The relation between cartilage biomarkers (C2C,C1,2C,CS846, and CPII) and the long-term outcome of rheumatoid arthritis patients within the CAMERA trial

Introduction  

The aim of this study was to investigate whether serum biomarker levels of C2C, C1,2C, CS846, and CPII can predict the long-term course of disease activity and radiographic progression early in the disease course of rheumatoid arthritis (RA).     

Complement activation: a critical mediator of adverse fetal outcomes in placental malaria?

Malaria infection is a significant risk factor for low birth weight outcomes in pregnancy. Despite efforts to define the molecular mechanisms that cause low birth weight as a result of intrauterine growth restriction, the roles of inflammation and mononuclear cells in the process are incompletely understood. Data from adverse pregnancy outcomes in humans and from murine models of pathological pregnancies suggest that C5a could be an important upstream regulator of placental angiogenesis, and excessive C5a could lead to functional placental insufficiency by impairing adequate vascularization of the placenta. Based on recent evidence, we hypothesize that complement factor C5a is a central initiator of poor birth outcomes associated with placental malaria by promoting mononuclear cell migration, activation and dysregulated angiogenesis.     

Finding fossils in new ways: an artificial neural network approach to predicting the location of productive fossil localities

Chance and serendipity have long played a role in the location of productive fossil localities by vertebrate paleontologists and paleoanthropologists. We offer an alternative approach, informed by methods borrowed from the geographic information sciences and using recent advances in computer science, to more efficiently predict where fossil localities might be found. Our model uses an artificial neural network (ANN) that is trained to recognize the spectral characteristics of known productive localities and other land cover classes, such as forest, wetlands, and scrubland, within a study area based on the analysis of remotely sensed (RS) imagery. Using these spectral signatures, the model then classifies other pixels throughout the study area. The results of the neural network classification can be examined and further manipulated within a geographic information systems (GIS) software package. While we have developed and tested this model on fossil mammal localities in deposits of Paleocene and Eocene age in the Great Divide Basin of southwestern Wyoming, a similar analytical approach can be easily applied to fossil-bearing sedimentary deposits of any age in any part of the world. We suggest that new analytical tools and methods of the geographic sciences, including remote sensing and geographic information systems, are poised to greatly enrich paleoanthropological investigations, and that these new methods should be embraced by field workers in the search for, and geospatial analysis of, fossil primates and hominins.     

Combinations of host biomarkers predict mortality among Ugandan children with severe malaria: a retrospective case-control study

Background

Severe malaria is a leading cause of childhood mortality in Africa. However, at presentation, it is difficult to predict which children with severe malaria are at greatest risk of death. Dysregulated host inflammatory responses and endothelial activation play central roles in severe malaria pathogenesis. We hypothesized that biomarkers of these processes would accurately predict outcome among children with severe malaria.

Methodology/Findings

Plasma was obtained from children with uncomplicated malaria (n = 53), cerebral malaria (n = 44) and severe malarial anemia (n = 59) at time of presentation to hospital in Kampala, Uganda. Levels of angiopoietin-2, von Willebrand Factor (vWF), vWF propeptide, soluble P-selectin, soluble intercellular adhesion molecule-1 (ICAM-1), soluble endoglin, soluble FMS-like tyrosine kinase-1 (Flt-1), soluble Tie-2, C-reactive protein, procalcitonin, 10 kDa interferon gamma-induced protein (IP-10), and soluble triggering receptor expressed on myeloid cells-1 (TREM-1) were determined by ELISA. Receiver operating characteristic (ROC) curve analysis was used to assess predictive accuracy of individual biomarkers. Six biomarkers (angiopoietin-2, soluble ICAM-1, soluble Flt-1, procalcitonin, IP-10, soluble TREM-1) discriminated well between children who survived severe malaria infection and those who subsequently died (area under ROC curve>0.7). Combinational approaches were applied in an attempt to improve accuracy. A biomarker score was developed based on dichotomization and summation of the six biomarkers, resulting in 95.7% (95% CI: 78.1–99.9) sensitivity and 88.8% (79.7–94.7) specificity for predicting death. Similar predictive accuracy was achieved with models comprised of 3 biomarkers. Classification tree analysis generated a 3-marker model with 100% sensitivity and 92.5% specificity (cross-validated misclassification rate: 15.4%, standard error 4.9%).

