Anemia and Risk Factors in HAART Na?ve and HAART Experienced HIV Positive Persons in South West Ethiopia: A Comparative Study

Background

Human immunodeficiency virus (HIV) infection and its treatment cause a range of hematological abnormalities. Anemia is one of the commonly observed hematologic manifestations in HIV positive persons and it has multifactorial origin.

Objective

We aimed to determine the prevalence and risk factors of anemia in highly active antiretroviral therapy (HAART) naïve and HAART experienced HIV positive persons.

Methods

A facility-based comparative cross sectional study was conducted in Jimma University Specialized Hospital from February 1 to March 30, 2012. A total of 234 HIV positive persons, 117 HAART naïve and 117 HAART experienced, were enrolled in this study. Blood and stool specimens were collected from each participant. Blood specimens were examined for complete blood count, CD4 count and blood film for malaria hemoparasite; whereas stool specimens were checked for ova of intestinal parasites. Socio-demographic characteristics and clinical data of the participants were collected using pre-tested questionnaire. Statistical analysis of the data (Chi-square, student’s t-test, logistic regression) was done using SPSS V-16.

Results

The overall prevalence of anemia was 23.1%. The prevalence of anemia in HAART naïve and HAART experienced persons was 29.9% and 16.2%, respectively (P = 0.014). Presence of opportunistic infections (P = 0.004, 95% CI = 1.69–15.46), CD4 count <200 cells/µl (P = 0.001, 95% CI = 2.57–36.89) and rural residence (P = 0.03, 95% CI = 1.12–10.39) were found to be predictors of anemia for HAART naïve participants. On the other hand, HAART regimen (ZDV/3TC/NVP) (P = 0.019, 95% CI = 0.01–1.24) and the duration of HAART (P = 0.007, 95% CI = 0.003–0.40.24) were found to be predictors of anemia for HAART experienced groups.

Conclusion

The prevalence of anemia in HAART naïve persons was higher than HAART experienced persons. Risk factors for anemia in HAART naïve and HAART experienced HIV positive persons were different. Hence, there is a need for longitudinal study to further explore the causes of HIV associated anemia and the pattern of hemoglobin changes with initiation of HAART.     

Modeling Disease Vector Occurrence When Detection Is Imperfect II: Drivers of Site-Occupancy by Synanthropic Triatoma brasiliensis in the Brazilian Northeast

Background

Understanding the drivers of habitat selection by insect disease vectors is instrumental to the design and operation of rational control-surveillance systems. One pervasive yet often overlooked drawback of vector studies is that detection failures result in some sites being misclassified as uninfested; naïve infestation indices are therefore biased, and this can confound our view of vector habitat preferences. Here, we present an initial attempt at applying methods that explicitly account for imperfect detection to investigate the ecology of Chagas disease vectors in man-made environments.

Methodology

We combined triplicate-sampling of individual ecotopes (n = 203) and site-occupancy models (SOMs) to test a suite of pre-specified hypotheses about habitat selection by Triatoma brasiliensis. SOM results were compared with those of standard generalized linear models (GLMs) that assume perfect detection even with single bug-searches.

Principal Findings

Triatoma brasiliensis was strongly associated with key hosts (native rodents, goats/sheep and, to a lesser extent, fowl) in peridomestic environments; ecotope structure had, in comparison, small to negligible effects, although wooden ecotopes were slightly preferred. We found evidence of dwelling-level aggregation of infestation foci; when there was one such focus, same-dwelling ecotopes, whether houses or peridomestic structures, were more likely to become infested too. GLMs yielded negatively-biased covariate effect estimates and standard errors; both were, on average, about four times smaller than those derived from SOMs.

Conclusions/Significance

Our results confirm substantial population-level ecological heterogeneity in T. brasiliensis. They also suggest that, at least in some sites, control of this species may benefit from peridomestic rodent control and changes in goat/sheep husbandry practices. Finally, our comparative analyses highlight the importance of accounting for the various sources of uncertainty inherent to vector studies, including imperfect detection. We anticipate that future research on infectious disease ecology will increasingly rely on approaches akin to those described here.     

