An efficient delivery of historical information for the Mendelian Inheritance in Man database.

The ability to manage information with regard to changes in a database is critical for quality control. This information can also provide audit trails about the time of the change and the person who made the change. In addition, historical information can provide the proper context in which to interpret the relationships between the current and past data. In most genomic databases, only the most recent copy of the information is presented to the user, thereby losing the audit trail and the historical context. Therefore, we have constructed a delivery mechanism for the historical information in the Mendelian Inheritance in Man database. Furthermore, this feature was designed to optionally display only the changes so that the user can bypass the unchanged portions of the text. It was anticipated that technical problems would influence the acceptance of this information delivery. However, the involvement of the editorial staff became the critical factor.

Evolving a legacy system: restructuring the Mendelian Inheritance in Man database.

Mendelian Inheritance in Man (MIM) is an encyclopedia of medical genetics that has been in electronic form for over 30 years. In its lifetime, MIM has undergone many organizational and software changes. In 1994, a major transition was made based on three basic principles: industry standards, open systems architecture, and extensibility. The resulting MIM database allows users to navigate to other genomic databases, permits the delivery of multimedia information, and improves the quality of data. The new MIM database also improved its administration because of 1) an internal format that enforces consistency; 2) a lower maintenance cost of software; and 3) a better ability to migrate MIM content. In addition, the new architecture will allow MIM easily to adopt emergent technologies as they mature.

Gamma-aminobutyric acid type A receptor blockade at the intermediate area of the ventral surface of the medulla counteracts the cardiorespiratory depression produced by intravenous midazolam.

Intravenous administration of midazolam (2 mg/kg) to 8 pentobarbital-anesthetized cats produced a significant decrease in minute ventilation, tidal volume, blood pressure and heart rate. Treatment with the gamma-aminobutyric acid (GABA) type A receptor antagonist bicuculline (10 micrograms/side) at the intermediate area of the ventral surface of the medulla (VSM) oblongata completely reversed the cardiorespiratory depressant effects of intravenous midazolam. In contrast, treatment with bicuculline at the same area failed to counteract the respiratory depressant effects of intravenous morphine (1 mg/kg). We conclude that the cardiorespiratory depressant effects of intravenously administered midazolam are due to enhancement of GABAergic transmission at the intermediate area of the VSM.

A beta-carboline derivative (ZK 93426) counteracts the cardiorespiratory depressant effects of intravenous midazolam.

The purpose of this study was to test the effects of the new beta-carboline ZK 93426 on midazolam-induced cardiorespiratory depression. Seven pentobarbital-anesthetized (35 mg/kg i.p.) cats were treated with intravenous midazolam (2 mg/kg) while monitoring the respiratory minute volume (VE), tidal volume, respiratory rate, blood pressure, heart rate and expired CO2. Midazolam caused significant decreases in VE (p less than 0.05) and blood pressure (p less than 0.05). ZK 93426 (5 mg/kg i.v.) antagonized these effects and produced significant increases in VE and blood pressure that resulted in the return of these variables to premidazolam control values. In 4 animals with morphine-induced respiratory depression, intravenous ZK 93426 failed to antagonize the respiratory effects of morphine. Administration of intravenous ZK 93426 alone to 4 pentobarbital-anesthetized animals also failed to produce significant changes in cardiorespiratory activity. We conclude that ZK 93426 is effective in counteracting the cardiorespiratory depressant effects of midazolam and that these effects appear to be specific. The present data suggest that this compound may be useful for the treatment of benzodiazepine oversedation and overdose.

Importance of central nervous system serotonin-1A receptors for mediating the hypotensive effect of urapidil.