Conclusions

We identified novel host biomarkers of pediatric severe and fatal malaria (soluble TREM-1 and soluble Flt-1) and generated simple biomarker combinations that accurately predicted death in an African pediatric population. While requiring validation in further studies, these results suggest the utility of combinatorial biomarker strategies as prognostic tests for severe malaria.     

Circulating soluble endoglin levels in pregnant women in Cameroon and Malawi--associations with placental malaria and fetal growth restriction

Placental infections with Plasmodium falciparum are associated with fetal growth restriction resulting in low birth weight (LBW). The mechanisms that mediate these effects have yet to be completely described; however, they are likely to involve inflammatory processes and dysregulation of angiogenesis. Soluble endoglin (sEng), a soluble receptor of transforming growth factor (TGF)-β previously associated with preeclampsia in pregnant women and with severe malaria in children, regulates the immune system and influences angiogenesis. We hypothesized that sEng may play a role in development of LBW associated with placental malaria (PM). Plasma levels of sEng were measured in women (i) followed prospectively throughout pregnancy in Cameroon (n = 52), and (ii) in a case-control study at delivery in Malawi (n = 479). The relationships between sEng levels and gravidity, peripheral and placental parasitemia, gestational age, and adverse outcomes of PM including maternal anemia and LBW were determined. In the longitudinal cohort from Cameroon, 28 of 52 women (54%) experienced at least one malaria infection during pregnancy. In Malawi we enrolled two aparasitemic gravidity-matched controls for every case with PM. sEng levels varied over the course of gestation and were significantly higher in early and late gestation as compared to delivery (P<0.006 and P<0.0001, respectively). Circulating sEng levels were higher in primigravidae than multigravidae from both Cameroon and Malawi, irrespective of malarial infection status (p<0.046 and p<0.001, respectively). Peripheral parasitemia in Cameroonian women and PM in Malawian women were each associated with elevated sEng levels following correction for gestational age and gravidity (p = 0.006 and p = 0.033, respectively). Increased sEng was also associated with the delivery of LBW infants in primigravid Malawian women (p = 0.017); the association was with fetal growth restriction (p = 0.003) but not pre-term delivery (p = 0.286). Increased circulating maternal sEng levels are associated with P. falciparum infection in pregnancy and with fetal growth restriction in primigravidae with PM.     

Performance characteristics of combinations of host biomarkers to identify women with occult placental malaria: a case-control study from Malawi

Background

Because of its propensity to sequester in the placental intervillous space, Plasmodium falciparum can evade detection by peripheral smear in women with placental malaria (PM). We evaluated host biomarkers as potential indicators of occult PM infections.

Methods and Findings

Using a case-control design, we evaluated the ability of biomarkers to identify PM in the absence of circulating peripheral parasites (n = 24) compared to placental smear-negative controls (n = 326). We measured levels of biomarkers (C3a, C5a, CRP, angiopoietin-1, angiopoietin-2, sTie-2, sEndoglin, VEGF, sFlt-1, tissue factor, and leptin) in maternal peripheral plasma at delivery. Using ROC curve analysis, we assessed the ability of clinical parameters and biomarkers to accurately detect PM infections identified by placental smear. We show that decreases in sFlt-1 and leptin and increases in CRP were associated with occult PM infections (p<0.01) and correlated with placental parasitaemia (p<0.01). Individually, all markers had moderate ability to diagnose occult PM infections with areas under the ROC between 0.62 and 0.72. In order to improve diagnostic performance, we generated simple scoring systems to identify PM infections using either a clinical score (0–2), a biomarker score (0–3) or a clinical plus biomarker score (0–5). The combinatorial model that incorporated both clinical parameters and biomarkers had an area under curve (AUC) of 0.85 (95% CI, 0.81-0.89), which was significantly better at identifying occult PM infections than the clinical score alone (p = 0.001).

Conclusion

These data suggest that host biomarkers in the maternal peripheral blood may improve the detection of PM in the absence of peripheral parasitaemia.     

