Subtherapeutic voriconazole concentrations associated with concomitant dexamethasone: case report and review of the literature.

WHAT IS KNOWN AND OBJECTIVE: Voriconazole has significant drug interactions due to metabolism by CYP enzymes. Subtherapeutic voriconazole concentrations associated with concomitant dexamethasone are not well described. CASE DESCRIPTION: An 84-year-old male was started on voriconazole for a fungal brain abscess. He was readmitted due to clinical failure thought to be the result of subtherapeutic voriconazole concentrations. Dexamethasone was identified as a potential cause due to its induction of CYP enzymes. This interaction was substantiated by sequential troughs that demonstrated a rise in voriconazole concentrations as dexamethasone was tapered off. WHAT IS NEW AND CONCLUSION: Therapeutic drug monitoring for patients on voriconazole and dexamethasone is essential to prevent suboptimal clinical outcomes.

Inhibition of a novel fibrogenic factor Tl1a reverses established colonic fibrosis.

Intestinal fibrostenosis is among the hallmarks of severe Crohn's disease. Patients with certain TNFSF15 (gene name for TL1A) variants over-express TL1A and have a higher risk of developing strictures in the small intestine. In addition, sustained Tl1a expression in mice leads to small and large intestinal fibrostenosis under colitogenic conditions. The aim of this study was to determine whether established murine colonic fibrosis could be reversed with Tl1a antibody (Ab). Treatment with neutralizing Tl1a Ab reversed colonic fibrosis back to the original pre-inflamed levels, potentially as a result of lowered expression of connective tissue growth factor, Il31Ra, transforming growth factor ß1 and insulin-like growth factor-1. In addition, blocking Tl1a function by either neutralizing Tl1a Ab or deletion of death domain receptor 3 (Dr3) reduced the number of fibroblasts and myofibroblasts, the primary cell types that mediate tissue fibrosis. Primary intestinal myofibroblasts expressed Dr3 and functionally responded to direct Tl1a signaling by increasing collagen and Il31Ra expression. These data demonstrated a direct role for TL1A-DR3 signaling in tissue fibrosis and that modulation of TL1A-DR3 signaling could inhibit gut fibrosis.

Interleukin-10/Ceftriaxone prevents E. coli-induced delays in sensorimotor task learning and spatial memory in neonatal and adult Sprague-Dawley rats.

Intrauterine infection during pregnancy is associated with early activation of the fetal immune system and poor neurodevelopmental outcomes. Immune activation can lead to alterations in sensorimotor skills, changes in learning and memory and neural plasticity. Both interleukin-10 (IL-10) and Ceftriaxone have been shown to decrease immune system activation and increase memory capacity, respectively. Using a rodent model of intrauterine infection, we examined sensorimotor development in pups, learning and memory, via the Morris water maze, and long-term potentiation in adult rats. Pregnant rats at gestational day 17 were inoculated with 1 x 10(5) colony forming units of Escherichia coli (E. coli) or saline. Animals in the treatment group received IL-10/Ceftriaxone for 3 days following E. coli administration. Intrauterine infection delayed surface righting, negative geotaxis, startle response and eye opening. Treatment with IL-10/Ceftriaxone reduced the delay in these tests. Intrauterine infection impaired performance in the probe trial in the Morris water maze (saline 25.13+/-1.01; E. coli 20.75+/-1.01; E. coli+IL-10/Ceftriaxone 20.2+/-1.62) and reduced the induction of long-term potentiation (saline 141.5+/-4.3; E. coli 128.7+/-3.9; E. coli+IL-10/Ceftriaxone 140.0+/-10). In summary, the results of this study indicate that E. coli induced intrauterine infection delays sensorimotor and learning and memory, while IL-10/Ceftriaxone rescues some of these behaviors. These delays were also accompanied by an increase in interleukin-1beta levels, which indicates immune activation. IL-10/Ceftriaxone prevents these delays as well as decreases E. coli-induced interleukin-1beta activation and may offer a window of time in which suitable treatment could be administered.

Oropharyngeal scintigraphy: a reliable technique for the quantitative evaluation of oral-pharyngeal swallowing.

