family history of the disease.     

Severe pandemic H1N1 2009 infection is associated with transient NK and T deficiency and aberrant CD8 responses

Background

It is unclear why the severity of influenza varies in healthy adults or why the burden of severe influenza shifts to young adults when pandemic strains emerge. One possibility is that cross-protective T cell responses wane in this age group in the absence of recent infection. We therefore compared the acute cellular immune response in previously healthy adults with severe versus mild pandemic H1N1 infection.

Methods and Principal Findings

49 previously healthy adults admitted to the National Hospital of Tropical Diseases, Viet Nam with RT-PCR-confirmed 2009 H1N1 infection were prospectively enrolled. 39 recovered quickly whereas 10 developed severe symptoms requiring supplemental oxygen and prolonged hospitalization. Peripheral blood lymphocyte subset counts and activation (HLADR, CD38) and differentiation (CD27, CD28) marker expression were determined on days 0, 2, 5, 10, 14 and 28 by flow cytometry. NK, CD4 and CD8 lymphopenia developed in 100%, 90% and 60% of severe cases versus 13% (p<0.001), 28%, (p = 0.001) and 18% (p = 0.014) of mild cases. CD4 and NK counts normalized following recovery. B cell counts were not significantly associated with severity. CD8 activation peaked 6–8 days after mild influenza onset, when 13% (6–22%) were HLADR+CD38+, and was accompanied by a significant loss of resting/CD27+CD28+ cells without accumulation of CD27+CD28− or CD27−CD28− cells. In severe influenza CD8 activation peaked more than 9 days post-onset, and/or was excessive (30–90% HLADR+CD38+) in association with accumulation of CD27+CD28− cells and maintenance of CD8 counts.

Conclusion

Severe influenza is associated with transient T and NK cell deficiency. CD8 phenotype changes during mild influenza are consistent with a rapidly resolving memory response whereas in severe influenza activation is either delayed or excessive, and partially differentiated cells accumulate within blood indicating that recruitment of effector cells to the lung could be impaired.     

HIV prevalence and impact on renutrition in children hospitalised for severe malnutrition in Niger: an argument for more systematic screening

Background

In developing countries, malnutrition is a contributing factor in over 50% of child deaths. Mortality rates are higher in underweight children, and HIV-infection is known to increase underweight. Our goals were to evaluate the prevalence of HIV among children hospitalised for severe malnutrition (SM) at the Niamey national hospital (Niger), and to compare renutrition and mortality by HIV-status.

Methods

Retrospective study based on all children <5 years hospitalised for SM between January 1^st 2008 and July 1^st 2009. HIV-prevalence was the ratio of HIV+ children on the number of children tested. Duration of renutrition and mortality were described using survival curves.

Results

During the study period, 477 children were hospitalised for SM. HIV testing was accepted in 470 (98.5%), of which 40 were HIV+ (HIV prevalence (95% confidence interval) of 8.6% (6.2–11.5)). Duration of renutrition was longer in HIV+ than HIV− children (mean: 22 vs. 15 days; p = 0.003). During renutrition, 8 (20%) and 61 (14%) HIV+ and HIV− children died, respectively (p = 0.81).

Conclusion

Around 9% of children hospitalised for severe malnutrition were HIV infected, while in Niger HIV prevalence in adults is estimated at 0.8%. This pleads for wider access to HIV testing in this population.     

Apoptotic effects of antilymphocyte globulins on human pro-inflammatory CD4+CD28- T-cells

Background

Pro-inflammatory, cytotoxic CD4⁺CD28⁻ T-cells with known defects in apoptosis have been investigated as markers of premature immuno-senescence in various immune-mediated diseases. In this study we evaluated the influence of polyclonal antilymphocyte globulins (ATG-Fresenius, ATG-F) on CD4⁺CD28⁻ T-cells in vivo and in vitro.

Principal Findings

Surface and intracellular three colour fluorescence activated cell sorting analyses of peripheral blood mononuclear cells from 16 consecutive transplant recipients and short-term cell lines were performed. In vivo, peripheral levels of CD3⁺CD4⁺CD28⁻ T-cells decreased from 3.7±7.1% before to 0±0% six hours after ATG-F application (P = 0.043) in 5 ATG-F treated but not in 11 control patients (2.9±2.9% vs. 3.9±3.0%). In vitro, ATG-F induced apoptosis even in CD4⁺CD28⁻ T-cells, which was 4.3-times higher than in CD4⁺CD28⁺ T-cells. ATG-F evoked apoptosis was partially reversed by the broad-spectrum caspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) and prednisolon-21-hydrogensuccinate. ATG-F triggered CD25 expression and production of pro-inflammatory cytokines, and induced down-regulation of the type 1 chemokine receptors CXCR-3, CCR-5, CX3CR-1 and the central memory adhesion molecule CD62L predominately in CD4⁺CD28⁻ T-cells.

