Reduction of renal uptake of monoclonal antibody fragments by amino acid infusion

The renal uptake of radiolabeled antibody fragments and peptides presents a problem in radioimmunodetection and therapy, compromising lesion sensitivity, especially with intracellularly-retained isotopes. Previously, we showed that cationic amino acids and their derivatives are capable of significantly reducing kidney uptake in animals. We report our initial clinical results of successful renal uptake reduction in five patients who underwent cancer radioimmunodetection with 99mTc-anti-CEA Fab' fragments. METHODS: The patients were infused with two liters of a commercially-available nutritive amino acid solution (containing approximately 2.25 g/liter lysine-glutamate and 2.50 g/liter arginine), whereas 75 control patients received the same volume of saline (quantification of organ and tumor kinetics from conjugate whole-body views by ROI technique). RESULTS: The renal uptake in the amino acid group was significantly lower (p<0.05) than in the control group (11.1 +/- 2.0% injected dose versus 17.7 +/- 7.0% injected dose at 24 hr postinjection), whereas the uptake of all other organs remained unaffected. Gel filtration chromatography of the urine taken from amino-acid-treated patients showed that a significantly higher amount of excreted activity was bound to intact Fab' (53% of excreted activity) in contrast to only less than 10% in the control group. CONCLUSION: The renal uptake of monoclonal antibody fragments in patients can be reduced significantly by amino acid infusion, even at considerably lower doses than those that were safe and effective in animals. As was found in animals, the mechanism seems to rely on an inhibition of the re-absorption of tubularly-filtered proteins by the proximal tubule cells. These results encourage further clinical trials to lower the renal uptake experienced in radioimmunodetection, as well as in therapeutic trials with antibody fragments and peptides.     

Matrilineal inheritance of complex I dysfunction in a multigenerational Parkinson's disease family

Recent data suggesting complex I dysfunction in Parkinson's disease (PD) arises from mitochondrial DNA (mtDNA) mutation does not conclusively answer whether the responsible genetic lesion is inherited (primary) or somatic (secondary). To address this question, we identified a family in which multiple members over three generations are affected with PD through exclusively maternal lines. Cytoplasmic hybrids (cybrids) were created for 15 family members over two generations by transferring each individual's mtDNA to mtDNA-depleted human neuroblastoma cells. Eight of the 15 cybrid lines contained mtDNA obtained from maternally descended family members and seven contained mtDNA from paternally descended family members. After 6 weeks of culture, cybrid cell lines were assayed for complex I activity and oxidative stress, and mitochondrial morphology was analyzed by electron microscopy. Compared with the cybrid lines containing mtDNA from paternal descendants, cybrid lines containing mtDNA from maternal descendants had lower complex I activity, increased reactive oxygen species production, increased radical scavenging enzyme activities, and more abnormal mitochondrial morphologic features. These findings were present in cybrid lines containing mtDNA from maternal descendants with PD as well as in currently asymptomatic young maternal descendants, and support a precedent for inherited mtDNA mutation in some persons with PD.     

Moult speed predicts pairing success in male harlequin ducks

The bright plumage of male ducks in sexually dichromatic species is thought to have evolved through intense sexual selection. This study examined the relationship between the timing and speed of moult into this bright plumage and subsequent mating success of male harlequin ducks, Histrionicus histrionicus. Males that moulted relatively slowly had a lower chance of establishing a pair bond than others. The timing of moult was unrelated to whether a male obtained a mate. Moult speed and timing were not correlated within individual males, but were significantly repeatable in individual males over 2 years. Moult speed probably reflects the condition of males, whereas timing of moult is more likely to be related to the distance to an individual's breeding area, which determines the timing of arrival to the moulting grounds. In waterfowl species that have been studied, males usually form dominance hierarchies before pairing and females tend to choose dominant males. We suggest that male harlequin ducks that moult slowly are poor-quality individuals, which are relegated to subordinate status and are unlikely to attract a mate the following autumn. Copyright 1998 The Association for the Study of Animal Behaviour. Copyright 1998 The Association for the Study of Animal Behaviour.     

Cerebrospinal fluid fistula: detection with MR cisternography

PURPOSE: Our goal was to assess the role of MR cisternography in the examination of patients with suspected CSF rhinorrhea. METHODS: MR cisternography was performed as a heavily T2-weighted fast spin-echo study with fat suppression and video reversal of the images in 37 patients over a 3-year interval. Twenty-four of the patients subsequently had exploratory surgery for fistula. Statistical analysis of the surgical results was compared with the findings at MR cisternography. RESULTS: MR cisternography showed significant correlation with surgical findings, with sensitivity, specificity, and accuracy of 0.87, 0.57, and 0.78, respectively. CONCLUSION: MR cisternography proved to be an accurate diagnostic imaging technique in the evaluation of suspected CSF rhinorrhea.     

