Metabolic fate of valproic acid in the rhesus monkey. Formation of a toxic metabolite, 2-n-propyl-4-pentenoic acid

The metabolic fate of an iv bolus dose (13.5 mg kg-1) of valproic acid (VPA) was studied in adult male rhesus monkeys. Renal excretion proved to be the major route of elimination of the drug and a total of 17 metabolites, accounting collectively for some 82% of the administered dose, were identified in urine by GC-MS techniques. Many of these metabolites were present largely in the form of glucuronide conjugates, as was VPA itself. The principal pathways of VPA biotransformation were, in order of decreasing quantitative importance, ester glucuronide formation, omega-oxidation, beta-oxidation and (omega-1)-hydroxylation. In addition, three mono-unsaturated metabolites, identified as (E)-delta 2-, (E)-delta 3-, and delta 4-VPA, were detected in both plasma and urine. Quantitative analysis of these unsaturated VPA metabolites indicated that the delta 4 olefin, which is known to be a potent hepatotoxic agent, was the predominant isomer of the group.     

Challenges in geriatric oral health research methodology concerning caregivers of cognitively impaired elderly adults

Little is known about oral health care behaviors of community-dwelling, cognitively impaired elderly (CIE) persons. Few studies have been conducted regarding the actual provision of oral care for CIE persons or the attitudes and concerns about oral health among their caregivers. The CIE person's ability to perform self-care decreases over time, and the role of the caregiver in daily oral care becomes increasingly important. The purpose of this pilot study was to explore the attitudes toward oral health and identify related concerns among caregivers who care for community-dwelling CIE persons. Caregivers were surveyed by means of a self-administered, mailed questionnaire. To maintain confidentiality, an intermediary was used for recruitment and data collection. Overall, 148 caregivers were invited by an intermediary to participate in the survey; only 21 (14%) consented to participate and returned the questionnaire. This paper discusses some of the numerous methodological challenges identified when an attempt was made to survey caregivers' attitudes toward and barriers to providing oral care for a dependent CIE.     

The Relationship Between Daily Life Stress and Gastrointestinal Symptoms in Women with Irritable Bowel Syndrome

Research on irritable bowel syndrome (IBS), a functional disorder of the gastrointestinal (GI) system, has linked GI symptoms to stress. This study examined the relationship between daily stress and GI symptoms across women and within woman in IBS patients (n = 26), IBS nonpatients (IBS-NP; n = 23), and controls (n = 26), controlling for menstrual cycle phase. Women (ages 20–45) completed daily health diaries for two cycles in which they monitored daily GI symptoms and stress levels. The Life Event Survey (LES) was used as a retrospective measure of self-reported stress. The across-women analyses showed higher mean GI symptoms and stress in the IBS and IBS-NP groups relative to controls but no group differences in LES scores. The within-woman analyses found a significant and positive relationship between daily stress and daily symptoms in both the IBS-NP and the IBS groups. Controlling for menstrual cycle had no substantial impact on the results.     

Initial healing in the dog of submerged versus non‐submerged porous‐coated endosseous dental implants

It has previously been reported that porous‐coated root form endosseous dental implants, became well integrated when used in the traditional 2‐stage surgical approach. In this study, the placement of the implant in a 1‐stage (non‐submerged)technique was to be explored. Implants were placed in the mandibles of dogs, and 2 designs were used differing only in that one (experimental) had a 3mm transgingival extension, permitting it to be exposed lo the oral cavity from the outset. 12 (3 per animal) non‐submerged implants were placed on I side of 4 beagle dogs and 12 control (submerged) implants were placed contralaterally. All implants were allowed to heal for 6 weeks, after which histological preparations were made. 2 of 12 non‐submerged implants were lost due to post‐operative complications: otherwise, all implants healed uneventfully. Histomorphometric analysis revealed bone‐implant contact, as assessed by absolute bone contact (ABC) and contact length fraction (CLF). to be greater for the submerged design, suggesting that bone healing may be delayed with the non‐submerged approach. As well. at this early stage of healing, for both implant designs, ABC and CLF were significantly greater on proximal than on buccal and lingual aspects.     

Effect of intracellular injection of inositol trisphosphate on cytosolic calcium and membrane currents in Aplysia neurons.