Conclusion

In summary, in vivo depletion of peripheral CD3⁺CD4⁺CD28⁻ T-cells by ATG-F in transplant recipients was paralleled in vitro by ATG-F induced apoptosis. CD25 expression and chemokine receptor down-regulation in CD4⁺CD28⁻ T-cells only partly explain the underlying mechanism.     

Interferon-gamma release assay for the diagnosis of latent TB infection--analysis of discordant results, when compared to the tuberculin skin test

Background

With the Interferon-γ release assays (IGRA) a new method for the diagnosis of latent tuberculosis infections (LTBI) is available. Due to the lack of a gold standard for the diagnosis of LTBI, the IGRA is compared to the Mantoux Tuberculin Skin Test (TST), which yields discordant results in varying numbers. Therefore we assessed to which extent discordant results can be explained by potential risk factors such as age, BCG vaccination and migration.

Methods and Findings

In this pooled analysis, two German studies evaluating the Quantiferon-Gold In-Tube test (QFT) by comparison with the TST (RT23 of SSI) were combined and logistic regressions for potential risk factors for TST+/QFT− as well as THT−/QFT+ discordance were calculated. The analysis comprises 1,033 participants. Discordant results were observed in 15.4%, most of them being TST+/QFT− combinations. BCG vaccination or migration explained 85.1% of all TST+/QFT− discordance. Age explained 49.1% of all TST−/QFT+ discordance. Agreement between the two tests was 95.6% in German-born persons younger than 40 years and not BCG-vaccinated.

Conclusions

After adjustment for potential risk factors for positive or negative TST results, agreement of QFT and TST is excellent with little potential that the TST is more likely to detect old infections than the QFT. In surveillance programs for LTBI in high-income, low TB incidence countries like Germany the QFT is especially suited for persons with BCG vaccination or migrants due to better specificity and in older persons due to its superior sensitivity.     

Improved outcome prediction using CT angiography in addition to standard ischemic stroke assessment: results from the STOPStroke study

Purpose

To improve ischemic stroke outcome prediction using imaging information from a prospective cohort who received admission CT angiography (CTA).

Methods

In a prospectively designed study, 649 stroke patients diagnosed with acute ischemic stroke had admission NIH stroke scale scores, noncontrast CT (NCCT), CTA, and 6-month outcome assessed using the modified Rankin scale (mRS) scores. Poor outcome was defined as mRS>2. Strokes were classified as “major” by the (1) Alberta Stroke Program Early CT Score (ASPECTS+) if NCCT ASPECTS was≤7; (2) Boston Acute Stroke Imaging Scale (BASIS+) if they were ASPECTS+ or CTA showed occlusion of the distal internal carotid, proximal middle cerebral, or basilar arteries; and (3) NIHSS for scores>10.

Results

Of 649 patients, 253 (39.0%) had poor outcomes. NIHSS, BASIS, and age, but not ASPECTS, were independent predictors of outcome. BASIS and NIHSS had similar sensitivities, both superior to ASPECTS (p<0.0001). Combining NIHSS with BASIS was highly predictive: 77.6% (114/147) classified as NIHSS>10/BASIS+ had poor outcomes, versus 21.5% (77/358) with NIHSS≤10/BASIS− (p<0.0001), regardless of treatment. The odds ratios for poor outcome is 12.6 (95% CI: 7.9 to 20.0) in patients who are NIHSS>10/BASIS+ compared to patients who are NIHSS≤10/BASIS−; the odds ratio is 5.4 (95% CI: 3.5 to 8.5) when compared to patients who are only NIHSS>10 or BASIS+.

Conclusions

BASIS and NIHSS are independent outcome predictors. Their combination is stronger than either instrument alone in predicting outcomes. The findings suggest that CTA is a significant clinical tool in routine acute stroke assessment.     

Rapid recovery of fat mass in small for gestational age preterm infants after term

Background

Preterm small for gestational age (SGA) infants may be at risk for increased adiposity, especially when experiencing rapid postnatal weight gain. Data on the dynamic features of body weight and fat mass (FM) gain that occurs early in life is scarce. We investigated the postnatal weight and FM gain during the first five months after term in a cohort of preterm infants.

