Introducing an lsoprenaline Eluting Guidewire: Report on its Design and the Results of the Dose-Determining Pilot Study.

Introduction: Retrograde intrarenal surgery (RIRS) is associated with complications, many of which are related to the intrarenal pressure (IRP). We aim to describe the design of a novel isoprenaline-eluting guidewire ("IsoWire") and present the results from the first in vitro release studies and the first animal studies showing its effect on IRP. Materials and Methods: The IsoWire comprises a Nitinol core surrounded by a stainless-steel wire wound into a tight coil. The grooves created by this coil provided a reservoir for adding a hydrogel coating into which isoprenaline, a beta-agonist, was loaded. Animal studies were performed using a porcine model. For the control, IRP, heart rate (HR), and mean arterial pressure (MAP) were measured continuously for 6 minutes with a standard guidewire in place. For the experiment, the standard hydrophilic guidewire was removed, the IsoWire was inserted into the renal pelvis, and the same parameters were measured. Results: In vitro analysis of the isoprenaline release profile showed that most (63.9 ± 5.9%) of the loaded drug mass was released in the 1st minute, and almost all of the drug was released in the first 4 minutes exponentially. Porcine studies showed a 25.1% reduction in IRP in the IsoWire that released 10 µg in the 1st minute; however, there was a marked increase in HR. The average percentage reduction in IRP was 8.95% and 21.3% in the IsoWire that released 5 and 7.5 µg of isoprenaline, respectively, with no changes in HR or MAP. Conclusions: The IsoWire, which releases 5 and 7.5 µg of isoprenaline in the 1st minute, appears to be safe and effective in reducing the IRP. Further studies are needed to establish whether the isoprenaline-induced ureteral relaxation will render easier insertion of a ureteral access sheath, reduce IRP during sheathless RIRS, or even promote the practice of sheathless RIRS.

Ototoxic effects of single-dose versus 19-day daily-dose gentamicin.

INTRODUCTION: Gentamicin is one of the most extensively studied aminoglycoside antibiotics. The dogma of gentamicin ototoxicity theorizes that (1) the toxic effects of the drug are cumulative and dose dependent, despite clinical observations of ototoxicity after a single dose, and (2) gentamicin's ototoxic effects are irreversible, although clinicians have observed improvement in hearing over time. The objective of this study was to evaluate this basic dogma by examining the ototoxic differences between single-dose and 19-day daily dosing of gentamicin over a 60-day period. METHODS: Thirty-six C57 mice were randomly assigned to one of three treatment groups: (1) 19-day daily normal saline intraperitoneal injections (control; n = 10), (2) single-dose intraperitoneal 120 mg/kg gentamicin (n = 12), and (3) 19-day daily intraperitoneal 120 mg/kg gentamicin (n = 14). Pure-tone testing using auditory brainstem response was performed at frequencies of 6, 8, 12, 20, and 30 kHz. Hearing threshold was determined at each frequency by presenting stimuli from 90 dB to 5 dB using 10 dB decrements. Pure-tone testing was performed at days 1, 35, and 60 +/- 2 days. RESULTS: The results showed that hearing (1) improved between days 35 and 60 (p = .023) and (2) was not significantly different between a single dose versus 19 daily doses of gentamicin (p = .285). CONCLUSION: This study concurs with clinical observations that a single large dose of gentamicin may have ototoxic effects similar to those of multiple doses of gentamicin and that, over time, there is the potential for hearing recovery from gentamicin ototoxicity.

Differences in Ototoxicity across Species.

OBJECTIVE: To illustrate some differences between humans and rodents in the dose-effect relationships for two ototoxic drugs. STUDY DESIGN: Controlled animal study using typical research regimens for gentamicin and cisplatin compared with human data from the clinical literature. METHODS: Auditory brainstem response testing was carried out over months in two groups of animals exposed to typical dose regimens for ototoxic drugs. In the first group, 30 guinea pigs received either 3 or 6 mg/kg of cisplatin on alternate days for 5 days (total dose 15 or 30 mg/kg). In the second group, 24 C57 mice received saline or 19 daily doses of gentamicin 120 mg/kg. The findings in rodents were contrasted with human toxicity in the literature. RESULTS: Cisplatin increased click thresholds (32 +/- 27 dB) in guinea pigs. Doses of 15 mg/kg caused less hearing loss than 30 mg/kg, but the higher dose was associated with greater mortality owing to renal insufficiency. These findings are comparable with expectations of similar doses of cisplatin in humans. In contrast, gentamicin produced less hearing loss in mice, although the dose employed was well above the lethal dose for humans. CONCLUSIONS: Ototoxic doses of cisplatin in guinea pigs are similar to those of humans, but C57 mice appear to be highly resistant to gentamicin-induced hearing loss compared to humans. Animal models of ototoxicity need to be considered carefully in translational research.

Prevention of aminoglycoside-induced sensorineural hearing loss.