A valid and reliable technique to quantify the efficiency of the oral-pharyngeal phase of swallowing is needed to measure objectively the severity of dysphagia and longitudinal changes in swallowing in response to intervention. The objective of this study was to develop and validate a scintigraphic technique to quantify the efficiency of bolus clearance during the oral-pharyngeal swallow and assess its diagnostic accuracy. To accomplish this, postswallow oral and pharyngeal counts of residual for technetium-labeled 5- and 10-ml water boluses and regional transit times were measured in 3 separate healthy control groups and in a group of patients with proven oral-pharyngeal dysphagia. Repeat measures were obtained in one group of aged (> 55yr) controls to establish test-retest reliability. Scintigraphic transit measures were validated by comparison with radiographic temporal measures. Scintigraphic measures in those with proven dysphagia were compared with radiographic classification of oral vs. pharyngeal dysfunction to establish their diagnostic accuracy. We found that oral ( p = 0.04), but not pharyngeal, isotope clearance is swallowed bolus-dependently. Scintigraphic transit times do not differ from times derived radiographically. All scintigraphic measures have extremely good test-retest reliability. The mean difference between test and retest for oral residual was -1% (95% CI -3%-1%) and for pharyngeal residual it was -2% (95% CI -5%-1%). Scintigraphic transit times have very poor diagnostic accuracy for regional dysfunction. Abnormal oral and pharyngeal residuals have positive predictive values of 100% and 92%, respectively, for regional dysfunction. We conclude that oral-pharyngeal scintigraphic clearance is highly reliable, bolus volume-dependent, and has a high predictive value for regional dysfunction. It may prove useful in assessment of dysphagia severity and longitudinal change.

Reduced placental perfusion causes an increase in maternal serum leptin.

OBJECTIVE: We tested the hypothesis that the inadequately perfused placenta increases production of leptin, which can be detected in maternal serum. STUDY DESIGN: Sprague-Dawley rats (n=13), on day 14 of gestation, had placement of clips on the aorta and the ovarian arteries providing 35 per cent occlusion of the vessels. Eight rats had sham surgery and 14 rats served as non-surgical controls. All animals were sacrificed on day 19 of gestation. Maternal serum was obtained, and pups and placentae were weighed. RESULTS: Both placental weights and pup weights were reduced due to reduced uterine perfusion and were negatively correlated with maternal serum leptin (P=0.018 and 0.028, respectively). Maternal serum leptin was increased in the treatment group (2.21 ng/ml+/-64 ng/ml) compared to controls (1.66 ng/ml+/-38 ng/ml) (P=0.031). CONCLUSIONS: Our findings suggest that reduced placental perfusion results in an increase in maternal serum leptin. Further investigation is needed to determine if maternal serum leptin may be useful in identifying pregnancies with uteroplacental insufficiency.

Diagnostic use of physicians' detection of urine fluorescence in a simulated ingestion of sodium fluorescein-containing antifreeze.

STUDY OBJECTIVE: We sought to assess physicians' ability to accurately determine the presence or absence of sodium fluorescein (SF) in urine at a concentration corresponding to that present after ingestion of a toxic amount of commercial automotive antifreeze. METHODS: We studied 2 different urine specimen evaluation formats--one presenting isolated specimens, and the other presenting specimens grouped for comparison--to determine whether the visual clues afforded by grouped comparison aided the accuracy of the evaluation. On each study day, 3 urine specimens (1 control specimen obtained before SF administration and 2 specimens obtained after SF administration) were obtained from each of 9 or 10 volunteers. Each of these 27 or 30 urine specimens were presented sequentially and in random order to 2 emergency physicians during separate evaluation time periods. Each physician was asked to classify each specimen as fluorescent or nonfluorescent (sequential format). After a rest period, each physician, again separately, was asked to look at the same 27 or 30 urine specimens, this time all together in a test tube rack so that grouped comparisons were possible. The physicians again classified each sample as either fluorescent or nonfluorescent (grouped format). We assessed sensitivity, specificity, and accuracy of the evaluation by each presentation format (sequential or grouped). RESULTS: Mean examiner sensitivity, specificity, and accuracy for detecting the presence of SF in urine using the sequential presentation format were 35%, 75%, and 48%, respectively, whereas the same test performance indices were 42%, 66%, and 50%, respectively, when the grouped format was used. CONCLUSION: Wood's lamp determination of urine fluorescence is of limited diagnostic utility in the detection of SF ingestion in an amount equivalent to toxic ingestion of some ethylene glycol--containing automotive antifreeze products.