Chagas Disease Vector Control in a Hyperendemic Setting: The First 11 Years of Intervention in Cochabamba,Bolivia

Background

Chagas disease has historically been hyperendemic in the Bolivian Department of Cochabamba. In the early 2000s, an extensive vector control program was implemented; 1.34 million dwelling inspections were conducted to ascertain infestation (2000–2001/2003–2011), with blanket insecticide spraying in 2003–2005 and subsequent survey-spraying cycles targeting residual infestation foci. Here, we assess the effects of this program on dwelling infestation rates (DIRs).

Methodology/Principal Findings

Program records were used to calculate annual, municipality-level aggregate DIRs (39 municipalities); very high values in 2000–2001 (median: 0.77–0.69) dropped to ∼0.03 from 2004 on. A linear mixed model (with municipality as a random factor) suggested that infestation odds decreased, on average, by ∼28% (95% confidence interval [CI₉₅] 6–44%) with each 10-fold increase in control effort. A second, better-fitting mixed model including year as an ordinal predictor disclosed large DIR reductions in 2001–2003 (odds ratio [OR] 0.11, CI₉₅ 0.06–0.19) and 2003–2004 (OR 0.22, CI₉₅ 0.14–0.34). Except for a moderate decrease in 2005–2006, no significant changes were detected afterwards. In both models, municipality-level DIRs correlated positively with previous-year DIRs and with the extent of municipal territory originally covered by montane dry forests.

Conclusions/Significance

Insecticide-spraying campaigns had very strong, long-lasting effects on DIRs in Cochabamba. However, post-intervention surveys consistently detected infestation in ∼3% of dwellings, underscoring the need for continuous surveillance; higher DIRs were recorded in the capital city and, more generally, in municipalities dominated by montane dry forest – an eco-region where wild Triatoma infestans are widespread. Traditional strategies combining insecticide spraying and longitudinal surveillance are thus confirmed as very effective means for area-wide Chagas disease vector control; they will be particularly beneficial in highly-endemic settings, but should also be implemented or maintained in other parts of Latin America where domestic infestation by triatomines is still commonplace.     

Direct Contra Na?ve-Indirect Comparison of Clinical Failure Rates between High-Viscosity GIC and Conventional Amalgam Restorations: An Empirical Study

Background

Naïve-indirect comparisons are comparisons between competing clinical interventions’ evidence from separate (uncontrolled) trials. Direct comparisons are comparisons within randomised control trials (RCTs). The objective of this empirical study is to test the null-hypothesis that trends and performance differences inferred from naïve-indirect comparisons and from direct comparisons/RCTs regarding the failure rates of amalgam and direct high-viscosity glass-ionomer cement (HVGIC) restorations in permanent posterior teeth have similar direction and magnitude.

Methods

A total of 896 citations were identified through systematic literature search. From these, ten and two uncontrolled clinical longitudinal studies for HVGIC and amalgam, respectively, were included for naïve-indirect comparison and could be matched with three out twenty RCTs. Summary effects sizes were computed as Odds ratios (OR; 95% Confidence intervals) and compared with those from RCTs. Trend directions were inferred from 95% Confidence interval overlaps and direction of point estimates; magnitudes of performance differences were inferred from the median point estimates (OR) with 25% and 75% percentile range, for both types of comparison. Mann-Whitney U test was applied to test for statistically significant differences between point estimates of both comparison types.

Results

Trends and performance differences inferred from naïve-indirect comparison based on evidence from uncontrolled clinical longitudinal studies and from direct comparisons based on RCT evidence are not the same. The distributions of the point estimates differed significantly for both comparison types (Mann–Whitney U  =  25, n_indirect  =  26; n_direct  =  8; p  =  0.0013, two-tailed).

Conclusion

The null-hypothesis was rejected. Trends and performance differences inferred from either comparison between HVGIC and amalgam restorations failure rates in permanent posterior teeth are not the same. It is recommended that clinical practice guidance regarding HVGICs should rest on direct comparisons via RCTs and not on naïve-indirect comparisons based on uncontrolled longitudinal studies in order to avoid inflation of effect estimates.     