BACKGROUND: Aminoglycoside antibiotics are some of the most commonly used agents for treating gram-negative bacterial infections. They are extremely efficacious but can result in ototoxicity. It has been postulated that the mechanism inducing damage is the formation of oxygen free radicals. Many compounds have been employed in an attempt to reduce aminoglycoside-induced hearing loss. We endeavour to do likewise using sodium thiosulphate. This free radical scavenging agent has a proven ability to minimize cochlear damage owing to the chemotherapeutic agent cisplatin. OBJECTIVES: This study had two distinct objectives. The first was to determine if sodium thiosulphate can reduce hearing loss in C57 mice concurrently subjected to gentamicin. The second goal was to assess the value of this animal model. METHODS: This study was accomplished by creating four treatment arms. The animals were provided with daily intraperitoneal injections of gentamicin (120 mg/kg), sodium thiosulphate (1600 mg/kg), gentamicin plus sodium thiosulphate, or normal saline. Auditory brainstem response threshold changes were calculated comparing differences between baseline values and those observed at day 35. RESULTS: The results indicate a trend suggesting that sodium thiosulphate may afford some degree of otologic protection when provided in conjunction with gentamicin. However, a statistical significance could not be established. Our mice appear to be more resistant to gentamicin-induced ototoxicity than found in previously reported animal models. CONCLUSION: We were unable to demonstrate that sodium thiosulphate can attenuate gentamicin-induced ototoxicity. Furthermore, we observe that the susceptibility to hearing loss varies considerably between individual C57 mice. Consequently, we hold some degree of reservation with the use of this model to assess the benefit of prospective rescue agents.

Sensorineural hearing loss in postmeningitic children.

OBJECTIVE: To establish the proportion of children who develop sensorineural hearing loss after bacterial meningitis and to correlate such loss with patient factors. STUDY DESIGN: Retrospective case review. SETTING: McMaster University Children's Hospital, a tertiary referral center. PATIENTS: Children between the ages of 1 day and 18 years admitted to McMaster University Children's Hospital with a confirmed diagnosis of bacterial meningitis between January 1, 1991 and December 30, 2000. INTERVENTIONS: Audiological assessment including auditory brainstem responses and cortical electric-response audiometry or standard audiometry. MAIN OUTCOME MEASURES: The nature of sensorineural hearing loss was assessed according to the degree (mild to profound) and course (transient versus permanent). Correlations between sensorineural hearing loss and the patient's age, sex, duration of illness before admission, use of dexamethasone, concurrent neurologic complications, and types of pathogens were evaluated. Patterns of inpatient and outpatient audiological assessment were determined. RESULTS: Seventy-nine children had confirmed bacterial meningitis. Streptococcus pneumoniae accounted for 36.7 percent of all cases, followed-up by Neisseria meningitides (16.5%), group B Streptococcus (15.2%), and Hemophilus influenzae (13.9%). Sixty-eight (86.1%) children underwent hearing assessment, either as inpatients or after discharge. Of the remaining 11 (13.9%) in whom audiological evaluation could not be confirmed, only two made mention of a referral. As such, a nonreferral rate of 11.4 percent was identified. Abnormal auditory brainstem response findings were present in 22 cases (32.3%), with 11 cases (13.9%) of permanent sensorineural hearing loss identified. A statistically significant association between sensorineural hearing loss and Streptococcus pneumoniae was found (p < 0.001). No association between age, sex, duration of illness before admission, use of dexamethasone, and number of concurrent neurologic complications could be established. CONCLUSIONS: In our series, 11 children (13.9%) experienced permanent sensorineural hearing loss, consistent with previously reported rates of 5 to 35 percent within the pediatric population. Since introduction of the Hemophilus influenzae type B vaccine, Streptococcus pneumoniae has emerged as the dominant causative organism of bacterial meningitis in children. Our study additionally confirms the role of Streptococcus pneumoniae as a precipitant of sensorineural hearing loss (p < 0.001). Audiological assessment in our series (86.1%) exceeds most of the screening rates previously reported in the literature. Because of compliance problems with outpatient audiological assessment and because early identification and expedient amplification lead to better academic and language outcomes, routine inpatient audiological screening of postmeningitic children is advocated.

Paranasal sinus teratocarcinosarcoma with intradural extension.

Teratocarcinosarcoma, although a rare neoplastic entity, should be considered as a differential diagnosis in any middle-aged adult presenting with a history of intermittent unilateral epistaxis and nasal obstruction. Tissue biopsy may fail to reveal a full spectrum of histologic heterogeneity in these tumours, and definitive diagnosis is usually made with tumour resection. Aggressive treatment including surgery followed by adjuvant radiation therapy is advocated and confers a better rate of survival than radiotherapy alone. Our current report is unique in two respects. First, disease recurrence is usually manifested very early on, leading some authors to conclude that a neoplastic-free interval of 3 years or longer probably indicates a good chance of being cured. Our patient, in contrast, experienced a disease-free interval of 4 years before evidence of recurrence emerged. Second, intracranial extension with brain parenchymal involvement has not been previously reported despite the tumour's proximity to the anterior cranial fossa and its locally aggressive behaviour with frequent bony invasion. Despite intracranial invasion, our patient experienced a long disease-free interval. As such, even advanced disease should be treated aggressively.

Diels-Alder Reactions of 5-Alkyl-1,3-cyclopentadienes.

Facial selectivity in the Diels-Alder reactions of 1,3-cyclopentadienes substituted at C-5 by a variety of simple alkyl groups has been assessed with a number of dienophiles. The results are consistent with an explanation based on steric hindrance. Syn addition is more favored with sterically less demanding dienophiles. Diene 6, which is substituted at C-5 with methoxymethyl, shows a remarkable preference for syn addition with less encumbered dienophiles. This may indicate a conformational difference in its syn transition state relative to the transition states for addition syn to methyl, ethyl, or n-butyl substituents (dienes 1, 4, and 5). Dienophiles are more reluctant to add syn to the larger C-5 group with 1,2,3,4,5-pentamethyl-1,3-cyclopentadiene (2) and derivatives (3, and 7) and conformational effects become very important when C-5 bears two alkyl groups, as in dienes 3 and 7.