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1. Studies were conducted in the Fischer 344 rat and beagle dog to determine the disposition of LY333531 and its equipotent active des-methyl metabolite, LY338522, both potent and selective inhibitors of the β-isozyme of protein kinase C. 2. Male Fischer 344 rats and female beagle dogs received a single 5-mgkg[sup -1] oral dose of [sup 14]C-LY333531. Urine, faeces, bile and plasma were collected and analysed for [sup 14]C, LY333531 and LY338522. 3. LY333531 was eliminated primarily in the faeces (91% by 120 h in rat, 90% by 96h in dog). Bile contributed the majority of the radioactivity excreted in the faeces in rat (66% in the cannulated bile duct study) and a variable but significant proportion in dog. 4. Pharmacokinetics following a single 5 mg kg[sup -1] oral dose of [sup 14]C-LY333531 to the male rat produced C[sub max] and AUC[sub 0-∞] for LY333531 of 14.7 ng ml[sup -1] and 60.8ng h ml[sup -1], respectively, with a half-life of 2.5 h. LY338522 and total radioactivity showed similar profiles. 5. In the female dog at the same dose, C[sub max] and AUC[sub 0-∞] of LY333531 were higher, producing 245 ± 94 ng ml[sup -1] and 1419 ± 463ng h ml[sup -1], respectively, with a half-life of 5.7 h. 6. The data indicate that the disposition of LY333531 is similar in rat and dog. [ABSTRACT FROM AUTHOR]

Controversy exists concerning stapedectomy for patients with small air-bone gaps. The purpose of this study was to examine the results for patients who had a stapedectomy to correct a small (10 dB or less) air-bone gap. One hundred fifty-four patients with suspected otosclerosis were explored and a stapedectomy was performed in 136 (88.3%) of these cases. The mean pure-tone average (PTA) improved 16.7 dB and overdosed the preoperative bone conduction PTA by 8.1 dB. The majority of the stapedectomy patients (89.7%) had a PTA closure greater than or equal to 0 dB. These results showed that stapedectomy can be an effective procedure for eliminating and overdosing even small air-bone gaps due to otosclerosis. [ABSTRACT FROM AUTHOR]

Patient records were reviewed to determine whether persons with absent acoustic reflexes have a higher incidence of abnormal auditory brainstem response (ABR) results in the absence of a cerebellopontine angle (CPA) tumor than those with normal acoustic reflexes. Results showed patients with absent reflexes to have borderline or abnormal ABR results in 45.2% of the cases. Patients with normal reflexes had borderline or abnormal ABR results in 14.2% of the cases. Results indicate that magnetic resonance imaging is a more appropriate test for patients with absent reflexes, since ABR was often nondiagnostic for a CPA tumor in this group. [ABSTRACT FROM AUTHOR]

Novel urinary protein biomarkers have recently been identified and qualified in rats for the early detection of renal injury in drug development studies. However, there are few reports on the utility of these renal biomarkers in mice, another important and widely used preclinical animal species for drug development studies. The purpose of this study was to assess the value of these recently qualified biomarkers for the early detection of drug-induced kidney injury (DIKI) in different strains of mice using multiple assay panels. To this end, we evaluated biomarker response to kidney injury induced by several nephrotoxic agents including amphotericin B, compound X, and compound Y. Several of the biomarkers were shown to be sensitive to DIKI in mice. When measured, urinary albumin and neutrophil gelatinase-associated lipocalin were highly sensitive to renal tubular injury, regardless of the assay platforms, mouse strain, and nephrotoxic agents. Depending on the type of renal tubular injury, kidney injury molecule-1 was also highly sensitive, regardless of the assay platforms and mouse strain. Osteopontin and cystatin C were modestly to highly sensitive to renal tubular injury, but the assay type and/or the mouse strain should be considered before using these biomarkers. Calbindin D28 was highly sensitive to injury to the distal nephron in mice. To our knowledge, this is the first report that demonstrates the utility of novel urinary biomarkers evaluated across multiple assay platforms and nephrotoxicants in different mice strains with DIKI. These results will help drug developers make informed decisions when selecting urinary biomarkers for monitoring DIKI in mice for toxicology studies.

