Loss of placental growth factor protects mice against vascular permeability in pathological conditions

Vascular leakage contributes to numerous disorders but only a limited number of molecules have been demonstrated to modulate permeability of the vessel wall. The vascular endothelial growth factor (VEGF) is a potent inducer of vascular leakage. Previous studies demonstrated that exogenous administration of placental growth factor (PlGF), a homologue of VEGF, stimulates vascular permeability but the role of endogenous PlGF in plasma extravasation during pathological conditions remains unknown. We recently generated PlGF deficient (PlGF(-/-)) mice and demonstrated that loss of PlGF impaired pathological angiogenesis by attenuating the response to VEGF. Here, we demonstrate that absence of PlGF reduces vascular leakage induced by skin wounding, allergens, and neurogenic inflammation. These findings suggest that inhibition of PlGF might be an attractive tool to reduce vascular leakage in various diseases.     

Coping with twins discordant for intellectual disabilities: the mothers' view.

In this exploratory study of 15 families with a twin-pair, of which one has an intellectual disability, the Nijmegen Questionnaire on Childrearing Situations (NQCS) was used to ask mothers about their perceptions and experiences of parenting. An interview with the mothers was done to understand the initial stages of coping with this double problem: educating a twin-pair and a child with an intellectual disability. Four groups of mothers were identified, depending on whether they accepted the intellectual disability of their child and/or whether they perceived their children as a twin-pair or not. Finally, some critical questions for further research and management were formulated.     

Multimodal biomarker discovery for active Onchocerca volvulus infection

The neglected tropical disease onchocerciasis, or river blindness, is caused by infection with the filarial nematode Onchocerca volvulus. Current estimates indicate that 17 million people are infected worldwide, the majority of them living in Africa. Today there are no non-invasive tests available that can detect ongoing infection, and that can be used for effective monitoring of elimination programs. In addition, to enable pharmacodynamic studies with novel macrofilaricide drug candidates, surrogate endpoints and efficacy biomarkers are needed but are non-existent. We describe the use of a multimodal untargeted mass spectrometry-based approach (metabolomics and lipidomics) to identify onchocerciasis-associated metabolites in urine and plasma, and of specific lipid features in plasma of infected individuals (O. volvulus infected cases: 68 individuals with palpable nodules; lymphatic filariasis cases: 8 individuals; non-endemic controls: 20 individuals). This work resulted in the identification of elevated concentrations of the plasma metabolites inosine and hypoxanthine as biomarkers for filarial infection, and of the urine metabolite cis-cinnamoylglycine (CCG) as biomarker for O. volvulus. During the targeted validation study, metabolite-specific cutoffs were determined (inosine: 34.2 ng/ml; hypoxanthine: 1380 ng/ml; CCG: 29.7 ng/ml) and sensitivity and specificity profiles were established. Subsequent evaluation of these biomarkers in a non-endemic population from a different geographical region invalidated the urine metabolite CCG as biomarker for O. volvulus. The plasma metabolites inosine and hypoxanthine were confirmed as biomarkers for filarial infection. With the availability of targeted LC-MS procedures, the full potential of these 2 biomarkers in macrofilaricide clinical trials, MDA efficacy surveys, and epidemiological transmission studies can be investigated.     

Microarray analysis of 1alpha,25-dihydroxyvitamin D3-treated MC3T3-E1 cells

The active form of Vitamin D, 1alpha,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], demonstrates potent antiproliferative actions on normal as well as on malignant cell types by blocking the transition from the G1- to the S-phase of the cell cycle. Key target genes for 1,25-(OH)(2)D(3) in this non-classic effect remain largely unknown. Therefore, this study aims to identify genes that, through changes in expression after 1,25-(OH)(2)D(3) treatment, contribute to the observed antiproliferative effect. cDNA microarrays containing 4600 genes were used to investigate changes in gene expression in MC3T3-E1 mouse osteoblasts at 6 and at 12h after treatment with 1,25-(OH)(2)D(3) (10(-8)M), preceding (6h) or coinciding with (12h) the G1/S block in these cells. Approximately one fifth of the genes that were significantly down-regulated after a 12h incubation period with 1,25-(OH)(2)D(3) were genes involved in the DNA replication process, a basic process for cell growth that starts at the end of G1-phase and continues in S-phase. Down-regulation of these genes by 1,25-(OH)(2)D(3) was confirmed by quantitative RT-PCR in MC3T3-E1. In conclusion, cDNA microarrays revealed that treatment of MC3T3-E1 cells with 1,25-(OH)(2)D(3) resulted in the down-regulation of DNA replication genes in parallel with the observed G1/S-arrest.     

