Lorazepam-valproate interaction: studies in normal subjects and isolated perfused rat liver

Valproate (VPA) has been shown to interact with all the major antiepileptic drugs (AEDs) through two mechanisms of action: displacement from albumin binding sites and inhibition of drug metabolism. More recently, evidence showed that VPA inhibits the elimination of drugs metabolized by glucuronide conjugation. Lorazepam (LZP), which is primarily eliminated by conjugation with glucuronic acid, is administered concurrently with VPA both in treatment of epilepsy and in patients treated with VPA for psychiatric disorders. Therefore, a significant drug interaction is likely. We investigated such interaction both in in vitro isolated perfused rat liver (IPRL) and in normal subjects. LZP [2 mg, intravenous (i.v.) bolus] was administered to 8 normal volunteers before and after chronic dosing with VPA. In 6 of 8 subjects, VPA significantly decreased LZP plasma clearance by an average of 40% (p < 0.05) and increased LZP concentrations by decreasing formation clearance of the LZP glucuronide. In the IPRL studies, VPA also significantly decreased formation of LZP glucuronide (from 0.72 +/- 0.14 to 0.22 +/- 0.15 ml/h/kg, p < 0.05), indicating that IPRL is a useful tool for evaluation of the effect of VPA on drugs eliminated by glucuronide conjugation.     

The ground water behaviour pattern and foundation stabilisation practice at hartebeestfontein

Hartebeestfontein Gold Mining Company Limited, which produces 100 kg of gold per working day, has a mining lease area situated mainly over dolomite. A major river nearby governs the regional drainage. The formation of sinkholes and dolines, caused by fluctuations in the water table and the flow of water underground, often accelerated as the result of unavoidable or inadvertent surface activities, is common in such terranes. To maintain production, meticlous ground investigations under new installations plus periodic re-examination and stabilisation under existing ones, particularly key installations, is necessary. The local ground water behaviour pattern is controlled by three impervious major dykes and two major fissure zones, the latter draining surface water into the mine workings. Monthly water table measurements over 25 years show a steady rise to a limit over the area of one fissure zone and a drastic lowering over the other. The value of gravity techniques and thermal infra-red line scanning for cavity detection in the Hartebeestfontein context, is discussed. The procedures followed, for stabilising ground and foundations, are illustrated by means of case histories. The extension of the techniques, learnt from the stabilisation experience, to limiting water seepage into shafts sunk through dolomite, is also discussed.     

System Operational Evaluation of Mine Monitoring Systems

In the testing of mine monitoring systems, a software package was developed for the mine monitoring test facility designed at West Virginia University. The software establishes delay times of sensor input to annunciation for single alarms and multiple simultaneous alarms. The alarm measurement techniques for the test fixture are described, as is the software developed to analyze and graph monitoring system response data. Also included is the analysis capability of the facility, the criteria for evaluating mine monitoring systems, and typical test data from a sample system.     

COPD: using nutrition to prevent respiratory function decline

Close to three-fourths of patients with chronic obstructive pulmonary disease (COPD) suffer from weight loss. Identifying a single cause for this is difficult, as several factors-including chronic mouth breathing, dyspnea, aerophagia, certain medications, and depression-often act in concert. Malnutrition can exacerbate symptoms of COPD by decreasing ventilatory muscle strength, exercise tolerance, and immunocompetence, and by increasing the risk of depression and anxiety. Goals of nutrition intervention are to prevent or reverse malnutrition without worsening the disease process and to improve respiratory function, thereby reducing morbidity and delaying mortality. Recommendations for intake of fats, carbohydrates, protein, and water must be individualized.     

Converging inputs to the entorhinal cortex from the piriform cortex and medial septum: facilitation and current source density analysis

Converging inputs to the entorhinal cortex from the piriform cortex and medial septum: facilitation and current source density analysis. J. Neurophysiol. 78: 2602-2615, 1997. The entorhinal cortex receives sensory inputs from the piriform cortex and modulatory inputs from the medial septum. To examine short-term synaptic facilitation effects in these pathways, current source density (CSD) analysis was used first to localize the entorhinal cortex membrane currents, which generate field potentials evoked by stimulation of these afferents. Field potentials were recorded at 50-micron intervals through the medial entorhinal cortex in urethan-anesthetized rats and the one-dimensional CSD was calculated. Piriform cortex stimulation evoked a surface-negative, deep-positive field potential component in the entorhinal cortex with mean onset and peak latencies of 10.4 and 18.4 ms. The component followed brief 100-Hz stimulation, consistent with a monosynaptic response. CSD analysis linked the component to a current sink, which often began in layer I before peaking in layer II. A later, surface-positive field potential component peaked at latencies near 45 ms and was associated with a current source in layer II. Medial septal stimulation evoked positive and negative field potential components which peaked at latencies near 7 and 16 ms, respectively. A weaker and more prolonged surface-negative, deep-positive component peaked at latencies near 25 ms. The early components were generated by currents in the hippocampal formation, and the late surface-negative component was generated by currents in layers II to IV of the entorhinal cortex. Short-term facilitation effects in conscious animals were examined using electrodes chronically implanted near layer II of the entorhinal cortex. Paired-pulse stimulation of the piriform cortex at interpulse intervals of 30 and 40 ms caused the largest facilitation (248%) of responses evoked by the second pulse. Responses evoked by medial septal stimulation also were facilitated maximally (59%) by a piriform cortex conditioning pulse delivered 30-40 ms earlier. Paired pulse stimulation of the medial septum caused the largest facilitation (149%) at intervals of 70 ms, but piriform cortex evoked responses were facilitated maximally (46%) by a septal conditioning pulse 100-200 ms earlier. Frequency potentiation effects were maximal during 12- to 18-Hz stimulation of either the piriform cortex or medial septum. Occlusion tests suggested that piriform cortex and medial septal efferents activate the same neurons. The CSD analysis results show that evoked field potential methods can be used effectively in chronically prepared animals to examine synaptic responses in the converging inputs from the piriform cortex and medial septum to the entorhinal cortex. The short-term potentiation phenomena observed here suggest that low-frequency activity in these pathways during endogenous oscillatory states may enhance entorhinal cortex responsivity to olfactory inputs.     

Identification of a gene that causes primary open angle glaucoma

Glaucoma is a major cause of blindness and is characterized by progressive degeneration of the optic nerve and is usually associated with elevated intraocular pressure. Analyses of sequence tagged site (STS) content and haplotype sharing between families affected with chromosome 1q-linked open angle glaucoma (GLC1A) were used to prioritize candidate genes for mutation screening. A gene encoding a trabecular meshwork protein (TIGR) mapped to the narrowest disease interval by STS content and radiation hybrid mapping. Thirteen glaucoma patients were found to have one of three mutations in this gene (3.9 percent of the population studied). One of these mutations was also found in a control individual (0.2 percent). Identification of these mutations will aid in early diagnosis, which is essential for optimal application of existing therapies.     

Wooden sticks as the source of a pseudoepidemic of infection with Rhizopus microsporus var. rhizopodiformis among immunocompromised patients

Wooden sticks used to suspend feces obtained for surveillance cultures were found to be the source of Rhizopus microsporus var. rhizopodiformis causing a pseudo-outbreak among 17 immunocompromised patients cared for in three different wards. Nonsterile wooden products should therefore not be used for collecting, handling, and processing specimens for microbiological examination.