A pan-influenza monoclonal antibody neutralizes H5 strains and prophylactically protects through intranasal administration.

Avian A(H5N1) influenza virus poses an elevated zoonotic threat to humans, and no pharmacological products are currently registered for fast-acting pre-exposure protection in case of spillover leading to a pandemic. Here, we show that an epitope on the stem domain of H5 hemagglutinin is highly conserved and that the human monoclonal antibody CR9114, targeting that epitope, potently neutralizes all pseudotyped H5 viruses tested, even in the rare case of substitutions in its epitope. Further, intranasal administration of CR9114 fully protects mice against A(H5N1) infection at low dosages, irrespective of pre-existing immunity conferred by the quadrivalent seasonal influenza vaccine.

Recombinant C1 inhibitor in brain ischemic injury.

Objective: C1 inhibitor (C1-INH) is an endogenous inhibitor of complement and kinin systems. We have explored the efficacy and the therapeutic window of the recently available human recombinant (rh) C1-INH on ischemic brain injury and investigated its mechanism of action in comparison with that of plasma-derived (pd) C1-INH.

Methods: rhC1-INH was administered intravenously to C57Bl/6 mice undergoing transient or permanent ischemia, and its protective effects were evaluated by measuring infarct volume and neurodegeneration.

Sub-chronic (13-week) oral toxicity study in rats with recombinant human lactoferrin produced in the milk of transgenic cows.

The oral toxicity of recombinant human lactoferrin (rhLF) produced in the milk of transgenic cows was investigated in Wistar rats by daily administration via oral gavage for 13 consecutive weeks, 7 days per week. The study used four groups of 20 rats/sex/dose. The control group received physiological saline and the three test groups received daily doses of 200, 600 and 2000 mg of rhLF per kg body weight.

Effect of skin barrier competence on SLS and water-induced IL-1alpha expression.

For screening of a potential irritant it is essential that an early marker for irritation should be chosen which could be detected before the physiological signs of irritation occur. Interleukin 1 alpha (IL-1alpha) is widely accepted as such a marker in both in vivo and in vitro test systems. In this study, we have determined the mRNA levels of IL-1alpha in the epidermis after topical application of sodium dodecyl sulphate (SLS) in both a commercially available epidermal kit (EpiDerm) and in excised skin.

Targeted delivery of oligodeoxynucleotides to parenchymal liver cells in vivo.

Anti-sense oligodeoxynucleotides (ODNs) hold great promise for correcting the biosynthesis of clinically relevant proteins. The potential of ODNs for modulating liver-specific genes might be increased by preventing untimely elimination and by improving the local bioavailability of ODNs in the target tissue. In the present study we have assessed whether the local ODN concentration can be enhanced by the targeted delivery of ODNs through conjugation to a ligand for the parenchymal liver cell-specific asialoglycoprotein receptor.

Liver uptake of phosphodiester oligodeoxynucleotides is mediated by scavenger receptors.

The therapeutic activity of antisense oligodeoxynucleotides (ODNs) often is impaired due to premature degradation and poor ability to reach the (intra)cellular target. In this study, we addressed the in vivo fate of ODNs and characterized the major sites responsible for the clearance of intravenously injected phosphodiester ODN. On injection into rats, 32P-ODNs (miscellaneous sequences and GT-containing ODNs with variable G content) are rapidly cleared from the bloodstream (t1/2 = 0.

Antagonists of the mannose receptor and the LDL receptor-related protein dramatically delay the clearance of tissue plasminogen activator.

Background: Clinical application of tissue plasminogen activator (TPA) as a fibrinolytic agent is complicated by its rapid clearance from the bloodstream, which is caused by TPA liver uptake. The mannose receptor on endothelial liver cells and the LDL receptor-related protein (LRP) on parenchymal liver cells were reported to contribute to liver uptake.