Faster Rubisco is the key to superior nitrogen-use efficiency in NADP-malic enzyme relative to NAD-malic enzyme C4 grasses

In 27 C4 grasses grown under adequate or deficient nitrogen (N) supplies, N-use efficiency at the photosynthetic (assimilation rate per unit leaf N) and whole-plant (dry mass per total leaf N) level was greater in NADP-malic enzyme (ME) than NAD-ME species. This was due to lower N content in NADP-ME than NAD-ME leaves because neither assimilation rates nor plant dry mass differed significantly between the two C4 subtypes. Relative to NAD-ME, NADP-ME leaves had greater in vivo (assimilation rate per Rubisco catalytic sites) and in vitro Rubisco turnover rates (k(cat); 3.8 versus 5.7 s(-1) at 25 degrees C). The two parameters were linearly related. In 2 NAD-ME (Panicum miliaceum and Panicum coloratum) and 2 NADP-ME (Sorghum bicolor and Cenchrus ciliaris) grasses, 30% of leaf N was allocated to thylakoids and 5% to 9% to amino acids and nitrate. Soluble protein represented a smaller fraction of leaf N in NADP-ME (41%) than in NAD-ME (53%) leaves, of which Rubisco accounted for one-seventh. Soluble protein averaged 7 and 10 g (mmol chlorophyll)(-1) in NADP-ME and NAD-ME leaves, respectively. The majority (65%) of leaf N and chlorophyll was found in the mesophyll of NADP-ME and bundle sheath of NAD-ME leaves. The mesophyll-bundle sheath distribution of functional thylakoid complexes (photosystems I and II and cytochrome f) varied among species, with a tendency to be mostly located in the mesophyll. In conclusion, superior N-use efficiency of NADP-ME relative to NAD-ME grasses was achieved with less leaf N, soluble protein, and Rubisco having a faster k(cat).     

Preferential transmission of paternal alleles at risk genes in attention-deficit/hyperactivity disorder

Family, twin, and adoption studies have demonstrated a significant genetic contribution to the etiology of attention-deficit/hyperactivity disorder (ADHD). Pharmacological, neuroimaging, and animal-model findings suggest imbalances in monoaminergic (dopaminergic, serotonergic, and noradrenergic) neurotransmission in ADHD. We have examined monoaminergic candidate genes for possible genetic association with ADHD in the Irish population, focusing particularly on genes of the dopaminergic and serotonergic systems. We have observed that several of these genes are associated with ADHD, including DAT1, DBH, DRD4, DRD5, and 5HT1B. Here, we present what appears to be a systematic overtransmission of paternal alleles at candidate genes associated with ADHD. For the nine genes included in the analysis, the overall odds ratio for paternal transmission was 2, compared with 1.3 for maternal transmission (paternal vs. maternal chi 2=9.6; P=.0019). Transmission to females, from either parent, was significantly stronger than to males. Possible reasons for this preferential transmission include imprinting and ascertainment bias, although results of further analyses show that the latter is unlikely.     

Effects of leaf and branch removal on carbon assimilation and stem wood density of Eucalyptus grandis seedlings

The rate of leaf CO₂ assimilation (A _l) and leaf area determine the rate of canopy CO₂ assimilation (A _c) can be thought proportional to assimilate supply for growth and structural requirements of plants. Partitioning of biomass within plants and anatomy of cells within stems can determine how assimilate supply affects both stem growth and wood density. We examined the response of stem growth and wood density to reduced assimilate supply by pruning leaf area. Removing 42% of the leaf area of Eucalyptus grandis Hill ex Maiden seedlings did not stimulate leaf-level photosynthesis (A _l) or stomatal conductance, contrary to some previous studies. Canopy-level photosynthesis (A _c) was reduced by 41% immediately after pruning but due almost solely to continued production of leaves, and was only 21% lower 3 weeks later. Pruning consequently reduced seedling biomass by 24% and stem biomass by 18%. These reductions in biomass were correlated with reduced A _c. Pruning had no effect on stem height or diameter and reduced wood density to 338 kg m⁻³ compared to 366 kg m⁻³ in control seedlings. The lower wood density in pruned seedlings was associated with a 10% reduction in the thickness of fibre cell walls, and as fibre cell diameter was invariant to pruning, this resulted in smaller lumen diameters. These anatomical changes increased the ratio of cross-sectional area of lumen to area cell wall material within the wood. The results suggest changes to wood density following pruning of young eucalypt trees may be independent of tree volume and of longer duration.