Methodology/Principal Findings

Changes in growth parameters and FM were prospectively monitored in 195 infants with birth weight ≤1500 g. The infants were categorized as born adequate for gestational age (AGA) without growth retardation at term (GR−), born AGA with growth retardation at term (GR+), born SGA. Weight and FM were assessed by an air displacement plethysmography system. At five months, weight z-score was comparable between the AGA (GR+) and the AGA (GR−), whereas the SGA showed a significantly lower weight.The mean weight (g) differences (95% CI) between SGA and AGA (GR−) and between SGA and AGA (GR+) infants at 5 months were −613 (−1215; −12) and −573 (−1227; −79), respectively. At term, the AGA (GR+) and the SGA groups showed a significantly lower FM than the AGA (GR−) group. In the first three months, change in FM was comparable between the AGA (GR+) and the SGA groups and significantly higher than that of the AGA (GR−) group.The mean difference (95% CI) in FM change between SGA and AGA (GR−) and between AGA (GR+) and AGA (GR−) from term to 3 months were 38.6 (12; 65); and 37.7 (10; 65). At three months, the FM was similar in all groups.

Conclusions

Our data suggests that fetal growth pattern influences the potential to rapidly correct anthropometry whereas the restoration of fat stores takes place irrespective of birth weight. The metabolic consequences of these findings need to be elucidated.     

Oral antimicrobial rinse to reduce mycobacterial culture contamination among tuberculosis suspects in Uganda: a prospective study

Rationale

Contamination by bacterial or fungal organisms reduces the effectiveness of mycobacterial culture for diagnosis of pulmonary tuberculosis (TB). We evaluated the effect of an anti-microbial and an anti-fungal oral rinse prior to expectoration on culture-contamination rates.

Methods

We enrolled a consecutive random sample of adults with cough for ≥2 weeks and suspected TB admitted to Mulago Hospital (Kampala, Uganda) between October 2008 and June 2009. We randomly assigned patients to oral rinse (60 seconds with chlorhexidine followed by 60 seconds with nystatin) vs. no oral rinse prior to initial sputum collection. Uganda National Tuberculosis Reference Laboratory technicians blinded to the method of sputum collection (with or without oral rinse) processed all sputum specimens for smear microscopy (direct Ziehl-Neelsen) and mycobacterial culture (Lowenstein-Jensen media).

Results

Of 220 patients enrolled, 177 (80%) were HIV-seropositive (median CD4-count 37 cells/uL, IQR 13–171 cells/uL). Baseline characteristics were similar between patients in the oral-rinse (N = 110) and no oral-rinse (N = 110) groups. The proportion of contaminated cultures was significantly lower in the oral-rinse group compared to the no oral-rinse group (4% vs. 15%, risk difference −11%, 95% CI −18 to −3%, p = 0.005). Oral rinse significantly reduced the proportion of contaminated cultures among HIV-infected patients (3% vs. 18%, risk difference −14%, 95% CI −23 to −6%, p = 0.002) but not HIV-uninfected (6% vs. 4%, risk difference 2%, 95% CI −12 to +15%, p = 0.81) patients. However, the proportion of smear-positive specimens (25% vs. 35%, p = 0.10) and culture-positive specimens (48% vs. 56%, p = 0.24) were lower in the oral-rinse compared to the no oral-rinse group, although the differences were not statistically significant.

Conclusions

Oral rinse prior to sputum expectoration is a promising strategy to reduce mycobacterial culture contamination in areas with high HIV prevalence, if strategies can be devised to reduce the adverse impact of oral rinse on smear- and culture-positivity.     

Circulating CD62E+ microparticles and cardiovascular outcomes

Background

Activated endothelial cells release plasma membrane submicron vesicles expressing CD62E (E-selectin) into blood, known as endothelial microparticles (EMPs). We studied whether the levels of endothelial microparticles expressing CD62E⁺, CD31⁺/Annexin-V⁺, or CD31⁺/CD42⁻ predict cardiovascular outcomes in patients with stroke history.

Methods/Principal Findings

Patients with stroke history at least 3 months prior to enrolment were recruited. Peripheral blood EMP levels were measured by flow cytometry. Major cardiovascular events and death were monitored for 36 months. Three hundred patients were enrolled, of which 298 completed the study according to protocol. Major cardiovascular events occurred in 29 patients (9.7%). Nine patients died, five from cardiovascular causes. Cumulative event-free survival rates were lower in patients with high levels of CD62E⁺ microparticles. Multivariate Cox regression analysis adjusted for cardiovascular risk factors, medications and stroke etiologic groups showed an association between a high CD62E⁺ microparticle level and a risk of major cardiovascular events and hospitalization. Levels of other kinds of EMPs expressing CD31⁺/Annexin-V⁺ or CD31⁺/CD42⁻ markers were not predictive of cardiovascular outcomes.

