Successful pharmacotherapy for the treatment of severe feeding aversion with mechanistic insights from cross-species neuronal remodeling.

Pediatric feeding disorders affect up to 5% of children, causing severe food intake problems that can result in serious medical and developmental outcomes. Behavioral intervention (BI) is effective in extinguishing feeding aversions, and also expert-dependent, time/labor-intensive and not well understood at a neurobiological level. Here we first conducted a double-blind, placebo-controlled trial comparing BI with BI plus d-cycloserine (DCS). DCS is a partial N-methyl-d-aspartate (NMDA) receptor agonist shown to augment extinction therapies in multiple anxiety disorders. We examined whether DCS enhanced extinction of feeding aversion in 15 children with avoidant/restrictive food intake disorder (ages 20-58 months). After five treatment days, BI improved feeding by 37%. By contrast, BI+DCS improved feeding by 76%. To gain insight into possible mechanisms of successful intervention, we next tested the neurobiological consequences of DCS in a murine model of feeding aversion and avoidance. In mice with conditioned food aversion, DCS enhanced avoidance extinction across a broad dose range. Confocal fluorescence microscopy and three-dimensional neuronal reconstruction indicated that DCS enlarged dendritic spine heads-the primary sites of excitatory plasticity in the brain-within the orbitofrontal prefrontal cortex, a sensory-cognition integration hub. DCS also increased phosphorylation of the plasticity-associated extracellular signal-regulated kinase 1/2. In summary, DCS successfully augments the extinction of food aversion in children and mice, an effect that may involve plasticity in the orbitofrontal cortex. These results warrant a larger-scale efficacy study of DCS for the treatment of pediatric feeding disorders and further investigations of neural mechanisms.

Analysis of transition state mimicry by tight binding aminothiazoline inhibitors provides insight into catalysis by human O-GlcNAcase.

The modification of nucleocytoplasmic proteins with O-linked N-acetylglucosamine (O-GlcNAc) plays diverse roles in multicellular organisms. Inhibitors of O-GlcNAc hydrolase (OGA), the enzyme that removes O-GlcNAc from proteins, lead to increased O-GlcNAc levels in cells and are seeing widespread adoption in the field as a research tool used in cells and in vivo. Here we synthesize and study a series of tight binding carbohydrate-based inhibitors of human OGA (hOGA). The most potent of these 2'-aminothiazolines binds with a sub-nanomolar Ki value to hOGA (510 ± 50 pM) and the most selective has greater than 1 800 000-fold selectivity for hOGA over mechanistically related human lysosomal ß-hexosaminidase. Structural data of inhibitors in complex with an hOGA homologue reveals the basis for variation in binding among these compounds. Using linear free energy analyses, we show binding of these 2'-aminothiazoline inhibitors depends on the pKa of the aminothiazoline ring system, revealing the protonation state of the inhibitor is a key driver of binding. Using series of inhibitors and synthetic substrates, we show that 2'-aminothiazoline inhibitors are transition state analogues of hOGA that bind to the enzyme up to 1-million fold more tightly than the substrate. These collective data support an oxazoline, rather than a protonated oxazolinium ion, intermediate being formed along the reaction pathway. Inhibitors from this series will prove generally useful tools for the study of O-GlcNAc. The new insights gained here, into the catalytic mechanism of hOGA and the fundamental drivers of potency and selectivity of OGA inhibitors, should enable tuning of hOGA inhibitors with desirable properties.

The search for cost-effective prevention of postoperative nausea and vomiting in the child undergoing reconstructive burn surgery: ondansetron versus dimenhydrinate.