Intravenous pyridoxine-induced metabolic acidosis.

STUDY OBJECTIVE: Pyridoxine hydrochloride, the antidote for isonicotinic acid hydrazide (INH)--induced seizures, is available in solution at a concentration of 100 mg/mL at a pH of less than 3. Pyridoxine is often infused rapidly in large doses for INH-induced seizures. Effects of pyridoxine infusion on base deficit in amounts given for INH poisoning have not been studied in human subjects. We hypothesized that this infusion would result in transient worsening of acidosis. METHODS: We conducted a randomized, controlled crossover trial in human volunteers. Five healthy volunteers (mean age, 35 years; range, 29 to 43 years) were randomized to receive intravenous placebo (50 mL of normal saline solution) or 5 g of pyridoxine (50 mL) over 5 minutes. A peripheral intravenous catheter was established in each arm, and a heparinized venous blood sample was obtained for base deficit at baseline and 3, 6, 10, 20, and 30 minutes after infusion. After at least a 1-week washout period, the volunteers were assigned to the alternate arms of the experiments, thus acting as their own control subjects. Data were analyzed by using the 2-tailed paired t test, controlling for multiple comparisons. RESULTS: No difference was noted between groups at baseline. A statistically significant increased base deficit was noted after the pyridoxine infusion versus control at 3 to 20 minutes but not at 30 minutes (P =.1). Maximal mean increase in base deficit (2.74 mEq/L) was noted at 3 minutes. CONCLUSION: A transient increase in base deficit occurs after the infusion of 5 g of pyridoxine in normal volunteers.

Development and validation of a self-report symptom inventory to assess the severity of oral-pharyngeal dysphagia.

BACKGROUND & AIMS: The aim of this study was to develop and evaluate the validity and reliability of a self-report inventory to measure symptomatic severity of oral-pharyngeal dysphagia. METHODS: Test-retest reliability and face, content, and construct validity of a prototype visual analogue scale inventory were assessed in 45 patients who had stable, neuromyogenic dysphagia. RESULTS: Normalized scores varied over time by -0.5% +/- 17.6% (95% confidence interval, -9.2% to 8.2%). Factor analysis identified a single factor (dysphagia), to which 18 of 19 questions contributed significantly, that accounted for 56% of total variance (P < 0.0001). After deletion of 2 questions with poor face validity and patient compliance, this proportion increased to 59%; mean test-retest change was -2% (95% confidence interval, -11% to 7%); and total score correlated highly with an independent global assessment severity score (r = 0.7; P < 0.0001). A mean 70% reduction in score (P < 0.0001) was observed after surgery in patients with Zenker's diverticulum (discriminant validity). CONCLUSIONS: Applied to patients with neuromyogenic dysphagia, the 17-question inventory shows strong test-retest reliability over 2 weeks as well as face, content, and construct validity. Discriminant validity (responsiveness) has been demonstrated in a population with a correctable, structural cricopharyngeal disorder. Responsiveness of the instrument to treatment in neuromyogenic dysphagia remains to be quantified.

Cricopharyngeal myotomy does not increase the risk of esophagopharyngeal acid regurgitation.