Conclusion

A high level of CD62E⁺ microparticles is associated with cardiovascular events in patients with stroke history, suggesting that the systemic endothelial activation increases the risk for cardiovascular morbidities.     

Beneficial effects of alternate dietary regimen on liver inflammation, atherosclerosis and renal activation

Background

Alternate day calorie restriction (CR) has been shown to be almost as beneficial as daily CR. The question arises whether this concept is also applicable to alternating dietary composition.

Objective

To seek evidence that alternating high cholesterol (HC) - cholesterol-free (CON) Western diet can effectively diminish hepatic and renal inflammation and cardiovascular risk factors as compared with daily HC-supplemented Western diet.

Design

Four groups of ApoE*3Leiden mice, a humanized model for atherosclerosis, were subjected to different feeding treatments for 16 weeks. Mice were fed CON diet; CON diet with 1% w/w cholesterol (HC); alternate (ALT) diet regimen of CON (4 days) and HC (3 days); or CON diet supplemented with 0.43% (w/w) cholesterol (MC), with overall dietary cholesterol intake equal to ALT. Plasma was analyzed for cardiovascular risk factors, aorta for atherosclerotic lesion formation, and liver and kidney for inflammation.

Results

ALT diet but not MC was almost as effective as daily CON feeding in preventing disease development. Compared to HC, the ALT group showed 62% lower hepatic nuclear factor kappa B (NF-κB) activity (P<0.001), a reduction of the circulating inflammatory markers E-selectin (−20%; P<0.05), vascular cell adhesion molecule 1 (VCAM-1; −15%; P<0.05) and Serum Amyloid A (SAA; −31%; P<0.05), smaller atherosclerotic lesion sizes (−51%; 46497±10791 µm² vs. 94664±16470 µm²; P<0.05) and diminished renal expression of specific inflammation and activation markers (VCAM-1, −27%; P<0.05; monocyte chemotactic protein-1 (MCP-1); −37%; P<0.01).

Conclusion

Alternate HC-CON feeding reproduced most of the beneficial effects of daily cholesterol-free diet, including strongly diminished hepatic, vascular and renal activation and inflammation; also atherosclerosis was reduced by half as compared to HC, albeit still higher compared to the CON group.     

Alterations in the interleukin-1/interleukin-1 receptor antagonist balance modulate cardiac remodeling following myocardial infarction in the mouse

Background

Healing after acute myocardial infarction (AMI) is characterized by an intense inflammatory response and increased Interleukin-1 (IL-1) tissue activity. Genetically engineered mice lacking the IL-1 receptor (IL-1R1-/-, not responsive to IL-1) or the IL-1 receptor antagonist (IL-1Ra, enhanced response to IL-1) have an altered IL-1/IL-1Ra balance that we hypothesize modulates infarct healing and cardiac remodeling after AMI.

Methods

IL-1R1-/- and IL-1Ra-/- male mice and their correspondent wild-types (WT) were subjected to permanent coronary artery ligation or sham surgery. Infarct size (trichrome scar size), apoptotic cell death (TUNEL) and left ventricular (LV) dimensions and function (echocardiography) were measured prior to and 7 days after surgery.

Results

When compared with the corresponding WT, IL-1R1-/- mice had significantly smaller infarcts (−25%), less cardiomyocyte apoptosis (−50%), and reduced LV enlargement (LV end-diastolic diameter increase [LVEDD], −20%) and dysfunction (LV ejection fraction [LVEF] decrease, −50%), whereas IL-1Ra-/- mice had significantly larger infarcts (+75%), more apoptosis (5-fold increase), and more severe LV enlargement (LVEDD increase,+30%) and dysfunction (LVEF decrease, +70%)(all P values <0.05).

Conclusions

An imbalance in IL-1/IL-1Ra signaling at the IL-1R1 level modulates the severity of cardiac remodeling after AMI in the mouse, with reduced IL-1R1 signaling providing protection and unopposed IL-1R1 signaling providing harm.     

Progressive activation of CD127+132- recent thymic emigrants into terminally differentiated CD127-132+ T-cells in HIV-1 infection

Aim

HIV infection is associated with distortion of T-cell homeostasis and the IL-7/IL7R axis. Progressive infection results in loss of CD127+132− and gains in CD127−132+ CD4+ and CD8+ T-cells. We investigated the correlates of loss of CD127 from the T-cell surface to understand mechanisms underlying this homeostatic dysregulation.

