Microcirculation abnormalities in patients with fibromyalgia – measured by capillary microscopy and laser fluxmetry

This unblinded preliminary case-control study was done to demonstrate functional and structural changes in the microcirculation of patients with primary fibromyalgia (FM). We studied 10 women (54.0 ± 3.7 years of age) with FM diagnosed in accordance with the classification criteria of the American College of Rheumatology, and controls in three groups (n = 10 in each group) – age-matched women who were healthy or who had rheumatoid arthritis or systemic scleroderma (SSc). All 40 subjects were tested within a 5-week period by the same investigators, using two noninvasive methods, laser fluxmetry and capillary microscopy. The FM patients were compared with the healthy controls (negative controls) and with rheumatoid arthritis patients and SSc patients (positive controls). FM patients had fewer capillaries in the nail fold (P < 0.001) and significantly more capillary dilatations (P < 0.05) and irregular formations (P < 0.01) than the healthy controls. Interestingly, the peripheral blood flow in FM patients was much less (P < 0.001) than in healthy controls but did not differ from that of SSc patients (P = 0.73). The data suggest that functional disturbances of microcirculation are present in FM patients and that morphological abnormalities may also influence their microcirculation.     

Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice

Ras proteins signal through direct interaction with a number of effector enzymes, including type I phosphoinositide (PI) 3-kinases. Although the ability of Ras to control PI 3-kinase has been well established in manipulated cell culture models, evidence for a role of the interaction of endogenous Ras with PI 3-kinase in normal and malignant cell growth in vivo has been lacking. Here we generate mice with mutations in the Pi3kca gene encoding the catalytic p110alpha isoform that block its interaction with Ras. Cells from these mice show proliferative defects and selective disruption of signaling from growth factors to PI 3-kinase. The mice display defective development of the lymphatic vasculature, resulting in perinatal appearance of chylous ascites. Most importantly, they are highly resistant to endogenous Ras oncogene-induced tumorigenesis. The interaction of Ras with p110alpha is thus required in vivo for certain normal growth factor signaling and for Ras-driven tumor formation.     

Novel object exploration in ravens (Corvus corax): effects of social relationships

Social context has been shown to encourage, or to delay object exploration and learning. This ambiguity might be due to factors such as social relationships and personality of the individuals involved. Here, we investigated in ravens (Corvus corax) individuals' consistency in response to novel objects over development and across contexts: alone versus social. In the social setting we focussed on the effects of social relationships on social facilitation during the approach to novel objects. We tested 11 hand-raised ravens with novel objects individually at three and six months of age and in dyadic combinations at six months of age. Individuals were consistent over development and contexts in their response to different novel objects. Birds joined siblings faster to approach novel objects than non-siblings. They also spent more time sitting close to siblings than to non-siblings. In male-male dyads but not in female-female dyads, subordinates approached the novel objects significantly faster than dominant birds. In contrast, dominant males were the first to approach the novel objects in mixed-sex combinations. Hence, the effect of social context seems to depend on the social relationships towards the companions and on the combination of the sexes.     

TLR1, 2, 4, 6 and 9 Variants Associated with Tuberculosis Susceptibility: A Systematic Review and Meta-Analysis

Background

Studies investigating the influence of toll-like receptor (TLR) polymorphisms and tuberculosis susceptibility have yielded varying and often contradictory results in different ethnic groups. A meta-analysis was conducted to investigate the relationship between TLR variants and susceptibility to tuberculosis, both across and within specific ethnic groups.

Methods

An extensive database search was performed for studies investigating the relationship between TLR and tuberculosis (TB) susceptibility. Data was subsequently extracted from included studies and statistically analysed.

Results

32 articles involving 18907 individuals were included in this meta-analysis, and data was extracted for 14 TLR polymorphisms. Various genetic models were employed. An increased risk of TB was found for individuals with the TLR2 rs3804100 CC and the TLR9 rs352139 GA and GG genotypes, while decreased risk was identified for those with the AG genotype of TLR1 rs4833095. The T allele of TLR6 rs5743810 conferred protection across all ethnic groups. TLR2 rs5743708 subgroup analysis identified the A allele to increase susceptibility to TB in the Asian ethnic group, while conferring protection in the Hispanic group. The T allele of TLR4 rs4986791 was also found to increase the risk of TB in the Asian subgroup. All other TLR gene variants investigated were not found to be associated with TB in this meta-analysis.