Post-Control Surveillance of Triatoma infestans and Triatoma sordida with Chemically-Baited Sticky Traps

Background

Chagas disease prevention critically depends on keeping houses free of triatomine vectors. Insecticide spraying is very effective, but re-infestation of treated dwellings is commonplace. Early detection-elimination of re-infestation foci is key to long-term control; however, all available vector-detection methods have low sensitivity. Chemically-baited traps are widely used in vector and pest control-surveillance systems; here, we test this approach for Triatoma spp. detection under field conditions in the Gran Chaco.

Methodology/Principal Findings

Using a repeated-sampling approach and logistic models that explicitly take detection failures into account, we simultaneously estimate vector occurrence and detection probabilities. We then model detection probabilities (conditioned on vector occurrence) as a function of trapping system to measure the effect of chemical baits. We find a positive effect of baits after three (odds ratio [OR] 5.10; 95% confidence interval [CI₉₅] 2.59–10.04) and six months (OR 2.20, CI₉₅ 1.04–4.65). Detection probabilities are estimated at p≈0.40–0.50 for baited and at just p≈0.15 for control traps. Bait effect is very strong on T. infestans (three-month assessment: OR 12.30, CI₉₅ 4.44–34.10; p≈0.64), whereas T. sordida is captured with similar frequency in baited and unbaited traps.

Conclusions/Significance

Chemically-baited traps hold promise for T. infestans surveillance; the sensitivity of the system at detecting small re-infestation foci rises from 12.5% to 63.6% when traps are baited with semiochemicals. Accounting for imperfect detection, infestation is estimated at 26% (CI₉₅ 16–40) after three and 20% (CI₉₅ 11–34) after six months. In the same assessments, traps detected infestation in 14% and 8.5% of dwellings, whereas timed manual searches (the standard approach) did so in just 1.4% of dwellings only in the first survey. Since infestation rates are the main indicator used for decision-making in control programs, the approach we present may help improve T. infestans surveillance and control program management.     

An Evaluation of HIV Elite Controller Definitions within a Large Seroconverter Cohort Collaboration

Background

Understanding the mechanisms underlying viral control is highly relevant to vaccine studies and elite control (EC) of HIV infection. Although numerous definitions of EC exist, it is not clear which, if any, best identify this rare phenotype.

Methods

We assessed a number of EC definitions used in the literature using CASCADE data of 25,692 HIV seroconverters. We estimated proportions maintaining EC of total ART-naïve follow-up time, and disease progression, comparing to non-EC. We also examined HIV-RNA and CD4 values and CD4 slope during EC and beyond (while ART naïve).

Results

Most definitions classify ∼1% as ECs with median HIV-RNA 43–903 copies/ml and median CD4>500 cells/mm³. Beyond EC status, median HIV-RNA levels remained low, although often detectable, and CD4 values high but with strong evidence of decline for all definitions. Median % ART-naïve time as EC was ≥92% although overlap between definitions was low. EC definitions with consecutive HIV-RNA measurements <75 copies/ml with follow-up≥ six months, or with 90% of measurements <400 copies/ml over ≥10 year follow-up preformed best overall. Individuals thus defined were less likely to progress to endpoint (hazard ratios ranged from 12.5–19.0 for non-ECs compared to ECs).

Conclusions

ECs are rare, less likely to progress to clinical disease, but may eventually lose control. We suggest definitions requiring individuals to have consecutive undetectable HIV-RNA measurements for ≥ six months or otherwise with >90% of measurements <400 copies/ml over ≥10 years be used to define this phenotype.     

CD4+ T cells in aged or thymectomized recipients of allogeneic stem cell transplantations

Background

CD4+CD25highFOXP3+ regulatory T (Treg) cells, which include thymus-derived and peripherally induced cells, play a central role in immune regulation, and are therefore crucial to prevent graft-versus-host disease (GVHD). The increasing use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for elderly patients with thymus regression, and our case of allo-HSCT shortly after total thymectomy, raised questions about the activity of thymus-derived Treg cells and peripherally induced Treg cells, which are otherwise indistinguishable.