OBJECTIVE: It is not known whether cricopharyngeal myotomy predisposes to esophagopharyngeal regurgitation. Using ambulatory, dual pharyngeal, and esophageal pH monitoring before and after cricopharyngeal myotomy, our aim was to determine the effect, if any, of myotomy on the frequency of esophagopharyngeal acid regurgitation. METHODS: We studied prospectively 18 patients who underwent cricopharyngeal myotomy for pharyngeal dysphagia (10 Zenker's, eight neurogenic dysphagia), of whom 17 agreed to undergo dual pH monitoring preoperatively, and 10 who agreed to both pre- and postoperative monitoring. RESULTS: Symptoms of gastroesophageal reflux disease were present in 30%. Cricopharyngeal myotomy significantly reduced basal upper esophageal sphincter pressure by 49%, from 37+/-5 mm Hg to 19+/-3 mm Hg (p = 0.007). Esophagopharyngeal regurgitation was a rare event and the frequency of it did not differ between patients and healthy controls. Preoperatively, three regurgitation events in two patients did not differ from the postoperative frequency of a total of two events in the same two patients. CONCLUSIONS: Increased esophageal acid exposure is common and esophagopharyngeal regurgitation is rare in unselected patients undergoing cricopharyngeal myotomy for pharyngeal dysphagia. Myotomy does not increase the frequency of esophagopharyngeal acid regurgitation in such patients.

Esophagopharyngeal acid regurgitation: dual pH monitoring criteria for its detection and insights into mechanisms.

BACKGROUND & AIMS: A valid technique for the detection of esophagopharyngeal acid regurgitation would be valuable to evaluate suspected reflux-related otolaryngologic and respiratory disorders. The aim of this study was to derive pH criteria that optimally define esophagopharyngeal acid regurgitation and to examine patterns of regurgitation. METHODS: In 19 healthy controls and 15 patients with suspected regurgitation, dual or quadruple pH sensors were used to monitor pharyngeal and esophageal pH. For each combination of the 2 variables, DeltapH and nadir pH, proportions of pH decreases that occurred during or independent of esophageal acidification were calculated to determine the likelihood that an individual pharyngeal pH decrease was a candidate regurgitation event or a definite artifact. RESULTS: Overall, 92% of pharyngeal pH decreases of 1-2 pH units and 66% of pH decreases of this magnitude reaching a nadir pH of <4 were artifactual. Optimal criteria defining a pharyngeal acid regurgitation event were a pH decrease that occurred during esophageal acidification, had a DeltapH of >2 units, and reached a nadir of <4 units in less than 30 seconds. Regurgitation occurred more frequently in subjects in an upright (32 of 35) than in a supine (3 of 35 events; P

Self-inflicted burn injuries: an 11-year retrospective study.

The burns unit at the Royal Brisbane Hospital accepted a total of 2275 admissions from 1986 to 1996. During this 11-year period, 65 cases of self-inflicted burn injury were treated, which made up 2.9% of the total number of admissions. A mortality rate of 21.5% (14 patients) is noted, with all patients dying after admission to the hospital. A common feature of people that self-inflict burn injuries is a psychiatric history, with many patients having histories of self-harm or suicide attempts. Two distinct groups were identified--those with suicidal intent and those with intent of self-harm. Those patients with self-inflicted injuries have an increased mean of 31.4% total body surface area burned as compared with those patients whose injuries are accounted for as accidental, which have a mean total body surface area burned of 10%. Additionally, the mean length of stay in the hospital for patients with self-inflicted injuries was 40 days for acute injuries, which is prolonged; the mean length of stay for acute injuries that were not self-inflicted was 14 days. This investigation discovered 3 cases of repeated self-inflicted burn injury.

Acute cyanide toxicity caused by apricot kernel ingestion.

A 41-year-old woman ingested apricot kernels purchased at a health food store and became weak and dyspneic within 20 minutes. The patient was comatose and hypothermic on presentation but responded promptly to antidotal therapy for cyanide poisoning. She was later treated with a continuous thiosulfate infusion for persistent metabolic acidosis. This is the first reported case of cyanide toxicity from apricot kernel ingestion in the United States since 1979.

Effect of magnesium hydroxide on iron absorption following simulated mild iron overdose in human subjects.