Discussion

Although general associations were identified, most TLR variants showed no significant association with TB, indicating that additional studies investigating a wider range of pattern recognition receptors is required to gain a better understanding of this complex disease.     

Specific Acquisition of Functional CD59 but Not CD46 or CD55 by Hepatitis C Virus

Viruses of different families encode for regulators of the complement system (RCAs) or acquire such RCAs from the host to get protection against complement-mediated lysis (CML). As hepatitis C virus (HCV) shares no genetic similarity to any known RCA and is detectable at high titers in sera of infected individuals, we investigated whether HCV has adapted host-derived RCAs to resist CML. Here we report that HCV selectively incorporates CD59 while neither CD55, nor CD46 are associated with the virus. The presence of CD59 was shown by capture assays using patient- and cell culture-derived HCV isolates. Association of CD59 with HCV was further confirmed by Western blot analysis using purified viral supernatants from infected Huh 7.5 cells. HCV captured by antibodies specific for CD59 remained infectious for Huh 7.5 cells. In addition, blocking of CD59 in the presence of active complement reduced the titer of HCV most likely due to CML. HCV produced in CD59 knock-down cells were more significantly susceptible to CML compared to wild type virus, but neither replication, assembly nor infectivity of the virus seemed to be impaired in the absence of CD59. In summary our data indicate that HCV incorporates selectively CD59 in its envelope to gain resistance to CML in serum of infected individuals.     

Essential role of the coxsackie- and adenovirus receptor (CAR) in development of the lymphatic system in mice

The coxsackie- and adenovirus receptor (CAR) is a cell adhesion molecule predominantly associated with epithelial tight junctions in adult tissues. CAR is also expressed in cardiomyocytes and essential for heart development up to embryonic day 11.5, but not thereafter. CAR is not expressed in vascular endothelial cells but was recently detected in neonatal lymphatic vessels, suggesting that CAR could play a role in the development of the lymphatic system. To address this, we generated mice carrying a conditional deletion of the CAR gene (Cxadr) and knocked out CAR in the mouse embryo at different time points during post-cardiac development. Deletion of Cxadr from E12.5, but not from E13.5, resulted in subcutaneous edema, hemorrhage and embryonic death. Subcutaneous lymphatic vessels were dilated and structurally abnormal with gaps and holes present at lymphatic endothelial cell-cell junctions. Furthermore, lymphatic vessels were filled with erythrocytes showing a defect in the separation between the blood and lymphatic systems. Regionally, erythrocytes leaked out into the interstitium from leaky lymphatic vessels explaining the hemorrhage detected in CAR-deficient mouse embryos. The results show that CAR plays an essential role in development of the lymphatic vasculature in the mouse embryo by promoting appropriate formation of lymphatic endothelial cell-cell junctions.     

Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos

Lymphatic vessels play an important role in the regulation of tissue fluid balance, immune responses, and fat adsorption and are involved in diseases including lymphedema and tumor metastasis. Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3) is necessary for development of the blood vasculature during early embryogenesis, but later, VEGFR-3 expression becomes restricted to the lymphatic vasculature. We analyzed mice deficient in both of the known VEGFR-3 ligands, VEGF-C and VEGF-D. Unlike the Vegfr3^−/− embryos, the Vegfc^−/−; Vegfd^−/− embryos displayed normal blood vasculature after embryonic day 9.5. Deletion of Vegfr3 in the epiblast, using keratin 19 (K19) Cre, resulted in a phenotype identical to that of the Vegfr3^−/− embryos, suggesting that this phenotype is due to defects in the embryo proper and not in placental development. Interestingly, the Vegfr3^neo hypomorphic mutant mice carrying the neomycin cassette between exons 1 and 2 showed defective lymphatic development. Overexpression of human or mouse VEGF-D in the skin, under the K14 promoter, rescued the lymphatic hypoplasia of the Vegfc^+/− mice in the K14-VEGF-D; Vegfc^+/− compound mice, suggesting that VEGF-D is functionally redundant with VEGF-C in the stimulation of developmental lymphangiogenesis. Our results suggest VEGF-C- and VEGF-D-independent functions for VEGFR-3 in the early embryo.