Methods And Results: In this study, we addressed whether TPA clearance can be delayed by inhibiting receptor-mediated endocytosis of TPA.

Induction of hepatic uptake of lipoprotein(a) by cholesterol-derivatized cluster galactosides.

We have previously developed triantennary galactosides [TG(4A)C and TG(20A)C] that lower cholesterol levels by inducing liver uptake of lipoproteins via galactose-recognizing hepatic receptors. In this study, we have investigated whether this strategy could also be applied to reduce elevated serum levels of the atherogenic lipoprotein(a) [Lp(a)]. Both TG(4A)C and TG(20A)C could be incorporated into Lp(a).

Increased selective uptake in vivo and in vitro of oxidized cholesteryl esters from high-density lipoprotein by rat liver parenchymal cells.

Oxidation of low-density lipoprotein (LDL) leads initially to the formation of LDL-associated cholesteryl ester hydroperoxides (CEOOH). LDL-associated CEOOH can be transferred to high-density lipoprotein (HDL), and HDL-associated CEOOH are rapidly reduced to the corresponding hydroxides (CEOH) by an intrinsic peroxidase-like activity. We have now performed in vivo experiments to quantify the clearance rates and to identify the uptake sites of HDL-associated [3H]Ch18:2-OH in rats.

[Testicular epidermoid cyst: orchiectomy or enucleation resection?].

Our experience with 18 patients with simple epidermoid cysts of the testis is reported. In each patient the tumour was enucleated completely and two biopsies of the adjacent parenchyma were obtained for exclusion of associated germ cell cancer, scars or carcinoma in situ. There was no evidence of malignancy in any of the biopsy specimens.

Organ preserving surgery in testicular epidermoid cysts.

Our experience with 18 patients with simple epidermoid cysts of the testis (monodermal teratoma) is reported. In all patients the tumor was enucleated completely and 2 biopsies of the adjacent parenchyma were obtained for exclusion of associated germ cell cancer, scar or carcinoma in situ. There was no evidence of malignancy in any biopsy specimen.

Cholesterol derivative of a new triantennary cluster galactoside lowers serum cholesterol levels and enhances secretion of bile acids in the rat.

Background: Previous studies have demonstrated that cholesterol-derivatized galactosides exert a hypocholesterolemic effect by inducing hepatic uptake of atherogenic lipoproteins by means of galactose-recognizing receptors in the liver. However, a prolonged infusion of high concentrations of these compounds was required for this effect, possibly because of low affinity for the galactose-recognizing asialoglycoprotein receptor on the parenchymal liver cell.

Methods And Results: We have designed a new series of triantennary galactosides to optimize the affinity and specificity for this receptor.

Specific targeting of the antiviral drug 5-iodo 2'-deoxyuridine to the parenchymal liver cell using lactosylated poly-L-lysine.

In this study, we describe the development and characterization of lactosylated poly-L-lysine as a potential carrier for targeting anti-viral drugs to the parenchymal liver cell. Poly-L-lysine (M(r) 38,000) was modified with 2 to 130 lactose residues per molecule poly-L-lysine. In vitro competition studies for the asialoglycoprotein receptor on parenchymal liver cells using 125I-asialoorosomucoid as radioligand revealed that mild modification of poly-L-lysine with only five lactose residues was sufficient for high affinity competition.

Cholesterol derivative of a new triantennary cluster galactoside directs low- and high-density lipoproteins to the parenchymal liver cell.

We have developed a new triantennary galactoside, in which the terminal galactose moieties are connected to the branching point of the cluster galactoside via a 20 A (2 nm) spacer [TG(20A)]. In vitro binding studies have demonstrated that introduction of a 20 A spacer resulted in avid and specific binding of the triantennary galactoside to the asialoglycoprotein receptor on the parenchymal liver cell. Derivatization of this galactoside with a cholesterol moiety afforded a compound [TG(20A)C] that lowered the serum cholesterol concentration when injected into rats.