Role of thromboxane A2 in the induction of apoptosis of immature thymocytes by lipopolysaccharide

Lipopolysaccharide (LPS) causes apoptotic deletion of CD4(+) CD8(+) thymocytes, a phenomenon that has been linked to immune dysfunction and poor survival during sepsis. Given the abundance of thromboxane-prostanoid (TP) receptors in CD4(+) CD8(+) thymocytes and in vitro evidence that thromboxane A(2) (TXA(2)) causes apoptosis of these cells, we tested whether enhanced generation of TXA(2) plays a role in LPS-induced thymocyte apoptosis. Mice injected with 50 micro LPS intraperitoneally displayed a marked increase in generation of TXA(2) and prostaglandin E(2) in the thymus as well as apoptotic deletion of CD4(+) CD8(+) thymocytes. Administration of indomethacin or rofecoxib inhibited prostanoid synthesis but did not affect thymocyte death. In contrast, thymocyte apoptosis in response to LPS was significantly attenuated in TP-deficient mice. These studies indicate that TXA(2) mediates a portion of apoptotic thymocyte death caused by LPS. The absence of an effect of global inhibition of prostanoid synthesis suggests a complex role for prostanoids in this model.     

Follicular dendritic cells (FDC) in retroviral infection: host/pathogen perspectives

Summary: Follicular dendritic cells (FDC) are found in the follicles of virtually all secondary lymphoid tissues. In health, these cells trap and retain antigens (Ag) in the form of immune complexes and preserve them for months in their native conformation. FDC thus serve as a long-term repository of extracellular Ag important for induction and maintenance of memory responses. In retroviral infection. FDC trap and retain large numbers of retroviral particles with profound effects on FDC. FDC-trapped retrovirus induces follicular hyperplasia, and conventional Ag trapped prior to infection are lost and new Ag cannot be trapped. Concomitantly, antibody-forming cells (AFC) specific for Ag lost from FDC decrease follow I by loss of specific serum antibody (Ab). Eventually, FDC die and follicular lysis occurs. From the pathogen perspective, binding to FDC is remarkably beneficial, bringing together virus and activated target cells that are highly susceptible to infection. Furthermore, FDC permit HIV to infect surrounding cells even in the presence of a vast excess of neutralizing Ab. Preliminary data suggest that FDC maintain virus infectivity - even when the virus cannot replicate. Thus retrovirus infection monopolizes FDC networks, thereby transforming the FDC Ag repository into a highly infectious retroviral reservoir.     

Anatomical variation in the rudimentary horns of a unicornuate uterus: implications for laparoscopic surgery

A case of laparoscopic excision of a rudimentary horn is presented. The anatomical features of this case are contrasted with others in the published literature. A 23 year old nulligravida presented with severe dysmenorrhoea and a pelvic mass. At laparoscopy a unicornuate uterus with a rudimentary horn was identified. The patient had stage III endometriosis. The rudimentary horn was attached to the unicornuate uterus by a band of tissue. The blood supply was identified within this band of tissue. The rudimentary horn was removed laparoscopically with no complications. There are two anatomical variations in the attachment of the rudimentary horn to the unicornuate uterus. Knowledge of both types is important to avoid complications such as bleeding and possible compromise of myometrial wall thickness.      

Contrasting Actions of Selective Inhibitors of Angiopoietin-1 and Angiopoietin-2 on the Normalization of Tumor Blood Vessels

Angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) have complex actions in angiogenesis and vascular remodeling due to their effects on Tie2 receptor signaling. Ang2 blocks Ang1-mediated activation of Tie2 in endothelial cells under certain conditions but is a Tie2 receptor agonist in others. We examined the effects of selective inhibitors of Ang1 (mL4-3) or Ang2 (L1-7[N]), alone or in combination, on the vasculature of human Colo205 tumors in mice. The Ang2 inhibitor decreased the overall abundance of tumor blood vessels by reducing tumor growth and keeping vascular density constant. After inhibition of Ang2, tumor vessels had many features of normal blood vessels (normalization), as evidenced by junctional accumulation of vascular endothelial-cadherin, junctional adhesion molecule-A, and platelet/endothelial cell adhesion molecule-1 in endothelial cells, increased pericyte coverage, reduced endothelial sprouting, and remodeling into smaller, more uniform vessels. The Ang1 inhibitor by itself had little noticeable effect on the tumor vasculature. However, when administered with the Ang2 inhibitor, the Ang1 inhibitor prevented tumor vessel normalization, but not the reduction in tumor vascularity produced by the Ang2 inhibitor. These findings are consistent with a model whereby inhibition of Ang2 leads to normalization of tumor blood vessels by permitting the unopposed action of Ang1, but decreases tumor vascularity primarily by blocking Ang2 actions.Solid tumors require angiogenesis—the formation of new blood vessels from existing vessels—for survival, growth, and metastasis.¹ Tumor vessels are structurally and functionally abnormal.^1,2 They exist in a constantly dynamic state of sprout formation, proliferation, remodeling, or regression. Structurally, tumor vessels tend to be leaky and tortuous, lacking the hierarchical arrangement of arterioles, capillaries, and venules.² Pericytes that attach to and help stabilize normal vessels are loosely associated with the endothelium of tumor vessels.^1,2 These vascular abnormalities result in impaired and heterogeneous blood flow. In tumors, angiogenesis inhibitors not only cause vessel regression or retardation of vessel growth, but they can also induce vascular normalization.^1,2,3The complicated regulation of angiogenesis and vascular maturation involves multiple signaling cascades driven by endothelial-cell specific growth factors and their receptors. One of these, vascular endothelial growth factor (VEGF) has been extensively studied,⁴ but angiopoietins and other growth factors are also involved.^5,6 The angiopoietin ligands (Ang1 and Ang2) and their receptor (Tie2) have essential roles in vascular development.^7,8 Ang1 is produced by vascular mural cells, pericytes, and certain other cells, whereas Ang2 and Tie2 are expressed primarily by endothelial cells.Angiogenesis and vascular remodeling involve a complex coordination of Ang1 and Ang2 signaling through Tie2.⁵ The traditional view of Ang1 and Ang2 signaling is that the growth factors have opposing effects on Tie2 receptor activation: Ang1 binds to Tie2 to promote vascular maturation and integrity, whereas Ang2 acts as a naturally occurring antagonist of Ang1.^7,8,9,10,11 Although a number of studies indicate an antagonistic role of Ang2, recent studies have shown that Ang2 can have an agonistic role depending on the experimental environment.^12,13,14,15 If expressed at high concentrations or for long durations in cultured endothelial cells, Ang2—like Ang1—can induce Tie2 receptor phosphorylation.^13,16 Ang2 can also promote chemotaxis, tube formation, migration, and sprouting of endothelial cells in the absence of Ang1,¹⁴ which support the view that Ang2 actions are context- dependent.Normalization of tumor vascular morphology and function has been demonstrated with numerous angiogenesis inhibitors.^1,17,18 Ang1 and Ang2 regulate vascular maturation and integrity during development; however, their effects on normalization of tumor vessels are not known. Tumors grown in mice lacking Ang2 have a more mature vascular phenotype, but it is not known whether Ang1 plays a role.¹⁹ The effects of individual angiopoietins on the tumor vasculature have not been studied extensively in loss-of-function experiments, due largely to the limited availability of selective angiopoietin inhibitors. Some clues to the effects of Ang1 and Ang2 on tumor vessels have been garnered through overexpression of the ligands in tumor cell xenografts.^{20,21,22,23,24,25,26} These studies, however, have yielded conflicting data,^{20,21,22,23,24,25,26} the ligands were administered at nonphysiological levels, and the results were restricted to prevention studies. Studies blocking the Tie2 receptor have shown reduced tumor angiogenesis,^27,28,29,30 but the specific roles of each ligand cannot be differentiated. Pharmacological angiopoietin inhibitors using antisense, aptamer, and peptide-Fc fusion protein (peptibody) technologies are currently being developed, but published studies have been restricted to inhibition of Ang1 or Ang2 alone.^31,32,33 Studies using aptamers or peptibodies that potently neutralize Ang2 activity showed that Ang2 antagonism resulted in inhibition of angiogenesis and tumor growth.^31,32 Inhibition of Ang1 in a cell line stably transfected with antisense RNA resulted in reduced tumor growth and angiogenesis.³³To gain a better understanding of the effects of Ang1 and Ang2 on blood vessels in tumors, we used selective inhibitors (peptibodies) of Ang1 and Ang2, alone or in combination, in Colo205 tumors. These studies focused on Colo205 tumors, as this model is sensitive to angiopoietin inhibitors.³¹ We found that inhibition of Ang1 alone had little effect on the tumor vasculature, whereas inhibition of Ang2 resulted in fewer tumor vessels and normalization of the surviving tumor vessels. When the Ang2 inhibitor was administered with the Ang1 inhibitor, tumor vessel normalization did not occur, but the Ang2 inhibitor-mediated reduction in vascularity was unaffected. These findings suggest that inhibition of Ang2 leads to unopposed Ang1 activity and results in normalization of tumor vessels. In contrast, the Ang2 inhibitor-mediated reduction in tumor vascularity was Ang1-independent.     