Background and Purpose: With a prevalence of about one million d/Deaf and Hard of Hearing (HOH) patients that utilize American Sign Language (ASL) and the strong potential for communication barriers to adversely influence patient care outcomes, strategies must be developed to support health care professionals and students in learning to better care for d/Deaf and HOH patients. The primary objective of this project was to implement and assess a co-curricular course focused on helping student pharmacists become more confident and comfortable in communicating with d/Deaf and HOH patients., Educational Activity and Setting: The co-curricular course (ASL for the Pharmacy Professional) consisted of four 90-min classes, each covering different words/phrases and Deaf cultural competence. Students were taught basic ASL including the alphabet, numbers, vocabulary, and sentence structure. Deaf culture and d/Deaf patient interaction was also covered. Students interacted with a Deaf physician over Skype and with d/Deaf and HOH individuals from the local community., Findings: Pre- and post-surveys that contained an identical set of questions were administered before and after course completion. Surveys assessed confidence and level of comfort of first- and second-professional year student pharmacists surrounding Deaf culture and interacting with d/Deaf and HOH patients. Following the course, students reported significantly improved confidence in communicating with d/Deaf patients directly and with a translator., Summary: Following completion of a co-curricular ASL course, doctor of pharmacy students perceived an increase in confidence in working with d/Deaf and HOH patients. Program logistics were simplified through collaboration with an outside entity., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Novel urinary protein biomarkers have recently been identified and qualified in rats for the early detection of renal injury in drug development studies. However, there seems to be no standardized normalization method for analyzing these urinary biomarkers, as some users normalize with urinary creatinine (uCr), urine volume (uVol), or leave biomarker un-normalized. More recently, urinary cystatin C is also emerging as a urinary biomarker normalizer, given some of its characteristics as a glomerular filtration marker. The purpose of this study was to identify an optimal drug-induced kidney injury biomarker normalization method that can be adopted more uniformly in the field. To this end, we compared the variability of uVol, urinary cystatin C, and Cr in healthy rats; we evaluated the sensitivity of the renal biomarkers to renal injury after normalization with uVol, uCr, and cystatin C in rats with cisplatin-induced renal injury. We showed that, over time, uCr was less variable than urinary cystatin C and uVol. When the renal biomarkers were normalized with the 3 normalizing end points, the biomarkers showed (1) least variability following normalization with Cr in healthy animals and (2) poor sensitivity when normalized with urinary cystatin C in animals with renal injury. Overall, the results suggested that uCr is better than urinary cystatin C and uVol for normalizing renal biomarkers in rats under controlled preclinical conditions. To our knowledge, this is the first report that compared the variability of uVol, cystatin C, and Cr in the context of renal biomarkers' normalization.

Triantennary N-acetyl galactosamine (GalNAc 3 )-conjugated antisense oligonucleotides (ASOs) have greatly improved potency due to receptor-mediated uptake into hepatocyte. The disposition and pharmacokinetics of ISIS 681257, a GalNAc 3 -conjugated ASO, were studied in monkeys. Following subcutaneous (SC) injection, ISIS 681257 was rapidly absorbed into the systemic circulation, with peak plasma levels observed within hours after dosing. After reaching C max , plasma concentrations rapidly declined in a multiexponential manner and were characterized by a dominant initial rapid distribution phase in which drug transferred to tissues from circulation, followed by a much slower terminal elimination phase (half-life of 4 weeks). Intact ISIS 681257 is the major full-length oligonucleotide species in plasma (≥70%). In tissues, the conjugated-GalNAc sugar moiety was rapidly metabolized, leaving the fully unconjugated form as the only full-length oligonucleotide detected at 48 h after dosing. Unconjugated ISIS 681257 cleared slowly from tissues with a half-life of 4 weeks. ISIS 681257 was highly bound to plasma proteins (>97% bound), which limited its urinary excretion. Disposition of ISIS 681257 in plasma and liver appeared nonlinear over the 1-40 mg/kg dose range studied. The plasma and liver tissue concentration data were well described by a population based mixed-effects modeling approach with Michaelis-Menten uptake from plasma to liver. Safety data from the study and the good exposure, as well as the extended half-life of the unconjugated ASO in the liver, support further development and less frequent dosing in Phase I clinical study.

