1141174724Complement activation induces dysregulation of angiogenic factors and causes fetal loss

Complement is an important effector in pregnancy loss in the antiphospholipid syndrome. We now test the hypothesis that complement activation is a necessary intermediary event in the pathogenesis of recurrent spontaneous miscarriage in DBA/2-mated female CBA/J mice (CBAxDBA), a well-studied model of autoantibody-independent pregnancy failure. Blockade of C3 activation with Crry-Ig completely rescued pregnancies in CBAxDBA mice (Crry-Ig vs untreated 8.5 ± 6.3% fetal resorptions vs 28.0 ± 7.2%, P <  0.01). Inhibition of C5 cleavage with anti-C5 mAb and blockade of C5a receptors with a peptide antagonist also prevented pregnancy loss (8.6 ± 4.4% and 8.0 ± 5.9% resorptions, respectively, P <  0.01 versus control). Inhibition of the alternative pathway resulted in pregnancy outcomes similar to controls (8.4 ± 6.6% versus 9.2 ± 3.2% resorptions). In CBAxDBA matings, we observed elevated plasma levels of soluble VEGF receptor-1 (sVEGFR-1; a potent anti-angiogenic molecule), increased placental inflammatory infiltrates and defective development of placenta. Our complement inhibitory strategies blocked the increase in sVEGFR-1, prevented functional deficiency of VEGF and rescued pregnancies. We confirmed the importance of complement as a proximal effector in in vitro studies; monocytes stimulated with C5a released sVEGFR-1 which sequesters VEGF required for normal placental development. Our data indicate that complement activation leads to recruitment of inflammatory cells and production of inhibitors of angiogenesis (sVEGFR-1) which cause placental dysfunction and fetal injury. These studies identify key innate immune effectors that mediate poor pregnancy outcomes and provide novel and important targets for prevention of recurrent pregnancy loss in patients.     

Effect on platelet properties of exposure to temperatures below 20 degrees C for short periods during storage at 20 to 24 degrees C

Background : When platelet concentrates (PCs) are shipped over long distances, it is not always possible to ensure that their temperature is maintained at 20 to 24°C. In addition, PCs are not agitated as during routine storage. Study Design and Methods : Studies have been conducted to evaluate how exposure to temperatures below 20°C in the absence of agitation influences properties of platelets. In initial studies, exposure to 4°C for 3 or 5 hours or to 12°C for 5 or 17 hours on Day 2 of a 5- to 6-day storage period was associated with a loss of discoid shape. This was reflected by slightly lower but statistically different morphology scores after storage compared to those observed with control platelets that were stored only at 20 to 24°C. In addition, a qualitative difference in morphology was noted in controls and PCs held at 16°C for 17 hours. In more detailed studies, both the in vivo viability and in vitro properties of platelets exposed between Day 1 and Day 2 to either 12°C or 16°C for 17 hours were evaluated. The protocol involved a paired study design (n = 4 for each exposure temperature) with the simultaneous storage of two identical PCs, one exposed to 12 or 16°C and the other one maintained at 20 to 24°C throughout the 5-day storage. Results : Exposure to 12°C significantly reduced (p < 0.05 by paired t test) the in vivo recovery to 37.6 ± 13.8 percent (mean ± 1 SD) from 47.8 ± 11.5 percent and the survival time to 2.0 ± 0.3 days from 6.5 ± 1.4 days. On exposure to 16°C, the differences in viability from those of control units were much less but still significant. The in vivo recovery was 42.7 ± 3.8 percent compared to 49.2 ± 3.0 percent and the survival time was 3.5 ± 1.2 days compared to 6.6 ± 0.3 days. The loss of in vivo viability of the test platelets was associated with a loss of discoid shape, as reflected by morphology scores, extent of shape change, and mean platelet volume. In addition, platelet metabolism also appeared to be affected, as suggested by increased lactate production. All of the in vitro properties except for total ATP and residual glucose that were statistically different from those of controls on exposure to 12°C were also significantly different on exposure to 16°C. Conclusion : These findings demonstrate that platelets undergo substantial changes in in vivo viability and in vitro properties when they are exposed to temperatures below 20°C for short periods.     