Postoperative nausea and vomiting (PONV) is a common and unpleasant problem for children with burns who are undergoing reconstructive burn surgery. Ondansetron and dimenhydrinate have been found to be effective for the prevention of PONV in other patient populations, but they have not been directly compared in the pediatric population. A prospective, randomized, double-blind, placebo-controlled comparison of ondansetron and dimenhydrinate was performed. One hundred patients with a mean age of 11.8 years who were undergoing reconstructive burn surgery with general anesthesia were randomly assigned to receive either a placebo, 0.1 mg/kg of ondansetron, or 0.5 mg/kg of dimenhydrinate. The 3 groups were well matched for all demographic and procedural variables. The study drugs were given twice, first at the end of surgery and again 4 hours later, to ensure adequate blood levels during the 8-hour study period. Postoperatively, on the basis of the presence and amount of PONV experienced, all patients were assigned a PONV score by a blinded investigator. Statistically significant reductions in the incidence of PONV in the patients who received ondansetron or dimenhydrinate were found, as compared with the results of patients who received placebo. Postoperative vomiting was reduced from 61% in the placebo group to 29% and 40% in the ondansetron and dimenhydrinate groups, respectively, and PONV was similarly reduced from 69% to 47% and 40%, respectively. The differences between ondansetron and dimenhydrinate were not significant. The average cost to our pharmacy for the prescribed dose of ondansetron was $19.34; the cost for dimenhydrinate was $0.90. In this patient population, dimenhydrinate was as effective as ondansetron for the prevention of PONV and postoperative vomiting, and it was much less expensive.

Pharmacokinetics of dolasetron after oral and intravenous administration of dolasetron mesylate in healthy volunteers and patients with hepatic dysfunction.

In previous studies, dolasetron was shown to have both renal and hepatic elimination mechanisms. This study was conducted to determine the impact of varying degrees of hepatic dysfunction on the pharmacokinetics and safety of dolasetron and its reduced metabolites. Seventeen adults were studied: six healthy volunteers (group I), seven patients with mild hepatic impairment (Child-Pugh class A; group II), and four patients with moderate to severe hepatic impairment (Child-Pugh class B or C1; group III). Single 150-mg doses of dolasetron mesylate were administered intravenously and orally, with a 7-day washout period separating treatments. After intravenous administration, no differences were observed between healthy volunteers and patients with hepatic impairment in maximum plasma concentration (Cmax), areas under the plasma concentration-time curve (AUC), or elimination half-life (t1/2) of intact dolasetron. No significant differences were found in Cmax, AUC, or apparent clearance (C(lapp)) of hydrodolasetron, the primary metabolite of dolasetron. The mean t1/2 increased from 6.87 hours in group I to 11.69 hours in group III. After oral administration, C(lapp) of hydrodolasetron decreased by 42%, and Cmax increased by 18% in patients with moderate to severe hepatic impairment. There were less changes in patients with mildly hepatic impairment. Total percentage of dose excreted as metabolites was similar for healthy volunteers and patients with hepatic impairment, although urinary metabolite profiles differed slightly. Dolasetron was well tolerated and there were no apparent differences in adverse effects between groups or treatments. Because hepatic impairment did not influence Cl(app) of hydrodolasetron after intravenous administration, and the range of plasma concentrations of hydrodolasetron after oral administration was not different from those observed in healthy volunteers, dosage adjustments are not recommended for patients with hepatic disease and normal renal function.

Future time perspective, response rates, and older persons: another chapter in the story.

Data quality is compromised when response rates to items vary with age group. Shmotkin (1992) found a 29% nonresponse rate to future-oriented items in persons older than 60 years and suggested future apprehension as a cause. The authors administered similar items to 251 older persons and found fewer instances of nonresponding to future-oriented items. On the basis of the high response rate to an enlarged Cantril ladder measuring future quality of life, presented in interview, the authors question the generality of future apprehension as a determinant of nonresponding. The authors suggest that mode of administration, size of items, and scale complexity, as well as future apprehension, are determinants of nonresponding to future-oriented items and scales.

Subjective age and health perceptions of older persons: maintaining the youthful bias in sickness and in health.