Triantennary N-acetyl galactosamine (GalNAc3)-conjugated antisense oligonucleotides (ASOs) have greatly improved potency via receptor-mediated uptake. In the present study, the in vivo pharmacology of a 2'-O-(2-methoxyethyl)-modified ASO conjugated with GalNAc3 (ISIS 681257) together with its unmodified congener (ISIS 494372) targeting human apolipoprotein (a) (apo(a)), were studied in human LPA transgenic mice. Further, the disposition kinetics of ISIS 681257 was studied in CD-1 mice. ISIS 681257 demonstrated over 20-fold improvement in potency over ISIS 494372 as measured by liver apo(a) mRNA and plasma apo(a) protein levels. Following subcutaneous (SC) dosing, ISIS 681257 cleared rapidly from plasma and distributed to tissues. Intact ISIS 681257 was the major full-length oligonucleotide species in plasma. In tissues, however, GalNAc sugar moiety was rapidly metabolized and unconjugated ISIS 681257 accounted > 97% of the total exposure, which was then cleared slowly from tissues with a half-life of 7-8 days, similar to the half-life in plasma. ISIS 681257 is highly bound to plasma proteins (> 94% bound), which limited its urinary excretion. This study confirmed dose-dependent exposure to the parent drug ISIS 681257 in plasma and rapid conversion to unconjugated ASO in tissues. Safety data and the extended half-life support its further development and weekly dosing in phase 1 clinical studies.

ISIS 141923 is a model compound of 2'-O-(2-methoxyethyl) (2'-MOE) modified antisense oligonucleotides (ASOs). The purpose of this study is to determine whether ISIS 141923 is a substrate or an inhibitor against a panel of nine major uptake or efflux drug transporters, namely breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)1, OCT2, organic anion transporting polypeptide 1B (OATP1B)1, OATP1B3, and bile salt export pump (BSEP), in vitro. The uptake test system for transporters in the solute carrier (SLC) family (OAT1, OAT3, OCT1, OCT2, OATP1B1, and OATP1B3) was studied in Madin-Darby canine kidney (MDCK)-II cells transfected to express the transporters of interest. BCRP was studied using carcinoma colon-2 (Caco-2) cells with endogenously expressed BCRP. P-gp transporter was studied in MDCK-multi-drug resistance 1 (MDR1) cells, while BSEP was studied using Spodoptera frugiperda 9 (Sf9) membrane vesicles containing human BSEP. The ISIS 141293 concentrations evaluated were 10 and 100 μM for the substrate and inhibition study, respectively. Cellular uptake of ISIS 141923 was analyzed using a high performance liquid chromatography-mass spectrometry method, while concentrations of known substrates (used as positive controls) of each transporters evaluated were determined by radiometric detection. At 10 μM ISIS 141923, there was no significant transporter-mediated uptake of ISIS 141923 (P > 0.05) in the SLC family, and the efflux ratios were not above 2.0 for either BCRP or P-gp. Therefore, no transporter-mediated uptake of ISIS 141923 was observed by any of the nine transporters studied. At 100 μM ISIS 141923, the % inhibition was in the range of -16.0% to 19.0% for the nine transporters evaluated. Therefore, ISIS 141923 is not considered as an inhibitor of the nine transporters studied. Overall, the results from this study suggest that it is unlikely that ISIS 141923 or similar 2'-MOE ASOs would interact with small molecule drugs either as a victim (substrate) or perpetrator (inhibitor) of major transporters in humans. The results from available clinical drug-drug interaction studies conducted with this class of compounds to date are also supportive of this conclusion.