Methods

Peripheral and cord blood mononuclear cells (PBMCs; CBMC) from healthy volunteers and PBMC from patients with HIV infection were studied. CD127+132−, CD127+132+ and CD127−132+ T-cells were phenotyped by activation, differentiation, proliferation and survival markers. Cellular HIV-DNA content and signal-joint T-cell receptor excision circles (sjTRECs) were measured.

Results

CD127+132− T-cells were enriched for naïve cells while CD127−132+ T-cells were enriched for activated/terminally differentiated T-cells in CD4+ and CD8+ subsets in health and HIV infection. HIV was associated with increased proportions of activated/terminally differentiated CD127−132+ T-cells. In contrast to CD127+132− T-cells, CD127−132+ T-cells were Ki-67+Bcl-2^low and contained increased levels of HIV-DNA. Naïve CD127+132− T-cells contained a higher proportion of sjTRECs.

Conclusion

The loss of CD127 from the T-cell surface in HIV infection is driven by activation of CD127+132− recent thymic emigrants into CD127−132+ activated/terminally differentiated cells. This process likely results in an irreversible loss of CD127 and permanent distortion of T-cell homeostasis.     

A randomized, placebo controlled, double masked phase IB study evaluating the safety and antiviral activity of aprepitant, a neurokinin-1 receptor antagonist in HIV-1 infected adults

Background

Neurokinin-1 receptor (NK1R) antagonists have anti-HIV activity in monocyte-derived macrophages, decrease CCR5 expression and improve natural killer cell function ex vivo. Aprepitant is a NK1R antagonist approved by FDA as an antiemetic.

Methods

We conducted a phase IB randomized, placebo controlled, double masked study to evaluate the safety, antiviral activity, pharmacokinetics and immune-modulatory effects of aprepitant in HIV-infected adults not receiving antiretroviral therapy, with CD4+ cell count ≥350 cells/mm³ and plasma viral load ≥2,000 copies/ml. Subjects were stratified by viral load (< vs. ≥20,000 copies/ml) and randomized within each stratum to receive aprepitant at 125 mg QD(Low), or 250 mg QD(High), or placebo(PL) for 14 days, and followed for 42 days.

Results

Thirty subjects were randomized and 27 completed treatment (9, 8, 10 subjects in 125 (Low), 250 (High), and PL groups). 63% were male; 37% white; mean (SD) age 43 (9.3) years. Geometric mean baseline viral load (copies/ml) for Low, High, and PL was 15,709, 33,013, and 19,450, respectively. Mean (95%CI) change in log10 viral load at day 14 for Low, High, and PL was −0.02(−0.24,+0.20), −0.05(−0.21,+0.10), and +0.04(−0.08,+0.16), respectively. The number of subjects with AEs was 4(44.4%), 5(62.5%), and 1(10%) for Low, High, and PL. No Grade 4 AEs occurred.

Conclusions

Adverse events of aprepitant were more common in the treated groups. At the dose used in this two-week phase IB study, aprepitant showed biological activity, but no significant antiviral activity.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00428519","term_id":"NCT00428519"}}NCT00428519     

The accumulation and prognosis value of tumor infiltrating IL-17 producing cells in esophageal squamous cell carcinoma

Background

The role of IL-17 producing cells in tumors is controversial. In the present study, we investigated the prognostic value of measuring tumor-infiltrating IL-17 producing cell levels in human esophageal squamous cell carcinoma (ESCC).

Methodology/Principal Findings

Immunohistochemical staining was performed to investigate the levels of IL-17+ tumor infiltrating lymphocytes (TILs), as well as CD8+ cytotoxic T lymphocytes (CTLs) and CD57+ natural killer (NK) cells from 181 ESCC patients. The prognostic value of measuring the densities of IL-17+TILs and the correlation with CTLs and NK was evaluated. IL-17 producing cells were detected in esophageal squamous cell carcinoma tissues. The IL-17 producing cells were major CD4 positive, but Foxp3 negative. The median level of IL-17+TILs was 3.90 cells/high power microscopic field (HPF). The density of IL-17 producing cells correlated negatively with T stage (P = 0.042). The higher densities of tumor infiltrating IL-17+ lymphocytes were associated with better overall survival (P = 0.031). Furthermore, we found that there were positive correlations between levels of IL-17 producing cells and the densities of CD8+cells, as well as CD57+cells (r = 0.198, P = 0.008 for CD8+ cells and r = 0.261, P<0.001 for CD57+ cells, respectively). The prognosis analysis also showed that the higher levels of CD8+ CTLs and CD57+ NK cells correlated with better overall survival of ESCC patients.

Conclusions

Our study suggests that tumor infiltrating IL-17 producing cells in ESCC patients may have protective roles in the tumor microenvironment and may be treated as a prognostic marker for ESCC patients.