Results

We found that despite pre-transplant thymectomy or older age, both naïve and effector Treg cells, as well as naïve and effector conventional T cells, proliferated in allo-HSCT recipients. Higher proportions of total Treg cells 1 month post allo-HSCT, and naïve Treg cells 1 year post allo-HSCT, appeared in patients achieving complete chimera without developing significant chronic GVHD, including our thymectomized patient, compared with patients who developed chronic GVHD.

Conclusions

Treg cells that modulate human allogeneic immunity may arise peripherally as well as in the thymus of allo-HSCT recipients.     

Serious Treatment Related Adverse Drug Reactions amongst Anti-Retroviral Na?ve MDR-TB Patients

Background

Globally treatment outcomes for multidrug-resistant Mycobacterium tuberculosis (MDR-TB) remain poor and this is compounded by high drug toxicity. Little is known about the influence of adverse drug reactions (ADRs) on treatment outcomes in South Africa.

Methods

We evaluated the impact of severe ADRs among a prospective cohort of MDR-TB patients in South Africa (2000–2004). The HIV-infected study participants were anti-retroviral naïve.

Results

Of 2,079 patients enrolled, 1,390 (66.8%) were included in this analysis based on known HIV test results (39.1% HIV-infected). At least one severe ADR was reported in 83 (6.9%) patients with ototoxicity being the most frequent ADR experienced (38.9%).

Conclusions

We found that being HIV-infected but antiretroviral naïve did not increase occurrence of SADRs in patients on second-line anti-tuberculosis drugs. Early screening and proactive management of ADRs in this patient population is essential, especially given the rollout of decentralized care and the potential for overlapping toxicity of concomitant MDR-TB and HIV treatment.     

Highly Efficient Differentiation and Enrichment of Spinal Motor Neurons Derived from Human and Monkey Embryonic Stem Cells

Background

There are no cures or efficacious treatments for severe motor neuron diseases. It is extremely difficult to obtain naïve spinal motor neurons (sMNs) from human tissues for research due to both technical and ethical reasons. Human embryonic stem cells (hESCs) are alternative sources. Several methods for MN differentiation have been reported. However, efficient production of naïve sMNs and culture cost were not taken into consideration in most of the methods.

Methods/Principal Findings

We aimed to establish protocols for efficient production and enrichment of sMNs derived from pluripotent stem cells. Nestin+ neural stem cell (NSC) clusters were induced by Noggin or a small molecule inhibitor of BMP signaling. After dissociation of NSC clusters, neurospheres were formed in a floating culture containing FGF2. The number of NSCs in neurospheres could be expanded more than 30-fold via several passages. More than 33% of HB9+ sMN progenitor cells were observed after differentiation of dissociated neurospheres by all-trans retinoic acid (ATRA) and a Shh agonist for another week on monolayer culture. HB9+ sMN progenitor cells were enriched by gradient centrifugation up to 80% purity. These HB9+ cells differentiated into electrophysiologically functional cells and formed synapses with myotubes during a few weeks after ATRA/SAG treatment.

Conclusions and Significance

The series of procedures we established here, namely neural induction, NSC expansion, sMN differentiation and sMN purification, can provide large quantities of naïve sMNs derived from human and monkey pluripotent stem cells. Using small molecule reagents, reduction of culture cost could be achieved.     

Intensified Surveillance and Insecticide-based Control of the Chagas Disease Vector Triatoma infestans in the Argentinean Chaco

Background

The elimination of Triatoma infestans, the main Chagas disease vector in the Gran Chaco region, remains elusive. We implemented an intensified control strategy based on full-coverage pyrethroid spraying, followed by frequent vector surveillance and immediate selective insecticide treatment of detected foci in a well-defined rural area in northeastern Argentina with moderate pyrethroid resistance. We assessed long-term impacts, and identified factors and procedures affecting spray effectiveness.

