GeneClinics: a hybrid text/data electronic publishing model using XML applied to clinical genetic testing.

GeneClinics is an online genetic information resource consisting of descriptions of specific inherited disorders ("disease profiles") as well as information on the role of genetic testing in the diagnosis, management, and genetic counseling of patients with these inherited conditions. GeneClinics is intended to promote the use of genetic services in medical care and personal decision making by providing health care practitioners and patients with information on genetic testing for specific inherited disorders. GeneClinics is implemented as an object-oriented database containing a combination of data and semistructured text that is rendered as HTML for publishing a given "disease profile" on the Web. Content is acquired from authors via templates, converted to an XML document reflecting the underlying database schema (with tagging of embedded data), and then loaded into the database and subjected to peer review. The initial implementation of a production system and the first phase of population of the GeneClinics database content are complete. Further expansion of the content to cover more disease, significant scaling up of rate of content creation, and evaluation redesign are under way. The ultimate goal is to have an entry in GeneClinics for each entry in the GeneTests directory of medical genetics laboratories-that is, for each disease for which clinical genetic testing is available.

Reduced cerebrospinal fluid levels of alpha-secretase-cleaved amyloid precursor protein in aged rats: correlation with spatial memory deficits.

The amyloid precursor protein undergoes proteolysis at several sites to yield a number of functionally relevant peptides, including beta-amyloid and the soluble amyloid precursor protein derivatives alpha-soluble amyloid precursor protein and beta-soluble amyloid precursor protein. beta-Amyloid is the primary constituent of senile plaques associated with Alzheimer's disease, while a-soluble amyloid precursor protein promotes synaptogenesis and plays a role in neuroprotective processes. We tested for age-related alterations in these amyloid precursor protein proteolytically derived peptides by measuring the levels of alpha-soluble amyloid precursor protein, total soluble amyloid precursor proteins (alpha- and beta-soluble amyloid precursor protein combined) and beta-amyloid in cerebrospinal fluid from three-, 13- and 23-month-old Fischer-344 rats. Western blot analysis using selective antibodies revealed 50% less total soluble amyloid precursor protein and a-soluble amyloid precursor protein in cisternal cerebrospinal fluid from 23-month-old rats compared with three- and 13-month-old animals. Mass spectrometric analysis indicated, however, that beta-amyloid in cerebrospinal fluid was not different between the three age groups. In a second group of young (five to six months of age) and aged (24-25 months of age) rats, spatial working and reference memory were assessed in a water maze followed by collection of cerebrospinal fluid. As a group, the aged rats consistently performed below the young rats in both working and reference memory tests. The aged rats also had 49% less cerebrospinal fluid alpha-soluble amyloid precursor protein than did their younger counterparts. There was a positive correlation (r= 0.52-0.57, P < 0.001) between performance in spatial memory tasks and cerebrospinal fluid alpha-soluble amyloid precursor protein in these young and aged rats. These results suggest that there is a positive association between cerebrospinal fluid levels of alpha-soluble amyloid precursor protein and cognitive performance in rats, and that alpha-soluble amyloid precursor protein may be involved in the spatial learning and memory changes that accompany ageing.

Tremulous characteristics of the vacuous jaw movements induced by pilocarpine and ventrolateral striatal dopamine depletions.

Vacuous jaw movements induced by the muscarinic agonist pilocarpine and striatal dopamine depletions were examined using a slow motion videotape system. With this procedure, rats were videotaped in a Plexiglas tube so that the profile of the head region could be seen. Vacuous jaw movements were analyzed by examining the tape at 1/6 normal speed. An observer recorded each jaw movement using a computer, and the computer program re-calculated the temporal characteristics of jaw movement responses back to normal speed. The interresponse time was recorded for each jaw movement, and each jaw movement interresponse time was assigned to a 50 ms wide time bin. Thus, the distribution of interresponse times could be used to analyze the temporal characteristics of jaw movement responses. In the first experiment, rats were administered saline vehicle, 1.0 mg/kg and 2.0 mg/kg pilocarpine. The rats were videotaped 10-15 min after injection, and the data were analyzed as described above. Pilocarpine induced very high levels of vacuous jaw movements, and the vast majority of all movements occurred in "bursts" with interresponse times of 1.0 s or less. Analysis of the interresponse time distributions showed that most of the jaw movements were within the 150-350 ms range. The modal jaw movement interresponse time was in the 150-200 ms range, which corresponds to a local frequency of 5-6.66 Hz. In the second experiment, the neurotoxic agent 6-hydroxydopamine was injected directly into the ventrolateral striatum in order to produce a local dopamine depletion. The dopamine-depleted rats were observed for jaw movements 7 days after surgery. The overall level of jaw movement activity resulting from dopamine-depletion was much lower than that produced by pilocarpine. There was a significant inverse correlation between ventrolateral striatal dopamine levels and total number of vacuous jaw movements. Videotape analysis indicated that the temporal characteristics of jaw movements induced by dopamine depletions were similar to those shown with pilocarpine. These experiments indicate that vacuous jaw movements induced by pilocarpine and striatal dopamine depletion occur in a frequency range similar to that shown in parkinsonian tremor.

Vacuous jaw movements induced by acute reserpine and low-dose apomorphine: possible model of parkinsonian tremor.