Evaluation of species differences and systemic exposure multiples (or ratios) in toxicological animal species versus human is an ongoing exercise during the course of drug development. The systemic exposure ratios are best estimated by directly comparing area under the plasma concentration-time curves (AUCs), and sometimes by comparing the dose administered, with the dose being adjusted either by body surface area (BSA) or body weight (BW). In this study, the association between AUC ratio and the administered dose ratio from animals to human were studied using a retrospective data-driven approach. The dataset included nine antisense oligonucleotides (ASOs) with 2'-O-(2-methoxyethyl) modifications, evaluated in two animal species (mouse and monkey) following single and repeated parenteral administrations. We found that plasma AUCs were similar between ASOs within the same species, and are predictable to human exposure using a single animal species, either mouse or monkey. Between monkey and human, the plasma exposure ratio can be predicted directly based on BW-adjusted dose ratios, whereas between mouse and human, the exposure ratio would be nearly fivefold lower in mouse compared to human based on BW-adjusted dose values. Thus, multiplying a factor of 5 for the mouse BW-adjusted dose would likely provide a reasonable AUC exposure estimate in human at steady-state.

Purpose: Healthcare organizations are increasingly faced with an environment in which they must implement health information systems to achieve higher standards for efficiency and quality of care while at the same time being asked to provide needed services with fewer resources. This is particularly challenging for rural health systems where access to resources is often more limited. This study investigates the potential value of iPad tablets for enhancing health services delivery by primary care physicians in rural Nevada., Methods: Five physicians from rural Nevada were selected to receive iPads and funding for apps that would enhance their medical practices. Following a year of use, data was gathered on each physician's actual use and perceived value of the iPads. A case study approach was taken using both an online survey and semi-structured phone interviews to collect case data., Results: Use and perceived usefulness of the iPad was mixed but generally positive with some physicians utilizing it much more than others. The iPads were primarily used by the physicians to access medical information through online resources (e.g. Epocrates and UpToDate) for reference and diagnostic purposes, although they were also used for some interaction with patients. All felt that resources available through the iPad were limited and that better applications would improve the usefulness of the iPad, particularly in regard to graphical and video content suitable to sharing with patients., Conclusions: Physicians in this study felt that the iPad could fill a need between smartphones and desktops, which were their primary technology tools prior to receiving the iPad, but that useful medical applications and resources are currently limited for the iPad. In particular, better graphical and video content would improve the usefulness of the iPad as a tool for patient interactions. Apps that store content locally would serve to mitigate inconsistent internet access that is still common in rural settings, increasing the usefulness of the iPad in that context. Tablets like the iPad also have potential for use in accessing the electronic medical record systems that are increasingly being implemented in rural hospitals and healthcare facilities., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Rationale: Elevated plasma triglyceride levels have been recognized as a risk factor for the development of coronary heart disease. Apolipoprotein C-III (apoC-III) represents both an independent risk factor and a key regulatory factor of plasma triglyceride concentrations. Furthermore, elevated apoC-III levels have been associated with metabolic syndrome and type 2 diabetes mellitus. To date, no selective apoC-III therapeutic agent has been evaluated in the clinic., Objective: To test the hypothesis that selective inhibition of apoC-III with antisense drugs in preclinical models and in healthy volunteers would reduce plasma apoC-III and triglyceride levels., Methods and Results: Rodent- and human-specific second-generation antisense oligonucleotides were identified and evaluated in preclinical models, including rats, mice, human apoC-III transgenic mice, and nonhuman primates. We demonstrated the selective reduction of both apoC-III and triglyceride in all preclinical pharmacological evaluations. We also showed that inhibition of apoC-III was well tolerated and not associated with increased liver triglyceride deposition or hepatotoxicity. A double-blind, placebo-controlled, phase I clinical study was performed in healthy subjects. Administration of the human apoC-III antisense drug resulted in dose-dependent reductions in plasma apoC-III, concomitant lowering of triglyceride levels, and produced no clinically meaningful signals in the safety evaluations., Conclusions: Antisense inhibition of apoC-III in preclinical models and in a phase I clinical trial with healthy subjects produced potent, selective reductions in plasma apoC-III and triglyceride, 2 known risk factors for cardiovascular disease. This compelling pharmacological profile supports further clinical investigations in hypertriglyceridemic subjects.