Antibody-mediated neutralization of pertussis toxin-induced mitogenicity of human peripheral blood mononuclear cells

Antibody-mediated neutralization of pertussis toxin-induced proliferation of human peripheral blood mononuclear cells (PBMC) was assessed using alamarBlue and compared with results from the Chinese hamster ovary (CHO) cell assay using sera from vaccinated adults and convalescent children. Neutralization values for the CHO assay were similar for vaccinated and convalescent subjects; however. the convalescent group had higher titers in the PBMC assay. Results for pertussis toxin neutralization with the CHO assay appear to be distinct from those with the PBMC assay.     

Mental Health of Mothers of Children with Juvenile Rheumatoid Arthritis: Appraisal as a Mediator

Examined direct and mediated relations between condition parametersand maternal mental health for 53 mothers of 2- to 11-year-oldchildren with juvenile rheumatoid arthritis (JRA). Multivariateanalyses revealed that when considered simultaneously, indicesof both biological severity and functional severity were associatedsignificantly with maternal mental health. Further, mother'sappraisals of the impact of the child's illness on the familypartially mediated the effects of medication type and child'sfunctional status on mother's mental health. Results providesupport for conceptual models that emphasize the cognitive mechanismsby which condition parameters such as biological and functionalseverity might affect maternal mental health. Explicating theprocesses by which a child's JRA might lead to psychologicaladjustment problems in the parent has implications for developingpreventive and treatment interventions.     

Object recognition memory and BDNF expression are reduced in young TgCRND8 mice

The TgCRND8 mouse model of Alzheimer's disease exhibits progressive cortical and hippocampal β-amyloid accumulation, resulting in plaque pathology and spatial memory impairment by 3 months of age. We tested whether TgCRND8 cognitive function is disrupted prior to the appearance of macroscopic plaques in an object recognition task. We found profound deficits in 8-week-old mice. Animals this age were not impaired on the Morris water maze task. TgCRND8 and littermate controls did not differ in their duration of object exploration or optokinetic responses. Thus, visual and motor dysfunction did not confound the phenotype. Object memory deficits point to the frontal cortex and hippocampus as early targets of functional disruption. Indeed, we observed altered levels of brain-derived neurotrophic factor (BDNF) messenger ribonucleic acid (mRNA) in these brain regions of preplaque TgCRND8 mice. Our findings suggest that object recognition provides an early index of cognitive impairment associated with amyloid exposure and reduced brain-derived neurotrophic factor expression in the TgCRND8 mouse.     

Validating self-reported strokes in a longitudinal UK cohort study (Whitehall II): Extracting information from hospital medical records versus the Hospital Episode Statistics database

Background

Quantiles are a staple of epidemiologic research: in contemporary epidemiologic practice, continuous variables are typically categorized into tertiles, quartiles and quintiles as a means to illustrate the relationship between a continuous exposure and a binary outcome.

Discussion

In this paper we argue that this approach is highly problematic and present several potential alternatives. We also discuss the perceived drawbacks of these newer statistical methods and the possible reasons for their slow adoption by epidemiologists.

Summary

The use of quantiles is often inadequate for epidemiologic research with continuous variables.     

Atypical 22q11.2 deletion in a patient with DGS/VCFS spectrum

Deletions in region 22q11.2 usually occur between two low copy repeat regions (LCRs), which are preferred chromosome sites for rearrangements. Most of the deletions encompass the same 3 or 1.5 Mb region, with breakpoints at LCR A and D or at LCR A and B, respectively. We report on a patient with clinical features of the 22q deletion syndrome who presents a novel, atypical deletion, smaller than 1.5 Mb, with distal breakpoint in LCR B and proximal breakpoint within no known LCR site.