Coadministration of the monoamine-depleting agent reserpine with a low dose of apomorphine has been shown to result in high levels of vacuous jaw movements in rats. Two experiments were conducted to study the pharmacologic and motoric characteristics of the vacuous jaw movements induced by 5.0 mg/kg reserpine plus 0.1 mg/kg apomorphine. The first experiment was undertaken to determine whether the vacuous jaw movements induced by reserpine plus apomorphine could be reduced by coadministration of the muscarinic antagonist scopolamine. Injections of scopolamine produced a dose-related decrease in vacuous jaw movements induced by reserpine plus apomorphine, with the two highest doses (0.5 and 1.0 mg/kg scopolamine) producing significant differences relative to the control group that received reserpine plus apomorphine. In the second experiment, a slow-motion videotape system was used to study the temporal characteristics of the vacuous jaw movements induced by reserpine and apomorphine, and to study the effects of 1.0 mg/kg scopolamine on these movements. Most of the vacuous jaw movements shown by rats treated with reserpine and apomorphine occurred in rapid bursts of jaw movement. Analysis of the interresponse times (i.e., time between each jaw movement) showed that most of the jaw movements had a local frequency in the range of 2.86-6.67 Hz. Cotreatment with scopolamine significantly affected several measures of jaw movements. Thus, the vacuous jaw movements induced by reserpine plus apomorphine can be reversed by anticholinergic treatment, and these movements tend to occur as periodic oscillations of the lower jaw with a frequency of 3-7 Hz. Vacuous jaw movements in rats share some characteristics with parkinsonian symptoms and may represent an animal model of parkinsonian tremor.

Repeated scopolamine injections sensitize rats to pilocarpine-induced vacuous jaw movements and enhance striatal muscarinic receptor binding.

This experiment was conducted to determine if repeated administration of the muscarinic antagonist scopolamine could increase pilocarpine-induced vacuous jaw movements and also enhance muscarinic receptor binding. Rats received daily injections of either scopolamine (0.5 mg/kg IP) or saline for 14 days. On day 15 rats received no injections of scopolamine, but did receive injections of pilocarpine (1.0, 2.0 or 4.0 mg/kg IP) or saline. After administration of pilocarpine or saline, all rats were observed for vacuous jaw movements and rearing behavior. The day after pilocarpine injections, rats were sacrificed and samples of tissue from the lateral neostriatum were removed to assess muscarinic receptor binding using 3H-QNB as the ligand. Analyses of the vacuous jaw movement data indicated that there was a significant dose-related increase in vacuous jaw movements induced by pilocarpine, and also that there was a significant enhancement of pilocarpine-induced vacuous jaw movements in rats pretreated with repeated scopolamine injections. There was not a significant scopolamine x pilocarpine interaction, suggesting that pretreatment with scopolamine produced an apparent parallel shift in the pilocarpine dose-response curve. Pilocarpine significantly suppressed rearing behavior, and scopolamine pretreatment significantly enhanced the suppression of rearing produced by pilocarpine. Analysis of the receptor binding data indicated that there was a significant increase in the number of muscarinic receptor sites (Bmax) in rats that received repeated scopolamine injections as compared to saline-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Vacuous jaw movements in rats induced by acute reserpine administration: interactions with different doses of apomorphine.

Two experiments were conducted to study the vacuous jaw movements induced in rats by acute administration of the monoamine-depleting agent reserpine. In the first experiment, different doses of reserpine (1.25, 2.5, and 5.0 mg/kg) were assessed for their ability to induce vacuous jaw movements. Acute administration of reserpine induced a dose-related increase in vacuous jaw movements, with the two highest doses being significantly different from the vehicle control. In the second experiment, interactions between 5.0 mg/kg reserpine and the dopamine agonist apomorphine were investigated. Coadministration of reserpine with the lowest dose of apomorphine (0.1 mg/kg) significantly increased vacuous jaw movements relative to reserpine alone. The two higher doses of apomorphine (0.5 and 1.0 mg/kg) significantly decreased vacuous jaw movements in reserpine-treated rats. These results demonstrate that vacuous jaw movements are induced by acute reserpine treatment in a dose-related manner. In addition, the interactions with apomorphine suggest that vacuous jaw movements are stimulated by decreases in dopamine release produced by low doses of apomorphine that are thought to have mainly presynaptic actions, but that these movements are decreased by higher doses of apomorphine that are known to act postsynaptically.

Vacuous jaw movements induced by sub-chronic administration of haloperidol: interactions with scopolamine.

The present series of experiments was conducted to investigate the vacuous jaw movements induced by sub-chronic administration of haloperidol (HP). In the first experiment, daily injection of 0.4 mg/kg HP for 10 days increased vacuous jaw movements and decreased rearing behavior. The second and third experiments investigated the interaction between the effects of HP and the anticholinergic drug scopolamine. Co-administration of 0.5 mg/kg scopolamine with 0.4 mg/kg HP for 9 days reduced vacuous jaw movements and increased rearing responses relative to rats that received HP alone. Co-administration of HP with 0.25 mg/kg scopolamine for 9 days increased rearing relative to rats that received HP alone, but there was no effect of the lower dose of scopolamine on vacuous jaw movements. Administration of 0.5 mg/kg scopolamine plus 0.4 mg/kg HP on days 11-14 to rats that had received HP alone for 10 days reversed the effect of HP on rearing, but not on vacuous jaw movements. Rats that had received HP plus scopolamine for 10 days showed dramatic increases in vacuous jaw movements when scopolamine was withdrawn. Because vacuous jaw movements are produced within the first few days of administration, reduced by administration of scopolamine, and exacerbated by withdrawal of scopolamine, the pharmacological characteristics of these movements do not appear to bear a close relation to those of tardive dyskinesia in humans. The present results are consistent with the hypothesis that vacuous jaw movements in rats share some characteristics with Parkinsonian symptoms.