Pacemaker cells of Aplysia californica display a regular bursting that results from a complex interplay of Ca(2+)-mediated conductances and a continuous influx and extrusion of Ca2+. The effect of the second messenger 1,4,5-inositol trisphosphate (InsP3) on intracellular free Ca2+ concentration (Cai) regulation and electrical properties was investigated in identified neurons of the abdominal ganglion (R15, L2-L4, L6). Double-barreled Ca-selective microelectrodes were used to pressure inject InsP3 and measure Cai at the same point. Brief injection of InsP3 resulted in an average increase of Cai of 9.2 +/- 10.0 microM (+/- SE; n = 14) that decayed in about 1 min. The InsP3-induced elevation of Cai increased in a dose-dependent manner and saturated when large amounts of InsP3 were injected. The InsP3-induced Cai increase was the result of mobilization from intracellular stores; Cai could be repeatedly mobilized by InsP3 in cells superfused with 0 Ca artificial seawater for more than 60 min. Following multiple injections of InsP3, there was no evidence of immediate inhibition or facilitation. the spatial nature of the InsP3-induced Cai increase was investigated by moving the double-barreled Ca-selective microelectrode tip in a stepwise manner relative to the membrane surface. The largest InsP3-induced Cai increases were measured in an area 0-80 microns from the membrane surface; some cells had their largest InsP3-induced Cai increase some 120-160 microns away from the membrane. Injection of InsP3 in a bursting neuron induced an immediate train of action potentials followed by membrane hyperpolarization and a decrease in the burst frequency. Injection of InsP3 in voltage-clamped cells induced a biphasic response: a rapid inward current followed by a more prolonged outward current; the temporal overlap of the currents was depth dependent. Injection of InsP3 or Ca2+ from a double-barreled injecting electrode induced currents that were different in waveform and time course, indicating that part of the conductance change induced by InsP3 is direct and not mediated by the mobilized Ca2+. In BAPTA [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'tetra-acetic acid]-loaded cells, the InsP3-induced inward current was mostly unaffected while the Ca-induced outward current was largely attenuated. The results suggest that InsP3 mobilizes Ca2+ from discrete intracellular compartments and induces distinct changes in membrane currents that seem to be independent of the Cai increase.     

Cellular mechanism of the conduction abnormalities induced by serum from anti-Ro/SSA-positive patients in rabbit hearts.

In this study, IgG fractions from sera of SLE patients with anti-Ro/SSA or anti-Ro/SSA and anti-La/SSB activity were tested in Langendorff preparations of adult rabbit hearts, aiming to reproduce the cardiac manifestations observed in neonatal lupus in an experimental model. The hearts were perfused with normal Tyrode's solution for 30 min, followed by perfusion with Tyrode's containing 0.3 mg/ml of anti-Ro/SSA- (or anti-Ro/La-) positive IgG (nine sera), anti-ribonucleoprotein (RNP)-positive IgG (five sera), or IgG fractions from normal donors (five sera). In one third of the experiments done with anti-Ro/La-positive IgG, heart block was observed. With the remaining fractions, a decrease in heart rate of 17.1% was observed, but normal sinus rhythm was maintained. The IgG fractions with anti-RNP activity (five experiments) and from normal sera (six experiments) reduced heart rates by 12.9 and 3.3%, respectively, but heart block was not observed. To further characterize the cellular mechanisms involved in the conduction disturbances observed in the whole rabbit hearts, we conducted experiments with ventricular myocytes isolated from young rabbit hearts, studied by whole cell patch-clamp technique. In these experiments, the slow inward currents were analyzed during the superfusion of the cell with normal Tyrode's solution and 5 min after superfusion with Tyrode's solution containing 0.3 mg/ml of anti-Ro/SSA- (or anti-Ro/La-) positive IgG (five sera), anti-RNP-positive IgG (three sera), or IgG from normal donors (four sera). Resting and action potential amplitudes were not affected by any of the sera used. The anti-Ro/SSA IgG fraction induced a mean reduction in the peak slow inward current of 31.6%. IgG fractions with anti-RNP activity reduced slow inward current by 4.4%, whereas IgG fractions from normal donors increased this current by 3.3%. IgG-free fractions from sera of patients with anti-Ro/SSA activity did not alter the peak slow inward current. These results show, for the first time, that the presence of anti-Ro/SSA or anti-Ro/SSA and anti-La/SSB antibody activity in IgG fractions from lupus patients' sera can induce cardiac conduction disorders similar to those observed in neonatal lupus.