Methods and Findings

After initial control interventions, timed-manual searches were performed by skilled personnel in 4,053 sites of 353–411 houses inspected every 4–7 months over a 35-month period. Residual insecticide spraying was less effective than expected throughout the three-year period, mainly because of the occurrence of moderate pyrethroid resistance and the limited effectiveness of selective treatment of infested sites only. After initial interventions, peridomestic infestation prevalence always exceeded domestic infestation, and timed-manual searches consistently outperformed householders'' bug detection, except in domiciles. Most of the infestations occurred in houses infested at baseline, and were restricted to four main ecotopes. Houses with an early persistent infestation were spatially aggregated up to a distance of 2.5 km. An Akaike-based multi-model inference approach showed that new site-level infestations increased substantially with the local availability of appropriate refugia for triatomine bugs, and with proximity to the nearest site found infested at one or two preceding surveys.

Conclusions and Significance

Current vector control procedures have limited effectiveness in the Gran Chaco. Selective insecticide sprays must include all sites within the infested house compound. The suppression of T. infestans in rural areas with moderate pyrethroid resistance requires increased efforts and appropriate management actions. In addition to careful, systematic insecticide applications, housing improvement and development policies that improve material conditions of rural villagers and reduce habitat suitability for bugs will contribute substantially to sustainable vector and disease control in the Gran Chaco.     

Comparison of Sum Absolute QRST Integral,and Temporal Variability in Depolarization and Repolarization,Measured by Dynamic Vectorcardiography Approach,in Healthy Men and Women

Background

Recently we showed the predictive value of sum absolute QRST integral (SAI QRST) and repolarization lability for risk stratification of sudden cardiac death (SCD) in heart failure patients. The goal of this study was to compare SAI QRST and metrics of depolarization and repolarization variability in healthy men and women.

Methods

Orthogonal ECGs were recorded at rest for 10 minutes in 160 healthy men and women (mean age 39.6±14.6, 80 men). Mean spatial TT′ angle, and normalized variances of T loop area, of spatial T vector amplitude, of QT interval and Tpeak-Tend area were measured for assessment of repolarization lability. Normalized variances of spatial QRS vector and QRS loop area characterized variability of depolarization. In addition, variability indices (VI) were calculated to adjust for normalized heart rate variance. SAI QRST was measured as the averaged arithmetic sum of areas under the QRST curve.

Results

Men were characterized by shorter QTc (430.3±21.7 vs. 444.7±22.2 ms; P<0.0001) and larger SAI QRST (282.1±66.7 vs.204.9±58.5 mV*ms; P<0.0001). Repolarization lability negatively correlated with spatial T vector amplitude. Adjusted by normalized heart rate variance, QT variability index was significantly higher in women than in men (−1.54±0.38 vs. −1.70±0.33; P = 0.017). However, in multivariate logistic regression after adjustment for body surface area, QTc, and spatial T vector amplitude, healthy men had 1.5–3 fold higher probability of having larger repolarization lability, as compared to healthy women (T vector amplitude variability index odds ratio 3.88(95%CI 1.4–11.1; P = 0.012).

Conclusions

Healthy men more likely than women have larger repolarization lability.     

Clinical,Immunological and Treatment-Related Factors Associated with Normalised CD4+/CD8+ T-Cell Ratio: Effect of Na?ve and Memory T-Cell Subsets

Background

Although effective antiretroviral therapy(ART) increases CD4+ T-cell count, responses to ART vary considerably and only a minority of patients normalise their CD4+/CD8+ ratio. Although retention of naïve CD4+ T-cells is thought to predict better immune responses, relationships between CD4+ and CD8+ T-cell subsets and CD4+/CD8+ ratio have not been well described.

Methods

A cross-sectional study in a cohort of ambulatory HIV+ patients. We used flow cytometry on fresh blood to determine expanded CD4+ and CD8+ T-cell subsets; CD45RO+CD62L+(central memory), CD45RO+CD62L-(effector memory) and CD45RO-CD62L+(naïve) alongside routine T-cell subsets(absolute, percentage CD4+ and CD8+ counts), HIVRNA and collected demographic and treatment data. Relationship between CD4+/CD8+ T-cell ratio and expanded T-cell subsets was determined using linear regression analysis. Results are median[IQR] and regression coefficients unless stated.

