Enhanced thromboxane synthesis during chronic reductions in uterine perfusion pressure in pregnant rats

BACKGROUND: The purpose of this study was to determine the role of thromboxane A2 (TXA2) in a conscious, chronically instrumented rat model of pregnancy-induced hypertension (PIH) produced by chronic reductions in uterine perfusion pressure (RUPP). METHODS: Mean arterial pressure (MAP), glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and 24-h urinary excretion of TXB2 (metabolite of TXA2) were determined in normal pregnant rats and RUPP pregnant rats. RESULTS: At day 20 of pregnancy, RUPP rats showed a significantly (P < .05) higher MAP (125 +/- 3 mm Hg v 100 +/- 2 mm Hg) as compared with normal pregnant controls. The elevation in arterial pressure in RUPP group was associated with a marked increase (P < .05) in the urinary concentration of TXB2 compared with normal pregnant group (3663 +/- 488 v 2646 +/- 257 pg/24 h). Baseline GFR (1.74 +/- 0.13 v 2.40 +/- 0.20 mL/min, respectively, P < .05) and ERPF (5.13 +/- 0.44 v 6.44 +/- 0.58 mL/min, respectively) were decreased in RUPP rats relative to pregnant controls. Infusion of a TX receptor antagonist, SQ 29,548 (2 mg/kg bolus plus 2 mg/kg per h infusion) had no significant effect on increased MAP in RUPP pregnant rats. Similarly, ERPF and GFR did not change during acute blockade of TXA2 receptors in this group. CONCLUSION: These findings suggest that enhanced production of TXA2 does not play a major role in mediating the hypertension and renal vasoconstriction produced by chronic RUPP in pregnant rats.     

Heparan sulfate on endothelial cells mediates the binding of Plasmodium falciparum-infected erythrocytes via the DBL1alpha domain of PfEMP1

Plasmodium falciparum may cause severe forms of malaria when excessive sequestration of infected and uninfected erythrocytes occurs in vital organs. The capacity of wild-type isolates of P falciparum-infected erythrocytes (parasitized red blood cells [pRBCs]) to bind glycosaminoglycans (GAGs) such as heparin has been identified as a marker for severe disease. Here we report that pRBCs of the parasite FCR3S1.2 and wild-type clinical isolates from Uganda adhere to heparan sulfate (HS) on endothelial cells. Binding to human umbilical vein endothelial cells (HUVECs) and to human lung endothelial cells (HLECs) was found to be inhibited by HS/heparin or enzymes that remove HS from cell surfaces. (35)S-labeled HS extracted from HUVECs bound directly to the pRBCs' membrane. Using recombinant proteins corresponding to the different domains of P falciparum erythrocyte membrane protein 1 (PfEMP1), we identified Duffy-binding-like domain-1alpha (DBL1alpha) as the ligand for HS. DBL1alpha bound in an HS-dependent way to endothelial cells and blocked the adherence of pRBCs in a dose-dependent manner. (35)S-labeled HS bound to DBL1alpha-columns and eluted as a distinct peak at 0.4 mM NaCl. (35)S-labeled chondroitin sulfate (CS) of HUVECs did not bind to PfEMP1 or to the pRBCs' membrane. Adhesion of pRBCs of FCR3S1.2 to platelet endothelial cell adhesion molecule-1 (PECAM-1)/CD31, mediated by the cysteine-rich interdomain region 1alpha (CIDR1alpha), was found be operative with, but independent of, the binding to HS. HS and the previously identified HS-like GAG on uninfected erythrocytes may act as coreceptors in endothelial and erythrocyte binding of rosetting parasites, causing excessive sequestration of both pRBCs and RBCs.     

Cockroach allergens: Environmental distribution and relationship to disease

Cockroach allergy has been recognized as an important cause of asthma. Exposure to high levels of cockroach allergens in the home is a major risk factor for symptoms in sensitized individuals. Previously identified allergens from Blatella germanica and Periplaneta americana include Bla g 2 (inactive aspartic proteinase), Bla g 4 (calycin), Bla g 5 (glutathione-S-transferase), Bla g 6 (troponin), the Group 1 cross-reactive allergens Bla g 1 and Per a 1, Per a 3 (arylphorin), and Per a 7 (tropomyosin). The primary site of cockroach allergen accumulation is the kitchen. However, lower levels of allergen can be found in bedding, on the bedroom floor, and in sofa dust. Strategies for decreasing exposure to cockroach have been investigated. The results suggest that a sustained decrease in cockroach allergen levels is difficult to accomplish, even after successful extermination of cockroach populations. The use of recombinant cockroach allergens may lead to the development of new approaches to asthma treatment in the future.     

Preeclampsia enhances neuroglial marker expression in umbilical cord Wharton's jelly-derived mesenchymal stem cells

Objective: The aim of the study was to compare the neuroglial phenotype of Wharton's jelly-derived mesenchymal stem cells (WJ-MSC) from pregnancies complicated with preeclampsia and gestational age (GA)-matched controls.

Methods: WJ-MSC were isolated from umbilical cords from both groups and analyzed for the cell surface expression of MSC markers and the gene and protein expression of neuroglial markers.

Results: All WJ cells were highly positive for the MSC markers CD105, CD90 and CD73, but negative for markers specific for hematopoietic (CD34) and immunological cells (CD45, CD14, CD19 and HLA-DR). WJ-MSC from both groups expressed neuroglial markers (MAP-2, GFAP, MBP, Musashi-1 and Nestin) at the mRNA and protein level. The protein expressions of neuronal (MAP-2) and oligodendrocytic (MBP) markers were significantly increased in WJ-MSC from preeclampsia versus GA-matched controls.

Conclusions: WJ-MSC from preeclamptic patients are possibly more committed to neuroglial differentiation through the activation of pathways involved both in the pathophysiology of the disease and in neurogenesis.     

Long-term treatment with deferiprone in a L1 veteran

We studied a patient with mild beta-thalassaemia major under treatment with the oral chelator deferiprone (DFP or L1) for about 10 yr (L1 veteran). Due to poor compliance with desferrioxamine, the patient started compassionate use of DFP at an age of 23 yr with a serum ferritin of 5200 microg/L. Monitoring iron overload by SQUID biosusceptometry revealed a dramatic decrease of liver iron concentrations from 4500 to 950 microg/g(liver) within 9.5 yr. A good clinical response to chelation treatment with DFP was observed together with an improvement of liver and cardiac function and a reduction in the hepatitis virus load.     

Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies Implicate ZIC3 and FOXF1 in Human VATER/VACTERL Association

The VATER/VACTERL association describes the combination of congenital anomalies including vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects. As mutations in ciliary genes were observed in diseases related to VATER/VACTERL, we performed targeted resequencing of 25 ciliary candidate genes as well as disease‐associated genes (FOXF1, HOXD13, PTEN, ZIC3) in 123 patients with VATER/VACTERL or VATER/VACTERL‐like phenotype. We detected no biallelic mutation in any of the 25 ciliary candidate genes; however, identified an identical, probably disease‐causing ZIC3 missense mutation (p.Gly17Cys) in four patients and a FOXF1 de novo mutation (p.Gly220Cys) in a further patient. In situ hybridization analyses in mouse embryos between E9.5 and E14.5 revealed Zic3 expression in limb and prevertebral structures, and Foxf1 expression in esophageal, tracheal, vertebral, anal, and genital tubercle tissues, hence VATER/VACTERL organ systems. These data provide strong evidence that mutations in ZIC3 or FOXF1 contribute to VATER/VACTERL.