OBJECTIVE: To determine the effect of oral magnesium hydroxide [Mg(OH)2] on iron absorption after simulated iron overdose in human subjects. METHODS: A randomized, controlled crossover study was conducted in healthy adult male human volunteers taking no medications. Subjects received an average of 5.0 mg/kg elemental iron orally followed 1 hour later by either oral administration of 4.5 g of Mg(OH)2 per g ingested elemental iron or no treatment. Serial serum specimens were obtained over the 12 hours following iron ingestion and stored at -60 degrees C until standard serum iron assay was performed. After a 2-week washout period, the subjects were enrolled in the alternative trial arm. Individual baseline diurnal variation in serum iron levels was determined over a 12-hour period on the day prior to each trial. Area under time-concentration curves (AUCs) were calculated, and the AUC due to experimental iron ingestion (deltaAUC) was determined by subtracting the baseline diurnal AUC from the experimental AUC for each subject. RESULTS: Thirteen healthy adult male subjects were enrolled. Mean +/- SEM for deltaAUC due to experimental iron ingestion followed by treatment with Mg(OH)2, 78 +/- 23 micromol(hr)/L, was significantly less than that followed by no treatment, 144 +/- 33 micromol(hr)/L (p = 0.03 by signed rank test). CONCLUSIONS: Magnesium hydroxide, administered 1 hour post-iron ingestion at an oral dose of 4.5 g per g elemental iron ingested, significantly reduced iron absorption during a 12-hour period following simulated mild iron overdose in healthy adult human volunteers.

Influence of altered tongue contour and position on deglutitive pharyngeal and UES function.

The potential influence of altered lingual position and contour during the bolus loading phase of the swallow in mediating the swallowed bolus volume-dependent regulation of upper esophageal sphincter (UES) relaxation and opening was studied in 15 healthy volunteers using simultaneous videoradiography and manometry. A maxillary dental splint modulated tongue deformity during the early oral phase of deglutition. We examined the effect of the splint and swallowed bolus density on bolus volume-dependent changes in the timing of events in the swallow sequence and on hypopharyngeal intrabolus and midpharyngeal pressures. Peak mid-pharyngeal pressure (P = 0.001) and hypopharyngeal intrabolus pressure (P = 0.04) were significantly reduced by the splint. The normal volume-dependent earlier onset of sphincter relaxation and opening was preserved with the splint in situ. The splint significantly delayed the onset of hyoid motion and UES relaxation and opening without influencing transit times or total swallow duration. Alterations in tongue contour and position reduce intrabolus pressure and pharyngeal contraction without influencing normal bolus volume-dependent regulation of timing of UES relaxation and opening.

Antibiotic-induced convulsions.

Convulsive episodes are associated with the use of a number of antimicrobial agents. Although seizures may be a feature of the disease being treated, antibiotics should be considered possible causes of seizures, particularly if suggested by temporal relationships between seizure activity and drug administration. The astute clinician should be aware of the clinical settings in which antibiotic-induced seizures occur, be familiar with likely agents and their mechanisms of toxicity, and be prepared to institute appropriate management directed at this adverse effect of antimicrobial therapy.

Predictors of outcome following cricopharyngeal disruption for pharyngeal dysphagia.

The indications for, and predictors of outcome following cricopharyngeal disruption in pharyngeal dysphagia are not clearly defined. Our purpose was to examine the symptomatic response to cricopharyngeal disruption, by either myotomy or dilatation, in patients with oral-pharyngeal dysphagia and to determine pre-treatment manometric or radiographic predictors of outcome. Using simultaneous pharyngeal videoradiography and manometry, we studied 20 patients with pharyngeal dysphagia prior to cricopharyngeal dilatation (n = 11) or myotomy (n = 8), and 23 healthy controls. We measured peak pharyngeal pressure, hypopharyngeal intrabolus pressure, upper esophageal sphincter diameter, and coordination. Response rate to sphincter disruption was 65%. The extent of sphincter opening was significantly reduced in patients compared with controls (p = 0.004), but impaired sphincter opening was not a predictor of outcome. Increased hypopharyngeal intrabolus pressures (> 19 mmHg for 10 ml bolus; > 31 mmHg for 20 ml bolus) was a significant predictor of outcome (p = 0.01). Neither peak pharyngeal pressure nor incoordination were predictors of outcome. In pharyngeal dysphagia, hypopharyngeal intrabolus pressure, and not peak pharyngeal pressure, is a predictor of response to cricopharyngeal disruption. The relationship between intrabolus pressure and impaired sphincter opening is an indirect measure of sphincter compliance which helps predict therapeutic response.