Objective. Evaluate a porous polyethylene prosthesis with two-point stabilization in total ossiculoplasty. This approach utilizes a lateral as well as a medial graft to stabilize a total ossicular prosthesis (TOP). Study Design. Retrospective cohort review of total ossiculoplasty. Methods. All patients who underwent total ossiculoplasty during the years 2004-2007 were included in the study group. Only five patients (10%) had primary surgery whereas 45 (90%) underwent revision surgery. Cartilage grafts covering the prosthesis (Sheehy, Xomed) laterally were used in all patients with areolar tissue being used for medial stabilization at the stapes footplate. Follow-up examination and audiometrics were performed a mean of 8.1 months following surgery. Results. The percentage of patients closing their ABG to within 10 dB was 44% with 66% closing their ABG to within 20 dB. The mean four-frequency hearing gain was 15.7 dB. The mean postoperative ABG was 15.7 dB. Conclusion. Audiometric results following total ossiculoplasty surgery using two-point stabilization exceeded results from the otologic literature. Proper two-point fixation with areolar tissue and stabilization utilizing cartilage were the keys to achieving a relatively high percentage of success in chronic ear disease in this sample.

The aim of this study was to evaluate the success of stapedectomy in patients who have previously had a tympanoplasty because of chronic otitis media (COM). Fourteen patients from a private otology practice had undergone tympanoplasty for COM and subsequently underwent stapedectomy. Measurements were taken of the air-bone gap (ABG) closure and pure tone average (PTA) which showed hearing improvement. Patients had a mean 36.9 dB PTA hearing gain with 79 per cent closing the ABG to within 20 dB. The need for stapedectomy alone is a rare occurrence for patients with a history of COM requiring a tympanoplasty. Hearing improvement following stapedectomy in these cases was significant, although somewhat less than following traditional stapedectomy in otosclerosis alone.

Objective: The aim of this study was to evaluate the initial and longer term success of closing the air-bone gap (ABG) to 20 dB in ossiculoplasty with canal wall down mastoidectomy., Methods: This study was conducted at a private otologic practice. Patients included those who underwent ossiculoplasty from 1989 to 1996 with canal wall down mastoidectomy, whether primary or revision (33 from a total of 387 tympanomastoidectomies). Outcome measures included ABG closure, long-term hearing stability, mastoid appearance, extrusion, and sensorineural hearing loss., Results: Almost 64% of ABGs were closed to within 20 dB. The mean pure-tone average improvement was 12.3 dB. The mean PTA hearing decline in the years after surgery was slightly less than 1 dB/year., Conclusion: Hearing improvement with a stable long-term hearing result is possible with canal wall down mastoidectomy. The potential for hearing gain is greatest for patients having larger preoperative ABGs.

Objective: To evaluate the success of tympano-ossiculoplasty in patients with previous canal wall down mastoidectomy., Study Design: A retrospective review of 79 patients who underwent cavum major tympano-ossiculoplasty from a total of 1,910 tympanomastoidectomies from 1976 to 1998., Outcome Measures: The results of air-bone gap closure, surgical findings, and revision surgery are presented., Results: In 63% of patients, the air-bone gap closed to within 20 dB with a mean gain of 14.7 dB., Conclusion: A significant percentage of patients will gain substantial improvement in their hearing after cavum major tympano-ossiculoplasty with minimal risk.

Children younger than 2 years of age were initially excluded from cochlear implant candidacy for a variety of reasons. Reasons ranged from concerns about the reliability of the diagnosis of a profound hearing loss in very young children, to concerns about surgical safety and long-term durability of the device in a growing child. Results from several recent studies have shown that children younger than 2 years of age can safely and successfully be implanted. Provided this success, and the general agreement that early remediation of a hearing loss provides a greater potential for speech and language development, implantation of very young children may soon become the norm rather than the exception. This article discusses the issues related to the implantation of young children and the need for special tools and protocols to use with this population.

