Homing receptor expression is deviated on CD56+ blood lymphocytes during pregnancy in Type 1 diabetic women.

Type 1 Diabetes Mellitus (T1DM) is characterized by an augmented pro-inflammatory immune state. This contributes to the increased risk for gestational complications observed in T1DM mothers. In normal pregnancies, critical immunological changes occur, including the massive recruitment of lymphocytes, particularly CD56bright NK cells, into early decidua basalis and a 2nd trimester shift towards Type 2 immunity. Decidual CD56bright NK cells arise at least partly from circulating progenitors expressing adhesion molecules SELL and ITGA4 and the chemokine receptors CXCR3 and CXCR4. In vitro studies show that T1DM reduces interactions between blood CD56+ NK cells and decidual endothelial cells by reducing SELL and ITGA4-based interactions. To address the mechanisms by which specific lymphocyte subsets may be recruited from the circulation during pregnancy and whether these mechanisms are altered in T1DM, flow cytometry was used to examine eight peripheral blood lymphocyte subsets (Type 1 (IL18R1+) and Type 2 (IL1RL1+) CD56bright NK, CD56dim NK, NKT and T cells) from control and T1DM women. Blood was collected serially over pregnancy and postpartum, and lymphocytes were compared for expression of homing receptors SELL, ITGA4, CXCR3, and CXCR4. The decline of Type 1/Type 2 immune cells in normal pregnancy was driven by an increase in Type 2 cells that did not occur in T1DM. CD56bright NK cells from control women had the highest expression of all four receptors with greatest expression in 2nd trimester. At this time, these receptors were expressed at very low levels by CD56bright NK cells from TIDM patients. Type 1/Type 2 NKT cell ratios were not influenced by either pregnancy or TIDM. Our results suggest that T1DM alters immunological balances during pregnancy with its greatest impact on CD56bright NK cells. This implicates CD56bright NK cells in diabetic pregnancy complications.

A history of preeclampsia identifies women who have underlying cardiovascular risk factors.

OBJECTIVE: The objective of this study was to prospectively assess physical and biochemical cardiovascular risk markers in women who had developed preeclampsia (PE) at 1 year postpartum. STUDY DESIGN: Following an overnight fast, previously PE (n = 70) and normotensive women (n = 70) had weight and blood pressure recorded and levels of morning blood for insulin, glucose, C-reactive protein, lipids, cholesterol, and urine for microalbumin and creatinine measured. Body mass index, homeostatic model assessment index, and incidence of metabolic syndrome were determined. RESULTS: At 1 year postpartum, markers of cardiovascular disease were different between the groups. There were also differences in the number of women with abnormal values. Mathematical modeling of cardiovascular event risk suggests that PE increases the risk by 2- to 3-fold; the risk was greatest for women with severe PE. CONCLUSION: The development of PE is 1 of the earliest clinically identifiable markers of a woman's heightened risk of cardiovascular disease.

Hypertensive disorders of pregnancy and long-term risk of hypertension: what do Ontario prenatal care providers know, and what do they communicate?

OBJECTIVES: The objective of this study was to ascertain the knowledge base of Ontario maternity care providers (family physicians, obstetrician-gynaecologists, and midwives) regarding the future health risks of gestational hypertension and preeclampsia and the practices with respect to communication of these risks. METHODS: In 2004, all obstetricians (639) and midwives (249) in Ontario and a random sample of 600 Ontario family physicians were mailed a survey and a reminder. Non-responders were also sent a second, and in some cases, a third copy of the survey. The survey addressed areas of knowledge, reported practices, and both patient and interprofessional communication. Descriptive analysis was used for the responses. RESULTS: The overall response rate was 42%. The majority of respondents were familiar with the long-term risks of gestational hypertension and preeclampsia. Although maternity care providers stated that they inform women with these conditions about their subsequent risks and recommend follow-up, only 36% usually inform the women's primary care providers about that subsequent risk. Only 58% of family physicians reported that they are usually informed by the maternity care providers about their patients who developed hypertension in pregnancy, compared with the 83% of maternity care providers who reported that they usually communicate this information to family physicians. CONCLUSION: We have identified weaknesses in knowledge base and communication amongst Ontario maternity care providers that suggest that the identification and follow-up of women with hypertensive disorders of pregnancy is not occurring. These deficiencies would be amenable to directed educational activities, including reviews, presentations, and the development and implementation of guidelines.

CYP2U1, a novel human thymus- and brain-specific cytochrome P450, catalyzes omega- and (omega-1)-hydroxylation of fatty acids.

Long chain fatty acids have recently emerged as critical signaling molecules in neuronal, cardiovascular, and renal processes, yet little is presently known about the precise mechanisms controlling their tissue distribution and bioactivation. We have identified a novel cytochrome P450, CYP2U1, which may play an important role in modulating the arachidonic acid signaling pathway. Northern blot and real-time PCR analysis demonstrated that CYP2U1 transcripts were most abundant in the thymus and the brain (cerebellum), indicating a specific physiological role for CYP2U1 in these tissues. Recombinant human CYP2U1 protein, expressed in baculovirus-infected Sf9 insect cells, was found to metabolize arachidonic acid exclusively to two region-specific products as determined by liquid chromatography-mass spectrometry. These metabolites were identified as 19- and 20-hydroxy-modified arachidonic acids by liquid chromatography-tandem mass spectrometry analysis. In addition to omega/omega-1 hydroxylation of arachidonic acid, CYP2U1 protein also catalyzed the hydroxylation of structurally related long chain fatty acid (docosahexaenoic acid) but not fatty acids such as lauric acid or linoleic acid. This is the first report of the cloning and functional expression of a new human member of P450 family 2, CYP2U1, which metabolizes long chain fatty acids. Based on the ability of CYP2U1 to generate bioactive eicosanoid derivatives, we postulate that CYP2U1 plays an important physiological role in fatty acid signaling processes in both cerebellum and thymus.

A novel human cytochrome P450, CYP26C1, involved in metabolism of 9-cis and all-trans isomers of retinoic acid.

Retinoids are potent regulators of cell proliferation, cell differentiation, and morphogenesis and are important therapeutic agents in oncology and dermatology. The gene regulatory activity of endogenous retinoids is effected primarily by retinoic acid isomers (all-trans and 9-cis) that are synthesized from retinaldehyde precursors in a broad range of tissues and act as ligands for nuclear retinoic acid receptors. The catabolism of all-trans-retinoic acid (atRA) is an important mechanism of controlling RA levels in cell and tissues. We have previously identified two cytochrome P450s, P450RAI-1 and P450RAI-2 (herein named CYP26A1 and CYP26B1), which were shown to be responsible for catabolism of atRA both in the embryo and the adult. In this report, we describe the identification, molecular cloning, and substrate characterization of a third member of the CYP26 family, named CYP26C1. Transiently transfected cells expressing CYP26C1 convert atRA to polar water-soluble metabolites similar to those generated by CYP26A1 and -B1. Competition studies with all-trans, 13-cis, and 9-cis isomers of retinoic acid demonstrated that atRA was the preferred substrate for CYP26C1. Although CYP26C1 shares extensive sequence similarity with CYP26A1 and CYP26B1, its catalytic activity appears distinct from those of other CYP26 family members. Specifically, CYP26C1 can also recognize and metabolize 9-cis-RA and is much less sensitive than the other CYP26 family members to the inhibitory effects of ketoconazole. CYP26C1 is not widely expressed in the adult but is inducible by RA in HPK1a, transformed human keratinocyte cell lines. This third CYP26 member may play a specific role in catabolizing both all-trans and 9-cis isomers of RA.