Results

We recruited 190 subjects, age 42(36–48) years, 65% male, 65.3% Caucasian, 91% on ART(52.6% on protease inhibitors), 78.4% with HIVRNA<40cps/ml and median ART duration 6.8(2.6–10.2) years. Nadir and current CD4+ counts were 200(112–309) and 465(335–607) cells/mm³ respectively. Median CD4+/CD8+ ratio was 0.6(0.4–1.0), with 26.3% of subjects achieving CD4+/CD8+ ratio>1. Of the expanded CD4+ T-cell subsets, 27.3(18.0–38.3)% were naïve, 36.8(29.0–40.0)% central memory and 27.4(20.0–38.5)% effector memory. Of the CD8+ T-cells subsets, 16.5(10.2–25.5)% were naïve, 19.9(12.7–26.6)% central memory and 41.0(31.8–52.5)% effector memory. In the multivariable adjusted analysis, total cumulative-ART exposure(+0.15,p = 0.007), higher nadir CD4+ count(+0.011,p<0.001) and higher %CD8+ naive T-cells(+0.0085,p<0.001) were associated with higher CD4+/CD8+ ratio, higher absolute CD8+ T-cell(-0.0044,p<0.001) and higher %CD4+ effector memory T-cells(-0.004,p = 0.0036) were associated with lower CD4+/CD8+ ratio. Those with CD4+/CD8+ ratio>1 had significantly higher median %CD8+ naive T-cells; 25.4(14.0–36.0)% versus 14.4(9.4–21.6)%, p<0.0001, but significantly lower absolute CD8+ count; 464(384.5–567) versus 765(603–1084) cells/mm³, p<0.001.

Conclusions

Study suggests important role for naïve CD8+ T-cell populations in normalisation of the immune response to HIV-infection. How these findings relate to persistent immune activation on ART requires further study.     

Community participation in Chagas disease vector surveillance: systematic review

Background

Vector control has substantially reduced Chagas disease (ChD) incidence. However, transmission by household-reinfesting triatomines persists, suggesting that entomological surveillance should play a crucial role in the long-term interruption of transmission. Yet, infestation foci become smaller and harder to detect as vector control proceeds, and highly sensitive surveillance methods are needed. Community participation (CP) and vector-detection devices (VDDs) are both thought to enhance surveillance, but this remains to be thoroughly assessed.

Methodology/Principal Findings

We searched Medline, Web of Knowledge, Scopus, LILACS, SciELO, the bibliographies of retrieved studies, and our own records. Data from studies describing vector control and/or surveillance interventions were extracted by two reviewers. Outcomes of primary interest included changes in infestation rates and the detection of infestation/reinfestation foci. Most results likely depended on study- and site-specific conditions, precluding meta-analysis, but we re-analysed data from studies comparing vector control and detection methods whenever possible. Results confirm that professional, insecticide-based vector control is highly effective, but also show that reinfestation by native triatomines is common and widespread across Latin America. Bug notification by householders (the simplest CP-based strategy) significantly boosts vector detection probabilities; in comparison, both active searches and VDDs perform poorly, although they might in some cases complement each other.

Conclusions/Significance

CP should become a strategic component of ChD surveillance, but only professional insecticide spraying seems consistently effective at eliminating infestation foci. Involvement of stakeholders at all process stages, from planning to evaluation, would probably enhance such CP-based strategies.     

Reproductive Senescence Blunts Response of Estrogen Receptor-α Expression to Estrogen Treatment in Rat Post-Ischemic Cerebral Microvessels

Background

Several studies demonstrate that estrogen treatment improves cerebral blood flow in ischemic brain regions of young ovariectomized (OVX) rats. Estrogen receptor-α (ER-α) may mediate estrogen’s beneficial actions via its effects on the cerebral microvasculature. However, estrogen-derived benefit may be attenuated in aged, reproductively senescent (RS) rats. Our goal was to determine the effects of aging, estrogen deprivation and estrogen repletion with oral conjugated estrogens (CE) on postischemic cerebral microvascular protein expression of ER-α and ER-β.