Welfare, health, and hygiene of laying hens housed in furnished cages and in alternative housing systems

The aim of this review was to compare welfare, health, and hygienic status of laying hens housed in furnished cages and in alternative systems. In alternative systems (floor housing and aviaries), birds have more freedom of movement and a more complex environment than in furnished cages. However, housing birds in much larger flocks in alternative systems leads to an increased risk of feather-pecking. Furthermore, air quality can be poorer in alternative systems than in furnished cages. This can affect health and hygienic status. There are only limited data on a direct comparison between furnished cages and alternative systems. Therefore, there is a need for an on-farm comparison of welfare, health, and hygienic status in these systems.     

Actual and Preferred Place of Death of Home-Dwelling Patients in Four European Countries: Making Sense of Quality Indicators

Background

Dying at home and dying at the preferred place of death are advocated to be desirable outcomes of palliative care. More insight is needed in their usefulness as quality indicators. Our objective is to describe whether “the percentage of patients dying at home” and “the percentage of patients who died in their place of preference” are feasible and informative quality indicators.

Methods and Findings

A mortality follow-back study was conducted, based on data recorded by representative GP networks regarding home-dwelling patients who died non-suddenly in Belgium (n = 1036), the Netherlands (n = 512), Italy (n = 1639) or Spain (n = 565). “The percentage of patients dying at home” ranged between 35.3% (Belgium) and 50.6% (the Netherlands) in the four countries, while “the percentage of patients dying at their preferred place of death” ranged between 67.8% (Italy) and 86.0% (Spain). Both indicators were strongly associated with palliative care provision by the GP (odds ratios of 1.55–13.23 and 2.30–6.63, respectively). The quality indicator concerning the preferred place of death offers a broader view than the indicator concerning home deaths, as it takes into account all preferences met in all locations. However, GPs did not know the preferences for place of death in 39.6% (the Netherlands) to 70.3% (Italy), whereas the actual place of death was known in almost all cases.

Conclusion

GPs know their patients’ actual place of death, making the percentage of home deaths a feasible indicator for collection by GPs. However, patients’ preferred place of death was often unknown to the GP. We therefore recommend using information from relatives as long as information from GPs on the preferred place of death is lacking. Timely communication about the place where patients want to be cared for at the end of life remains a challenge for GPs.     

Coreceptor and cytokine concentrations may not explain differences in disease progression observed in HIV-1 clade A and D infected Ugandans

Background

The use of cellular coreceptors and modulation of cytokine concentrations by HIV to establish a productive infection is well documented. However, it is unknown whether the expression of these proteins affects the course of HIV clade A and D disease, reported to have different progression rates.

Methodology/Principal Findings

We investigated whether the number of CD4⁺ T-cells expressing CCR5 or CXCR4, the density of these coreceptors and concentrations of specific immune proteins linked to HIV pathogenesis vary between individuals infected with HIV clade A or D. We undertook additional analyses stratifying participants by early (CD4>500 cells/µl) or late (CD4<200 cells/µl) disease stage. Whole blood samples were taken from 50 HIV-1 infected individuals drawn from cohorts in rural south-west Uganda. Late stage participants had less than half the number of CD4⁺/CCR5⁺ T-cells (p = 0.0113) and 5.6 times fewer CD4⁺/CXCR4⁺ cells (p<0.0001) than early stage participants. There was also a statistically significant difference in the density of CXCR4 on CD4⁺ cells between clade A and D infected early stage participants (142 [A] vs 84 [D]; p = 0.0146). Across all participants we observed significantly higher concentration of Th₁ cytokines compared to Th₂ (66.4 vs 23.8 pg/ml; p<0.0001). Plasma concentrations of IFNγ and IL-2 were 1.8 and 2.4 fold lower respectively in Late-D infected participants compared to Late-A participants. MIP-1β levels also decreased from 118.0 pg/ml to 47.1 pg/ml (p = 0.0396) as HIV disease progressed.

Conclusions/Significance

We observed specific alterations in the abundance of CD4⁺/CCR5⁺ and CD4⁺/CXCR4⁺ T-cells, and concentrations of immune proteins across different HIV clades and as infection progresses. Our results suggest that these changes are unlikely to explain the observed differences in disease progression between subtype A and D infections. However, our observations further the understanding of the natural progression of non-clade B HIV infection and how the virus adapts to exploit the host environment.