Angiogenic growth factor messenger ribonucleic acids in uterine natural killer cells

Angiogenesis is essential for endometrial growth and repair, and disruption of this process may lead to common disorders of women, including menorrhagia and endometriosis. In pregnancy, failure of the endometrial spiral arterioles to undergo remodeling leads to preeclampsia. Here we report that in addition to vascular endothelial growth factor A (VEGF-A), human endometrium expresses messenger ribonucleic acids (mRNAs) encoding VEGF-C, placenta growth factor (PlGF), the angiopoietins, angiopoietin 1 (Ang1) and Ang2, and the receptors VEGFR-3 (Flt-4), Tie 1, and Tie 2. Levels of VEGF-C, PlGF, and Tie 2 changed during the menstrual cycle. Intense hybridization for VEGF-C and PlGF mRNAs was found in uterine nature killer cells in secretory phase endometrium and for Ang2 mRNA in the same cells in the late secretory phase. Interleukin-2 (IL-2) and IL-15 up-regulated VEGF-C, but not PlGF or Ang2, mRNA levels in isolated NK cells. Conditioned medium from decidual NK cells did not induce human umbilical vein endothelial cell apoptosis. These results indicate that human endometrium expresses a wide range of angiogenic growth factors and that uterine nature killer cells may play an important role in the abnormal endometrial angiogenesis that underlies a range of disorders affecting women.     

Plasma leptin concentration in fetal sheep during late gestation: ontogeny and effect of glucocorticoids

The ontogeny and developmental control of plasma leptin concentration in the fetus are poorly understood. The present study investigated plasma leptin concentration in chronically catheterized sheep fetuses near term, and in neonatal and adult sheep. The effect of glucocorticoids on plasma leptin in utero was examined by fetal adrenalectomy and exogenous cortisol or dexamethasone infusion. In intact, untreated fetuses studied between 130 and 140 d (term, 145 +/- 2 d), plasma leptin concentration increased in association with the prepartum cortisol surge. Positive relationships were observed between plasma leptin in utero and both gestational age and plasma cortisol. Plasma leptin was also inversely correlated with fetal p(a)O(2). The ontogenic rise in plasma leptin was abolished by fetal adrenalectomy. In intact fetuses at 123-127 d, plasma leptin was increased by infusions of cortisol (3-5 mg kg(-1)d(-1), +127 +/- 21%) for 5 d and dexamethasone (45-60 microg kg(-1)d(-1), +268 +/- 61%) for 2 d. However, the cortisol-induced rise in plasma leptin was transient; by the fifth day of infusion, plasma leptin was restored to within the baseline range. These findings show that, in the sheep fetus, an intact adrenal gland is required for the normal ontogenic rise in plasma leptin near term. Furthermore, fetal treatment with exogenous and endogenous glucocorticoids increases circulating leptin concentration in utero.     

Dietary fat affects immune response, production of antiviral factors, and immune complex disease in NZB/NZW mice.

Autoimmune-prone (NZB x NZW)F1 (B/W) mice fed three nearly isocaloric diets with varied fat content showed a marked difference in their spontaneous development of immune complex disease and their immune response. Those animals received the diets high in either unsaturated or saturated fats had more severe immune complex nephritis and died earlier than mice on the low-fat diet. Endogenous production of the mouse xenotropic virus was unaffected by dietary fats, but the serum lipoproteins associated with antiviral activity were increased to levels as high as 1:600,000 in the B/W mice on the high-fat diets. These lipoproteins may be partially responsible for the decreased mitogenic response of spleen cells from mice fed the two high-fat diets. The mice receiving a diet high in saturated fats produced substantially higher titers of natural thymocytotoxic autoantibody, an IgM class of antibody, than did the mice maintained either on the high-unsaturated-fat or low-fat diet. In contrast, the mice receiving the diet high in unsaturated fats made significantly greater levels of antibodies to double-stranded DNA, an IgG, than did the mice kept on the two other diets. These results suggest that the type of fat in the diet could affect the serum level of different immunoglobulin classes. The data provide further evidence that the amount of dietary lipids alone can influence cellular and humoral immune responses and the spontaneous development of immune complex disease.     

The warm-up effect protects against ischemic left ventricular dysfunction in patients with angina.

OBJECTIVES: The goal of this study was to investigate whether the "warm-up" effect in angina protects against ischemic left ventricular (LV) dysfunction. BACKGROUND: After exercise, patients with coronary disease demonstrate persistent myocardial dysfunction, which may represent stunning, as well as warm-up protection against further angina, which may represent ischemic preconditioning. The effect of warm-up exercise on LV function during subsequent exercise has not been investigated. METHODS: Thirty-two patients with multivessel coronary disease and preserved LV function performed two supine bicycle exercise tests 30 min apart. Equilibrium radionuclide angiography was performed before, during and up to 60 min after each test. Global LV ejection fraction and volume changes and regional ejection fraction for nine LV sectors were calculated for each acquisition. RESULTS: Onset of chest pain or 1 mm ST depression was delayed and occurred at a higher rate-pressure product during the second exercise test. Sectors whose regional ejection fraction fell during the first test showed persistent reduction at 15 min (68 +/- 20 vs. 73 +/- 20%, p < 0.0001). These sectors demonstrated increased function during the second test (71 +/- 20 vs. 63 +/- 20%, p = 0.0005). The reduction at 15 min and the increase during the second test were both in proportion to the reduction during the first test. Effects on global function were only apparent when the initial response to exercise was considered. CONCLUSIONS: The warm-up effect is accompanied by protection against ischemic regional LV dysfunction. The degree of stunning and protection after exercise is related to the severity of dysfunction during exercise, consistent with results from experimental models.     