Urapidil is thought to lower blood pressure by both a peripheral and a central mechanism. The former effect is caused by blockade of alpha-1 adrenoceptors whereas the latter effect has been shown to occur in the medulla, specifically at the intermediate area on the ventral surface of the medulla. The receptor mediating the central effect is not the alpha-1 adrenoceptor, but has been postulated to be the serotonin (5-HT)1A receptor. To determine whether urapidil lowers blood pressure by stimulating 5-HT1A receptors at the intermediate area, we applied urapidil bilaterally (50 micrograms/side) to the intermediate area of chloralose-anesthetized cats while monitoring arterial blood pressure and heart rate. Application of urapidil caused decreases in mean blood pressure and heart rate of 66 +/- 8 mm Hg and 31 +/- 7 beats/min, respectively. Pretreatment with the 5-HT1A and 5-HT2 receptor antagonist, spiperone (30 micrograms/side), counteracted the effects of urapidil. Pretreatment with the 5-HT2 receptor antagonist, ketanserin, did not alter the hypotensive effect of urapidil. Urapidil given i.v. in a dose of 2 mg/kg decreased mean blood pressure and heart rate by 53 +/- 6 mm Hg and 10 +/- 2 beats/min, respectively. At the peak of the i.v. response, spiperone (30 micrograms/side) was applied to the intermediate area and increased mean blood pressure and heart rate by 52 +/- 6 mm Hg and 20 +/- 4 beats/min, respectively, thus effectively reversing the effects of i.v. urapidil.(ABSTRACT TRUNCATED AT 250 WORDS)

TRH: immunocytochemical distribution in vagal nuclei of the cat and physiological effects of microinjection.

In the present study, we have applied antiserum to thyrotropin-releasing hormone (TRH) and avidin-biotin immunocytochemistry to determine the distribution of TRH-like immunoreactivity in the vagal nuclei of the cat. A dense network of TRH-immunoreactive (TRH-IR) fibers and terminals is noted in the dorsal motor nucleus of the vagus (DMV) from 0 to 2.5 mm rostral to the obex. Horseradish peroxidase conjugated wheat germ agglutinin (HRP-WGA)-labeled neurons are noted in this region of the DMV after application of the tracer to the musculature of the pylorus. In dual-stained sections, TRH-IR fibers and terminals appear to terminate in close proximity to HRP-WGA-labeled neurons in the DMV. In contrast, a moderate to low density of TRH-IR fibers and terminals is noted in the nucleus ambiguus (NA), and no HRP-WGA-labeled neurons are noted in this nucleus. To determine the physiological significance of TRH fibers in these vagal nuclei, TRH was microinjected into the DMV and NA while monitoring gastric (antrum and pylorus) and duodenal motility as well as mean blood pressure (MBP) and heart rate. Microinjections of TRH (16-500 ng) into the DMV resulted in increases in pyloric and antral motility (minute motility index increased from 1.28 to 8.70 in the pylorus, P less than 0.05, and from 2.29 to 4.25 in the antrum, P less than 0.05). TRH microinjection also increased the intraluminar pressure in the stomach by 6.1 +/- 1.3 mmHg. No significant changes in duodenal motility, MBP, or heart rate were noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Exaggeration of the cholecystokinin-induced motor response in the cat gastrointestinal tract.

A stimulation of distal colonic motor activity was produced in anesthetized cats following intravenous administration of cholecystokinin. The contractile response elicited by cholecystokinin was not reduced following pretreatment with atropine. However, when animals were treated with agents which increased the net cholinergic input to the colon, a marked exaggeration of the subsequent cholecystokinin-induced response occurred. This cholinergically mediated exaggeration was produced following administration of the cholinergic agonist bethanechol, or after removal of tonic inhibitory systems mediated by prostaglandin or alpha-adrenergic input, whose blockade results in atropine-sensitive colonic stimulation. Cholecystokinin was also found to produce stimulation of motor activity in the pylorus, jejunum, proximal colon and gallbladder. Cholinergically mediated exaggeration of the cholecystokinin response was also present in the pylorus and proximal colon, but not gallbladder or jejunum. An inhibition of spontaneous motor activity was produced in the ileum or duodenum following cholecystokinin administration.