Current concepts: spinal injuries and rehabilitation

Spinal cord injuries and their catastrophic effects require a treatment infrastructure able to provide an integrated process of management, including rehabilitation from injury and on an ongoing basis. This is particularly important because the incidence of spinal cord injuries is small. Better outcomes and cost efficiency with such an infrastructure have been established, but further knowledge is required to solve the remaining controversies in some aspects of management.     

Pulmonary vein stenosis after catheter ablation of atrial fibrillation

BACKGROUND: This report describes the complication of pulmonary vein stenosis with resultant severe pulmonary hypertension that developed in 2 patients after successful catheter ablation of chronic atrial fibrillation. METHODS AND RESULTS: Three months after successful catheter ablation of atrial fibrillation, both patients developed progressive dyspnea and pulmonary hypertension. Both were found to have severe stenosis of all 4 pulmonary veins near the junction with the left atrium. Balloon dilation of the stenotic pulmonary veins was performed in these patients, with improvement in dyspnea and pulmonary hypertension. CONCLUSIONS: The complication of pulmonary vein stenosis is potentially life-threatening, and the application of radiofrequency current within the pulmonary veins with standard catheter technology should be avoided. This complication can be treated with balloon dilation, although the long-term course is unknown.     

Application of high-performance liquid chromatograph-electrospray ionization mass spectrometry and matrix-assisted laser-desorption ionization time-of-flight mass spectrometry in combination with selective enzymatic modifications in the characterization of glycosylation patterns in single-chain plasminogen activator

The application of high-performance liquid chromatography (HPLC), electrospray ionization mass spectrometry (ESI-MS) and matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and selective enzymatic deglycosylation treatments is demonstrated in the analysis of glycosylation patterns in recombinant Desmodus salivary plasminogen activator, a heterogeneous glycoprotein. The sample was initially digested with a proteolytic enzyme (endoproteinase Lys-C) and then further treated with either PNGase F to remove N-linked carbohydrates or a combination of neuraminidase and O-glycosidase to remove sialic acid and O-linked carbohydrates. By comparison of the LC-ESI-MS peptide maps for the fully glycosylated and deglycosylated samples, it was possible to unambiguously identify the sites of N-linked glycosylation as well a number of N-linked glycopeptides. The O-link glycopeptides, which are present at low level ( < 1%), were not detected prior to the deglycosylation, nor could changes in peptide elution in the map following deglycosylation be correlated with potential O-linked glycosylation sites.     

The cardiovascular effects of diazepam and of diazepam and pancuronium during fentanyl and oxygen anaesthesia

A study of the physiological behaviour of the synthetic compound Orthonil (alpha-chloro-beta-(3-chloro-o-tolyl)-propionitrile revealed a strong auxin activity in higher plants. Otherwise, Orthonil appeared not to be a herbicide-auxin. It is metabolized intensively in plant tissues. Among the identified metabolites, two compounds were detected which also exert a high auxin activity. It is concluded that at least a part of the apparent auxin activity of Orthonil may be due to alpha-(3-chloro-o-tolyl) acetic acid, one metabolite of Orthonil. Although Orthonil strongly stimulates elongation growth, this growth is not accompanied by a stimulated ethylene evolution as is the case with other auxins. A possible metabolic pathway of Orthonil is discussed.     

The citric acid fermentation by Aspergillus niger: regulation by zinc of growth and acidogenesis

The citric acid fermentation by Aspergillus niger is divided into two consecutive phases, a growth phase when the cells proliferate but do not accumulate citrate, followed by an accumulating phase when they produce citrate but do not proliferate, or else do so at a much reduced rate. When studied in a low sucrose (0.4-0.8%) mpinimal salts medium the growth-accumulation alternative was controlled by the concentration of zinc: high zinc (about 1-2 muM) maintained growth phase, while at low zinc (below 1 muM) growth became limited by zinc deficiency and the cultures passed into accumulating phase. Addition of zinc to accumulating cultures resulted in their reversion to growth phase. Iron, manganese, calcium at concentrations as high as 5-10 muM had no influence on either growth or citrate accumulation. These results suggest that zinc plays a role in the regulation of growth and citric acid accumulation.