A blinded clinical comparison of MR imaging and CT in neuroradiology

The sensitivity and specificity of magnetic resonance (MR) imaging and computed tomography (CT) were compared in blinded readings of images of a consecutive series of patients with subsequently proved diagnoses. Overall, MR imaging was less sensitive than CT because of its lower sensitivity in detecting benign tumors. With a similar experimental protocol, the effects of technical refinements or contrast media on the sensitivity of MR imaging can be determined.     

Percutaneous transluminal dilatation of the iliac artery: long-term results

One hundred fifty-four patients with stenosis of the iliac artery underwent percutaneous transluminal angioplasty (PTA). These patients were followed for 1-7 years. The long-term results of the PTAs were analyzed by computer, and life tables were generated for dilatations of the iliac arteries with unimpaired flow and for those with an obstruction in the outflow tract. The accumulative 7-year patency rate was 90%, which agrees with other reports. This study demonstrates that the long-term results of PTA of iliac arterial stenoses are competitive with reconstructive vascular surgery. PTA should be the treatment of choice in patients with iliac arterial stenoses.     

Inhibition of Na,K-ATPase by dopamine in proximal tubule epithelial cells

In the current report we review the results that lay grounds for the model of intracellular sodium-mediated dopamine-induced endocytosis of Na,K-ATPase. Under conditions of a high salt diet, dopamine activates PKCzeta, which phosphorylates NKA alpha1 Ser-18. The phosphorylation produces a conformational change of alpha1 NH2-terminus, which through interaction with other domains of alpha1 exposes PI3K- and AP-2-binding domains. PI3K bound to the NKA alpha1 induces the recruitment and activation of other proteins involved in endocytosis, and PI3K-generated 3-phosphoinositides affect the local cytoskeleton and modify the biophysical conditions of the membrane for development of clathrin-coated pits. Plasma membrane phosphorylated NKA is internalized to specialized intracellular compartments where the NKA will be dephosphorylated. The NKA internalization results in a reduced Na+ transport by proximal tubule epithelial cells.     

Dermal autograft immersion plasty by a flap method for large postoperative hernias of the abdomen

The authors present results of treatment of 128 patients aged 32-75 with great ventral hernias using the method of autodermal immersion graft hernioplasty. Hernias most often appeared after low median laparotomies. Planned operations were performed in 94.6% of cases, in 5.4% plasty was carried out in patients with incarcerated hernias without pyo-inflammatory alterations in the hernia sac. The implant was treated by the V.N. Yanov method. The postoperative period was mainly favorable, without lethal outcomes. Suppuration of the wounds took place in 2.3% of cases. Long-term results were followed-up in 80.5% of the patients (during the periods 6 months--11 years). Recurrent hernias were found in 3.1%. The other patients had good results of operations.     

Multiple sclerosis: specificity of MR for diagnosis

The specificity of magnetic resonance (MR) imaging in the diagnosis of multiple sclerosis (MS) has not been measured systematically. Conventional MR head images with sagittal localizer and axial multiple-echo sequences with long repetition times were obtained in 92 patients with clinically verified MS (Schumacher criteria), 100 healthy volunteers, 60 subjects with hypertension, and eight patients with dementia. Two readers, without the aid of any clinical or demographic information, classified each of the 260 studies as MS or not MS. The readers classified the studies again after being supplied with the subjects' ages and sex. True-negative and true-positive diagnoses of MS were tabulated. The specificity of the MR diagnosis of MS (true-negative results in proportion to all non-MS studies) was 95%-99% with all the control groups included. There is a small risk of misinterpreting incidental periventricular white matter foci as plaques of MS in MR studies.