Vaccinia virus recombinants expressing chimeric proteins of human immunodeficiency virus and gamma interferon are attenuated for nude mice.

We have developed a method for attenuating vaccinia virus recombinants by expressing a fusion protein of a lymphokine and an immunogen. Chimeric genes were constructed that coded for gamma interferon (IFN-gamma) and structural proteins of the human immunodeficiency virus type 1 (HIV-1). In this study, we describe the biological and immunological properties of vaccinia virus recombinants expressing chimeric genes of murine or human IFN-gamma with glycoprotein gp120, gag, and a fragment of gp41. All fusion proteins retained the antigenic characteristics of both IFN-gamma and HIV as shown by immunoblot analysis. However, the antiviral activity of IFN-gamma could be demonstrated only for the IFN-gamma-gag fusion protein. In contrast, the attenuating activity of IFN-gamma for nude mice was retained by all of the recombinants, albeit at various rates. Unlike the antiviral activity, the attenuating activity of IFN-gamma was not species specific. Implications for the development of attenuated live recombinant vaccines for AIDS are discussed.     

Perceptions toward HIV, HIV screening, and the use of antiretroviral medications: a survey of maternity-based health care providers in Zambia

Mother-to-child transmission of HIV (MTCT) is a major contributor to Zambia's HIV burden. Based on our experience in Zambia, we felt that provider perceptions, knowledge base, and practice patterns toward HIV-positive mothers may pose as significant obstacles to preventing MTCT. Two hundred and twenty-five health care providers throughout Zambia were surveyed in 2002. Providers reported widespread stigma associated with HIV. Physicians (OR = 1.9), providers with research affiliations (OR = 2.3), and those located in Lusaka (OR = 9.0) were more likely to offer HIV testing. Only 30% routinely prescribed antiretroviral treatment (ART) to reduce MTCT. Practitioners from district facilities, those from Lusaka, and those employed at research facilities were more likely to prescribe ART routinely (OR = 2.8, 10.1 and 3.4 respectively). Among those never prescribing ART, most cited a lack of availability (83%). Our results highlight the need for further provider education, critical appraisal of the current system for HIV testing, and widespread distribution of ART.     

Changes induced by chronic in vivo load alteration in the tibiofemoral joint of mature rabbits

We investigated the relationship between the magnitude and duration of chronic compressive load alteration and the development and progression of degenerative changes in the rabbit tibiofemoral joint. Varus loading devices were attached to the hind limb of mature NZW rabbits. Altered compressive loads of 0%, 50%, and 80% body weight (BW) were applied to the tibiofemoral joint for 12 h per day for 12 and 24 weeks (n = 4 animals/group). Compartment‐specific assessment of the tibial plateau included histological assessments (articular cartilage, calcified cartilage, and subchondral bone thicknesses, degeneration score, and articular cartilage cellularity) and biomechanical measures (aggregate modulus, permeability, Poisson's ratio). Analyses of variance techniques were used to examine the relationship between each outcome measure with load magnitude and duration as independent variables in the model. Degenerative changes developed in the medial compartment with increased magnitude of compressive loading and included fibrillation, increased degeneration score, and reduced cellularity of the articular cartilage. Increased calcified cartilage thickness was observed in both the medial and lateral compartments following exposure to altered loading of 80% BW for 24 weeks. This work demonstrates that in vivo chronic compressive load alteration to the tibiofemoral joint can initiate progressive macroscopic and histological‐based degenerative changes analogous to the early changes occurring in OA. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1413–1422, 2012     

Re‐establishment of cytoskeletal tensional homeostasis in lax tendons occurs through an actin‐mediated cellular contraction of the extracellular matrix

Cytoskeletal tensional homeostasis is known to be an important factor in controlling catabolic gene expression in tendon cells. Loss of cell tension in lax rat tail tendon fascicles (RTTfs) has been associated with an upregulation of MMP‐13 gene expression and protein synthesis. To determine the role of the actin cytoskeleton in re‐establishing tensional homeostasis in lax tendons, RTTfs were allowed to freely contract in vitro for 8 days. The cultured RTTfs contracted rapidly, reaching 50% of their initial length by 3 days. This contraction was associated with the presence of α‐smooth muscle actin positive cells within the tendon. Disruption of the actin network by cytochalasian D caused an immediate and significant elongation of the contracted RTTfs. Subsequent removal of the cytochalasian D re‐initiated the contraction process. When lax RTTfs were allowed to contract between fixed clamps in culture and become taut, they demonstrated a marked decrease in MMP‐13 staining intensity when compared to freely contracting RTTfs. The ability of native tendon cells to contract lax tendons and re‐establish their homeostatic “set point” with respect to collagenase production may be an important mechanism in the recovery of tendons elongated by injury, surgical positioning, or cyclic, viscoelastic creep secondary to repetitive exercise. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1695–1701, 2012