Methods

Fisher-344 (n = 37) female rats were randomly divided into the following groups: OVX, OVX CE-treated, RS untreated, and RS CE-treated. After 30 days pretreatment with CE (0.01 mg/kg) rats were subjected to15 min. transient global cerebral ischemia. Non-ischemic naïve, OVX and RS rats were used as controls. Expression of ER-α and ER-β in isolated cortical cerebral microvessels (20 to 100 µm in diameter) was assessed using Western blot and immunohistochemistry techniques.

Results

Age and reproductive status blunted nonischemic ER-α expression in microvessels of OVX rats (0.31±0.05) and RS rats (0.33±0.06) compared to naïve rats (0.45±0.02). Postischemic microvascular expression of ER-α in OVX rats (0.01±0.0) was increased by CE treatment (0.04±0.01). Expression of ER-α in microvessels of RS rats (0.03±0.02) was unaffected by CE treatment (0.01±0.02). Western blot data are presented as a ratio of ER-α or ER-β proteins to β-actin and. Oral CE treatment had no effect on ER-β expression in postischemic microvessels of OVX and RS rats. Statistical analysis was performed by One-Way ANOVA and a Newman-Keuls or Student’s post-hoc test.

Conclusion

Chronic treatment with CE increases ER-α but not ER-β expression in cerebral microvessels of OVX rats. Aging appears to reduce the normal ability of estrogen to increase ER-α expression in postischemic cerebral microvessels.     

Leukocyte Redistribution: Effects of Beta Blockers in Patients with Chronic Heart Failure

Background

Overproduction of pro-inflammatory cytokines is a well established factor in the progression of chronic heart failure (CHF). Changes in cellular immunity have not been widely studied, and the impact of standard medication is uncertain. Here we investigate whether a leukocyte redistribution occurs in CHF and whether this effect is influenced by beta-blocker therapy.

Methodology

We prospectively studied 75 patients with systolic CHF (age: 68±11 years, left ventricular ejection fraction 32±11%, New York Heart Association class 2.5±0.7) and 20 age-matched healthy control subjects (age: 63±10 years). We measured the response of cells to endotoxin exposure in vitro, analysed subsets of lymphocytes using flow cytometry, and assessed plasma levels of the pro-inflammatory markers interleukin 1, 6, tumor necrosis factor-α, and soluble tumor necrosis factor receptors 1 and 2.

Principal findings

While no differences in the number of leukocytes were noted between patients with CHF and healthy controls, we detected relative lymphopenia in patients with CHF (p<0.001 vs. control), mostly driven by reductions in T helper cells and B cells (both p<0.05). The number of neutrophils was increased (p<0.01). These effects were pronounced in patients who were beta-blocker naïve (32% of all patients with CHF). Increased plasma levels of soluble tumor necrosis receptor-1 correlated with the relative number of lymphocyte subsets.

Conclusions

In patients with CHF, we detected a redistribution of leukocyte subsets, i.e. an increase in neutrophils with relative lymphopenia. These effects were pronounced in patients who were beta-blocker naïve. The underlying mechanism remains to be elucidated.     

In Vitro Priming Recapitulates In Vivo HIV-1 Specific T Cell Responses,Revealing Rapid Loss of Virus Reactive CD4+ T Cells in Acute HIV-1 Infection

Background

The requirements for priming of HIV-specific T cell responses initially seen in infected individuals remain to be defined. Activation of T cell responses in lymph nodes requires cell-cell contact between T cells and DCs, which can give concurrent activation of T cells and HIV transmission.

Methodology

The study aim was to establish whether DCs pulsed with HIV-1 could prime HIV-specific T cell responses and to characterize these responses. Both infectious and aldrithiol-2 inactivated noninfectious HIV-1 were compared to establish efficiencies in priming and the type of responses elicited.

Findings

Our findings show that both infectious and inactivated HIV-1 pulsed DCs can prime HIV-specific responses from naïve T cells. Responses included several CD4⁺ and CD8⁺ T cell epitopes shown to be recognized in vivo by acutely and chronically infected individuals and some CD4⁺ T cell epitopes not identified previously. Follow up studies of acute and recent HIV infected samples revealed that these latter epitopes are among the earliest recognized in vivo, but the responses are lost rapidly, presumably through activation-induced general CD4⁺ T cell depletion which renders the newly activated HIV-specific CD4⁺ T cells prime targets for elimination.

