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Delayed gastric emptying may be an important pharmacokinetic mechanism underlying some of the response fluctuations that develop after long-term levodopa therapy. We performed a radionuclide gastric emptying study using a standard Tc-99m colloid-labeled solid meal in 30 patients with Parkinson's disease (PD), 15 fluctuators with "delayed-on" and "no-on" phenomena, and 15 nonfluctuators. Fasting patients were given the standard meal, and gastric emptying was monitored with a gamma camera positioned over the stomach, recording data for 1 hour. PD patients had prolonged gastric emptying measured after 60 minutes compared with the normal control subjects (70.7 +/- 16% versus < 60%). Gastric retention measured after 1 hour was increased in patients with fluctuations compared with patients without fluctuations (77.4 +/- 15.5% versus 64.0 +/- 14.3%; p < 0.05). Half-time emptying was significantly delayed in patients with, as compared with those without, response fluctuations (221 +/- 202 minutes versus 85 +/- 31 minutes; p < 0.05). This demonstrates that delayed gastric emptying is common in PD patients and is more marked in those with response fluctuations. The stomach is an important target organ in PD, affected either by the basic PD pathology, chronic drug administration, or both.

Shrinkage and collapse of the neuritic network are often observed during the process of neuronal apoptosis. However, the molecular and biochemical basis for the axonal damage associated with neuronal cell death is still unclear. We present evidence for the involvement of axon guidance molecules with repulsive cues in neuronal cell death. Using the differential display approach, an up-regulation of collapsin response mediator protein was detected in sympathetic neurons undergoing dopamineinduced apoptosis. A synchronized induction of mRNA of the secreted collapsin-1 and the intracellular collapsin response mediator protein that preceded commitment of neurons to apoptosis was detected. Antibodies directed against a conserved collapsin-derived peptide provided marked and prolonged protection of several neuronal cell types from dopamine-induced apoptosis. Moreover, neuronal apoptosis was inhibited by antibodies against neuropilin-1, a putative component of the semaphorin III/ collapsin-1 receptor. Induction of neuronal apoptosis was also caused by exposure of neurons to semaphorin III-alkaline phosphatase secreted from 293EBNA cells. Anti-collapsin-1 antibodies were effective in blocking the semaphorin III-induced death process. We therefore suggest that, before their death, apoptosis-destined neurons may produce and secrete destructive axon guidance molecules that can affect their neighboring cells and thus transfer a "death signal" across specific and susceptible neuronal populations. Key Words: Dopamine-Sympathetic neurons-Apoptosis-Semaphorin-Collapsin-1. J. Neurochem. 73, 961-971 (1999).

Endothelins are a recently discovered group of most powerful vasoconstrictor peptides. Endothelin-1 is produced by endothelial cells, and endothelin-3 is derived from neuronal tissue. Theoretically, endothelin-mediated vasoconstriction may enhance ischemic neuronal damage. This study aimed to measure plasma levels of both endothelins in patients with acute nonhemorrhagic cerebral infarction. Plasma levels of endothelin-1 and endothelin-3 were measured by radioimmunoassay in 16 consecutive patients within the first 72 hours after the onset of nonhemorrhagic cerebral infarct, as diagnosed clinically and by computed tomography. There was a marked (fourfold) elevation in plasma endothelin-1 levels in the patients (median, 11.7 pg/ml; 25th and 75th centiles, 5.4 and 13.2 pg/ml) compared with those in a control group of 13 age-matched subjects (median, 2.56 pg/ml; 25th and 75th centiles, 2.4 and 3.0 pg/ml; p less than 0.0001). The first 24 hours after stroke onset were associated with higher endothelin-1 levels, and there was a trend to elevated levels with more severe neurological deficits. In all patients and controls endothelin-3 levels were below 0.5 pg/ml. Ischemic stroke is associated with acute and marked increases in plasma levels of endothelin-1. This may reflect enhanced production by damaged endothelial cells within the infarcted tissue. Local leakage of endothelin-1 may induce severe and prolonged constriction of collateral vessels and may therefore have a deleterious role in the pathogenesis and final outcome of cerebral infarction.

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Apoptosis plays a pivotal role in the etiology or pathogenesis of numerous medical disorders, and thus, targeting of apoptotic cells may substantially advance patient care. In our quest for novel low-molecular-weight probes for apoptosis, we focused on the uncommon amino acid γ-carboxyglutamic acid (Gla), which plays a vital role in the binding of clotting factors to negatively charged phospholipid surfaces. Based on the alkyl-malonic acid motif of Gla, we have developed and now present ML-10 (2-(5-fluoro-pentyl)-2-methyl-malonic acid, MW=206 Da), the prototypical member of a novel family of small-molecule detectors of apoptosis. ML-10 was found to perform selective uptake and accumulation in apoptotic cells, while being excluded from either viable or necrotic cells. ML-10 uptake correlates with the apoptotic hallmarks of caspase activation, Annexin-V binding and disruption of mitochondrial membrane potential. The malonate moiety was found to be crucial for ML-10 function in apoptosis detection. ML-10 responds to a unique complex of features of the cell in early apoptosis, comprising irreversible loss of membrane potential, permanent acidification of cell membrane and cytoplasm, and preservation of membrane integrity. ML-10 is therefore the most compact apoptosis probe known to date. Due to its fluorine atom, ML-10 is amenable to radiolabeling with the 18 F isotope, towards its potential future use for clinical positron emission tomography imaging of apoptosis.