Self-reports of 250 persons fifty years of age and older confirm the increasing bias toward reporting a more youthful age as one increases in years. Optimistic perceptions of health care also maintained in older persons. Results from two subsets of this sample (N = 48) further indicate that the youthful and optimistic bias occurs in older persons with poorer and failing health (N = 23) as well as for persons in stable and good health (N = 25). Given the importance of self-perceptions in quality of life and in determining survivability, and given the indication that such measures are modifiable, it is suggested that future research be aimed at identifying those self-perceptions of health and age that are most susceptible to intervention.

Spironolactone metabolism: steady-state serum levels of the sulfur-containing metabolites.

Metabolism of spironolactone in man is extensive and complex. For many years the dethioacetylated metabolite, canrenone, was assumed to be the major metabolite. However, recent studies using specific high performance liquid chromatography (HPLC) have demonstrated the presence of spironolactone and the sulfur-containing metabolites 7 alpha-thiomethylspirolactone (IV) and 6 beta-hydroxy-7 alpha-thiomethylspirolactone (V), in addition to canrenone, in the serum after a single oral dose of spironolactone. The importance of spironolactone and metabolites IV and V relative to canrenone at steady state remains unknown and was the subject of the present investigation. Twelve healthy males received 100 mg spironolactone, once daily, for 15 days. Repeated blood samples were taken on days 1, 8 and 15 for estimation of spironolactone and its metabolites. Peak serum levels [mean (SD)] of spironolactone, canrenone, and sulfur-containing metabolites IV and V were 72 (45), 155 (43), 359 (106) and 101 (26) ng/ml, respectively on day 1 and 80 (20), 181 (39), 391 (118) and 125 (24) ng/ml, respectively on day 15. The AUC (0-24) values of these compounds on day 15 were 231 (50), 2173 (312), 2804 (777) and 1727 (367) ng.hr/ml, respectively and the post-steady state elimination half-life (t1/2) values were 1.4 (0.5), 16.5 (6.3), 13.8 (6.4), and 15.0 (4.0) hours, respectively. It was concluded that unmetabolized spironolactone is present in the serum and that the sulfur-containing metabolite IV rather than canrenone is the major metabolite in serum following single or repeated doses of spironolactone.

Abnormal fibrinolysis in retinal vein occlusion.

Some cases of central and branch retinal vein occlusion are associated with and may be caused by abnormal fibrinolytic mechanisms. The abnormality we described is that of plasminogen activator enzyme deficiency, which is a treatable condition. That seven cases were seen by one practitioner in a two year period may indicate that this particular condition is under-recognised.

Guidelines for the management of oral anticoagulant therapy in patients undergoing surgery.

The management of patients who require surgery while being treated with oral anticoagulants is a difficult balance between the risks of bleeding and those of recurrent thromboembolism. The urgency and the extent and site of surgery are important considerations, as are the strength of the indication for anticoagulants and the degree of anticoagulation. A practical approach is outlined for various situations that may be encountered.

Laboratory evaluation of an automated antimicrobial susceptibility system.

A newly introduced automated method for antibiotic susceptibility testing, AUTOBAC 1, has been evaluated by comparison with the disk agar diffusion method (Bauer-Kirby). A total of 2,518 strains of gram-positive (540) and gram-negative (1,978) organisms isolated from clinical specimens was examined by both methods with eight or ten antibiotics, including Tobramycin. An overall agreement of 97.4% was obtained when results were compared by individual antibiotic. However, many discrepancies were observed when individual genera or species were analyzed. Of 2,518 strains examined, 651 (26%) showed discrepancies in response to one or more antibiotics. Strains, showing discrepancies were re-examined by the broth dilution susceptibility method. The results obtained favored the disk agar diffusion method. Reproducibility experiments revealed a greater inconsistency in the AUTOBAC 1 system than in the agar diffusion test. It is concluded that although a rapid automated system for antibiotic sensitivity testing is desirable, the conventional disk agar diffusion method is easier to perform, more reliable, and a less expensive procedure for antibiotic sensitivity determination.