We describe a new generation of protein-targeted contrast agents for multimodal imaging of the cell-surface receptors for vascular endothelial growth factor (VEGF). These receptors have a key role in angiogenesis and are important targets for drug development. Our probes are based on a single-chain recombinant VEGF expressed with a cysteine-containing tag that allows site-specific labeling with contrast agents for near-infrared fluorescence imaging, single-photon emission computed tomography or positron emission tomography. These probes retain VEGF activities in vitro and undergo selective and highly specific focal uptake into the vasculature of tumors and surrounding host tissue in vivo. The fluorescence contrast agent shows long-term persistence and co-localizes with endothelial cell markers, indicating that internalization is mediated by the receptors. We expect that multimodal imaging of VEGF receptors with these probes will be useful for clinical diagnosis and therapeutic monitoring, and will help to accelerate the development of new angiogenesis-directed drugs and treatments.

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To assess their potential value as early indicators of gentamicin-induced kidney damage, lysosomal hydrolases were measured in the 24-h urines of rats receiving 30 or 60 mg of gentamicin per kg per day for 15 days. Proteinuria, urine osmolality, blood urea nitrogen, and creatinine clearance were also measured. Kidney tissue was examined by both light and electron microscopy. Beta-galactosidase, beta-n-acetyl-hexosaminidase, and alpha-fucosidase were sensitive indicators and were significantly elevated above control values by day 3 at both doses (P < 0.01). Proteinuria, urine osmolality, and tests reflecting glomerular filtration rate were later indicators of nephron damage. Changes by light microscopy were detected on day 5. Necrosis was most prominent in the proximal convoluted tubules on day 10. Electron microscopy revealed numerous cytosomes with myeloid bodies within the proximal tubular epithelium on day 5. Lysosomal enzymuria appears to be an early manifestation of gentamicin nephrotoxicity and may possibly be related to the lysosomal abnormalities seen on electron microscopy.

To study the possibility that cephalosporins augment the nephrotoxicity of gentamicin, groups of rats were given four hourly subcutaneous doses of: gentamicin (5 mg/kg), gentamicin plus cephalothin (100 mg/kg), gentamicin plus cefazolin (20 mg/kg), gentamicin plus cefazolin (50 mg/kg), gentamicin plus cephaloridine (50 mg/kg), or saline diluent for 15 days. Periodic measurements were made of urine volume, urine osmolality, urine protein excretion and lysosomal enzymuria, as well as blood urea nitrogen, creatinine clearance, and drug concentrations in renal cortex and medulla. Tissue was examined by light and electron microscopy. Enzymuria and proteinuria increased early in the course of all treatment groups, whereas urine osmolality declined. No distinct patterns of these variables were discernable among the groups. Gentamicin alone, gentamicin plus cephalothin, and gentamicin plus cefazolin (20 mg/kg) caused the same significant fall in glomerular filtrate rate from control values by day 15 (P < 0.05). Gentamicin plus cefazolin (50 mg/kg) and gentamicin plus cephaloridine failed to cause a decline in glomerular filtration rate compared with controls (P > 0.05). Gentamicin concentrations in renal cortex were 5 to 10 times higher than those in medulla in all groups. Cephaloridine and cefazolin (50 mg/kg) also displayed a gradient pattern in renal cortex, whereas cephalothin and cefazolin (20 mg/kg) did not. Cytosegrosomes with myeloid figures were characteristic ultra-structural changes seen in all groups; however, they tended to be smaller with less numerous myeloid bodies in the groups receiving gentamicin plus cephalothin, cefazolin (50 mg/kg), or cephaloridine. Cephalosporins did not augment gentamicin toxicity. High doses of cefazolin and cephaloridine protected kidneys from gentamicin nephrotoxicity. The protection may involve intracellular drug interaction within the renal cortex.The nephrotoxic potential of gentamicin is well documented in both man and experimental animals (10,12,20,28). The nephrotoxicity of cephalothin has been the subject of a number of recent articles; however, careful pathological documentation in man and experimental animals remains incomplete (5,19,21,24). Reports alleging increased nephrotoxicity of cephalothin and gentamicin in combination have appeared periodically as well (2,4,11,16

A new form of alpha-L-fucosidase deficiency has been found in a 20-year-old severely retarded male. Additional signs include angiokeratoma corporis diffusum and anhydrosis. The skin lesion is due to an accumulation of residual bodies, presumably containing oligosaccharides and glycoproteins, in endothelial cells and fibrocytes. The enzyme activity in blood relatives indicates that the disease is inherited as a simple autosomal recessive trait that segregates according to Mendelian principles. Because the enzyme activity in the heterozygotes was consistently below that of normal controls, the carriers of the trait in this family could be ascertained.