Conclusion

Our studies highlight the ability of DCs to efficiently prime naïve T cells and induce a broad repertoire of HIV-specific responses and also provide valuable insights to the pathogenesis of HIV-1 infection in vivo.     

Modeling Disease Vector Occurrence when Detection Is Imperfect: Infestation of Amazonian Palm Trees by Triatomine Bugs at Three Spatial Scales

Background

Failure to detect a disease agent or vector where it actually occurs constitutes a serious drawback in epidemiology. In the pervasive situation where no sampling technique is perfect, the explicit analytical treatment of detection failure becomes a key step in the estimation of epidemiological parameters. We illustrate this approach with a study of Attalea palm tree infestation by Rhodnius spp. (Triatominae), the most important vectors of Chagas disease (CD) in northern South America.

Methodology/Principal Findings

The probability of detecting triatomines in infested palms is estimated by repeatedly sampling each palm. This knowledge is used to derive an unbiased estimate of the biologically relevant probability of palm infestation. We combine maximum-likelihood analysis and information-theoretic model selection to test the relationships between environmental covariates and infestation of 298 Amazonian palm trees over three spatial scales: region within Amazonia, landscape, and individual palm. Palm infestation estimates are high (40–60%) across regions, and well above the observed infestation rate (24%). Detection probability is higher (∼0.55 on average) in the richest-soil region than elsewhere (∼0.08). Infestation estimates are similar in forest and rural areas, but lower in urban landscapes. Finally, individual palm covariates (accumulated organic matter and stem height) explain most of infestation rate variation.

Conclusions/Significance

Individual palm attributes appear as key drivers of infestation, suggesting that CD surveillance must incorporate local-scale knowledge and that peridomestic palm tree management might help lower transmission risk. Vector populations are probably denser in rich-soil sub-regions, where CD prevalence tends to be higher; this suggests a target for research on broad-scale risk mapping. Landscape-scale effects indicate that palm triatomine populations can endure deforestation in rural areas, but become rarer in heavily disturbed urban settings. Our methodological approach has wide application in infectious disease research; by improving eco-epidemiological parameter estimation, it can also significantly strengthen vector surveillance-control strategies.     

Decreased interleukin 27 expression is associated with active uveitis in Beh?et’s disease

Instruction

Interleukin 27 (IL-27) is an important regulator of the proinflammatory T-cell response. In this study, we investigated its role in the pathogenesis of Behçet’s disease (BD).

Methods

IL-27 mRNA in peripheral blood mononuclear cells (PBMCs) was examined by performing RT-PCRs. Cytokine levels in sera or supernatants of PBMCs, naïve CD4⁺ T cells, dendritic cells (DCs) and DC/T cells were determined by enzyme-linked immunosorbent assay. We used RNA interference in naïve CD4⁺ T cells to study the role of interferon regulatory factor 8 (IRF8) in the inhibitory effect of IL-27 on Th17 cell differentiation. Flow cytometry was used to evaluate the frequency of IL-17- and interferon γ–producing T cells.

Results

The expression of IL-27p28 mRNA by PBMCs and IL-27 in the sera and supernatants of cultured PBMCs were markedly decreased in patients with active BD. A higher frequency of IL-17-producing CD4⁺ T (Th17) cells and increased IL-17 production under Th17 polarizing conditions were observed in patients with active BD. IL-27 significantly inhibited Th17 cell differentiation. Downregulation of IRF8 by RNA interference abrogated the suppressive effect of IL-27 on Th17 differentiation. IL-27 inhibited the production of IL-1β, IL-6 and IL-23, but promoted IL-10 production, by DCs. IL-27-treated DCs inhibited both the Th1 and Th17 cell responses.

Conclusions

The results of the present study suggest that a decreased IL-27 expression is associated with disease activity in BD patients. Low IL-27 expression may result in a higher Th1 and Th17 cell response and thereby promote the autoinflammatory reaction observed in BD. Manipulation of IL-27 may offer a new treatment modality for this disease.