Role of kidney in the catabolic clearance of human platelet antiheparin proteins from rat circulation

Stimulated platelets release at least two antiheparin proteins: platelet factor 4 (PF4) and low affinity platelet factor 4 (LA-PF4) from which beta-thromboglobulin (beta TG) is derived. We have found previously marked elevation of LA-PF4/beta TG antigen in platelet poor plasma of patients with chronic renal failure, whereas levels of PF4 remained normal. Therefore, we examined the role of the kidneys in the metabolic clearance of LA-PF4/beta TG and PF4. The supernates of aggregates of thrombin-stimulated human platelets were injected into sham operated control rats, nephrectomized rats, and into rats with acute ureteral ligation. The disappearance of human LA-PF4/beta TG antigen and PF4 in rat plasma determined by specific radioimmunoassays followed biphasic exponential curves. The half-lives (t1/2) for the fast and slow components of LA-PF4 in control rats were 6.4 and 68.4 min. Nephrectomy significantly increased these times to 9.7 and 144 min, while ureteral ligation resulted in no significant change. Comparison of the level of LA-PF4/beta TG antigen and of creatinine in aorta and in renal vein showed 25%-30% extraction of these compounds by the kidney. Less than 0.1% of the total LA-PF4 antigen injected was recovered in the urine of control rats. In contrast to these results, the clearance of PF4 was not affected by nephrectomy. In conclusion: (1) functional renal tissue is necessary for normal clearance of LA- PF4/beta TG, but renal excretion does not play a major role in its elimination suggesting that the protein is catabolized by the kidney; and (2) catabolic clearance of PF4 does not depend on functioning kidney tissue.     

Immunoglobulin G from patients with heparin-induced thrombocytopenia binds to a complex of heparin and platelet factor 4

Heparin-induced thrombocytopenia (HIT) is an important complication of heparin therapy. Although there is general agreement that platelet activation in vitro by the HIT IgG is mediated by the platelet Fc receptor, the interaction among the antibody, heparin, and platelet membrane components is uncertain and debated. In this report, we describe studies designed to address these interactions. We found, as others have noted, that a variety of other sulfated polysaccharides could substitute for heparin in the reaction. Using polysaccharides selected for both size and charge, we found that reactivity depended on two independent factors: a certain minimum degree of sulfation per saccharide unit and a certain minimum size. Hence, highly sulfated but small (< 1,000 daltons) polysaccharides were not reactive nor were large but poorly sulfated polysaccharides. The ability of HIT IgG to recognize heparin by itself was tested by Ouchterlony gel diffusion, ammonium sulfate and polyethylene glycol precipitation, and equilibrium dialysis. No technique demonstrated reactivity. However, when platelet releasate was added to heparin and HIT IgG, a 50-fold increase in binding of radio-labeled heparin to HIT IgG was observed. The releasate was then depleted of proteins capable of binding to heparin by immunoaffinity chromatography. Only platelet factor 4-immunodepleted releasate lost its reactivity with HIT IgG and heparin. Finally, to determine whether the reaction occurred on the surface of platelets or in the fluid phase, washed platelets were incubated with HIT IgG or heparin and after a wash step, heparin or HIT IgG was added, respectively. Reactivity was only noted when platelets were preincubated with heparin. Consistent with these observations was the demonstration of the presence of PF4 on platelets using flow cytometry. These studies indicate that heparin and other large, highly sulfated polysaccharides bind to PF4 to form a reactive antigen on the platelet surface. HIT IgG then binds to this complex with activation of platelets through the platelet Fc receptors.     

Inferior Vena Caval and Right Atrial Thrombosis Complicating an Amebic Hepatic Abscess

We describe a 50-yr-old black laborer who presented with right lower chest pain, weight loss, and pedal edema. Ultrasonography and computed tomograms showed a large abscess cavity in the right lobe of the liver which extended very close to the inferior vena cava. The lumen of the adjacent inferior vena cava was partially occluded by thrombus, which could be traced up into the cavity of the right atrium. The hepatic veins were normally patent. Sterile blood-stained pus was aspirated from the abscess. Antibodies against Entamoeba histolytica were present in high titer in the patient's serum. Although propagation of hepatocellular carcinoma into the inferior vena cava and even up into the right atrium is well recognized, inferior vena caval thrombosis extending up into the right atrium has not hitherto been reported as a complication of amebic hepatic abscess.     

Reversible switching between superhydrophobic states on a hierarchically structured surface

Nature offers exciting examples for functional wetting properties based on superhydrophobicity, such as the self-cleaning surfaces on plant leaves and trapped air on immersed insect surfaces allowing underwater breathing. They inspire biomimetic approaches in science and technology. Superhydrophobicity relies on the Cassie wetting state where air is trapped within the surface topography. Pressure can trigger an irreversible transition from the Cassie state to the Wenzel state with no trapped air--this transition is usually detrimental for nonwetting functionality and is to be avoided. Here we present a new type of reversible, localized and instantaneous transition between two Cassie wetting states, enabled by two-level (dual-scale) topography of a superhydrophobic surface, that allows writing, erasing, rewriting and storing of optically displayed information in plastrons related to different length scales.     

Open and hybrid deep vein reconstructions: to do or not to do?

Endovascular reconstruction has become the standard treatment of chronic obstruction of large veins. Stenting is done with increasing frequency to treat iliac venous obstructions, with or without associated inferior vena caval or femoral vein occlusions. Open reconstruction with venous bypass is performed today in patients who fail attempts at venous stenting or who are not candidates for endovascular reconstructions. Patients with primary or secondary malignancies invading the vena cava undergo open caval reconstruction at the time of tumour excision. Open venous reconstructions are still preferred in patients with large vein injuries due to blunt or penetrating trauma or in those who suffer iatrogenic venous injuries. Hybrid reconstruction can be performed with endophlebectomy of the common femoral or femoral veins combined with iliofemoral stenting.     

Hypoxic Preconditioning Alleviates Ethanol Neurotoxicity: The Involvement of Autophagy

Ethanol is a neuroteratogen and neurodegeneration is the most devastating consequence of developmental exposure to ethanol. A sublethal preconditioning has been proposed as a neuroprotective strategy against several central nervous system neurodegenerative diseases. We have recently demonstrated that autophagy is a protective response to alleviate ethanol toxicity. A modest hypoxic preconditioning (1 % oxygen) did not cause neurotoxicity but induced autophagy (Tzeng et al. Free Radic Biol Med 49: 839–846, 2010). We, therefore, hypothesize that the modest hypoxic preconditioning may offer a protection against ethanol-induced neurotoxicity. We showed here that the modest hypoxic preconditioning (1 % oxygen) for 8 h significantly alleviated ethanol-induced death of SH-SY5Y neuroblastoma cells. Under the normoxia condition, cell viability in ethanol-exposed cultures (316 mg/dl for 48 h) was 49 ± 6 % of untreated controls; however, with hypoxic preconditioning, cell viability in the ethanol-exposed group increased to 78 ± 7 % of the controls (p < 0.05; n = 3). Bafilomycin A1, an inhibitor of autophagosome and lysosome fusion, blocked hypoxic preconditioning-mediated protection. Similarly, inhibition of autophagic initiation by wortmannin also eliminated hypoxic preconditioning-mediated protection. In contrast, activation of autophagy by rapamycin further enhanced neuroprotection caused by hypoxic preconditioning. Taken together, the results confirm that autophagy is a protective response against ethanol neurotoxicity and the modest hypoxic preconditioning can offer neuroprotection by activating autophagic pathways.