Educational Objective: The focus of this paper is on the changing patterns of presentation of otosclerosis over the past 37 years., Study Design: Retrospective chart review., Setting: Private otology practice., Patients: Randomized selection of 400 patients (100 per decade) from 15,372 who underwent stapedectomy over the past four decades., Outcome Measures: Extent of cochlear involvement, bilaterality of disease, length of history, degree of hearing loss, and pathological findings are noted., Results: The decreasing incidence of footplates necessitating drillouts is discussed. Changing audiometric patterns at presentation such as decreased pure-tone average hearing thresholds and smaller air-bone gaps are also reviewed., Conclusion: This review demonstrates the changing patterns of presentation of otosclerosis over the past 37 years and will help guide the stapes surgeon into the year 2000.

Studies have indicated that stapedectomy can be an effective procedure in children for correcting conductive hearing losses due to juvenile otosclerosis. However, because childhood otosclerosis is rare and children commonly choose to use hearing aids in lieu of undergoing surgery, little outcome data are available. The purpose of this retrospective study was to provide additional outcome data in both the short and the long term. Stapedectomies were performed on 47 children. Preoperative hearing results were compared with 6-month postoperative hearing results. Hearing results for the children who had long-term follow-up (5 years or more) were compared with the 6-month postoperative results. Stapedectomy was successful (postoperative air conduction pure-tone average [PTA] within 10 dB of the preoperative bone conduction PTA) in 91.7% of the cases. The mean overclosure of the preoperative bone conduction PTA by the postoperative air conduction PTA was 0.2 dB. The mean PTA hearing improvement was 32.8 dB. Results from the 21 children (28 ears) who had long-term follow-up indicated an average 0.7 dB/year PTA worsening from the 6-month postoperative PTA. Results from this study provide additional evidence that stapedectomy can be an effective procedure for correcting conductive hearing losses due to juvenile otosclerosis.

Objective: This study aimed to examine the reliability of the 512-Hz Rinne tuning fork test to detect conductive hearing losses. The effects of tester experience, the use of masking, and the interpretation of equivocal (+/-) Rinne results on test reliability also were examined., Study Design: Retrospective., Setting: Private otology practice., Patients: 1,000 adult patients (2,000 ears) seen for their initial otologic evaluation., Interventions: Diagnostic., Main Outcome Measure: Sensitivity of the 512-Hz Rinne tuning fork test was assessed by comparing tuning fork results with the pure-tone average air-bone gap., Results: Results showed the 512-Hz Rinne tuning fork test could be very effective at detecting conductive hearing losses when performed by an experienced tester and when masking was used. Sensitivity was lower when masking was not used and lowest when the Rinne was performed by a less-experienced tester. Sensitivity for all groups was improved by interpreting equivocal results as indicating a conductive loss., Conclusions: Despite reports of poor reliability, the 512-Hz Rinne tuning fork test can be an important tool in an otology practice for the detection of conductive hearing losses and for confirming audiometric findings. In primary care settings, the Rinne would be most effective as part of a screening program for conductive hearing losses, but not as the sole indicator for referral.

Objective: This study aimed to examine word recognition score (WRS) changes after stapedectomy for far-advanced otosclerosis (FAO). The WRS changes were examined to determine whether they were consistent with acclimatization or recovery from auditory deprivation changes that have been seen after the restoration of sound by amplification., Study Design: Retrospective., Setting: Private otology practice., Patients: A total of 24 patients were selected by including all the case in which a stapedectomy was performed within the past 10 years to improve the hearing of a severe or profoundly hearing-impaired patient with otosclerosis., Intervention: Diagnostic., Main Outcome Measure: Changes in WRSs., Results: One month after surgery, the mean WRS had improved 16.5%. The WRSs continued to improve an additional 12% or more for 17 (71%) of 24 patients within 2 years after their initial postoperative hearing test. The mean WRS improvement within 2 years of the initial postoperative test was 16.2%., Conclusions: Initial WRS changes were attributed to hearing thresholds no longer being at or beyond audiometric limits. Additional WRS changes were consistent with reports of acclimatization or recovery from auditory deprivation that have been seen after hearing aid use. The authors believe these additional WRS changes illustrate that at least some improvement in WRSs from acclimatization or auditory recovery may be fairly common after the restoration of sound. Finally, the authors believe the overall WRS improvement (32.7%) should be taken into account when considering stapedectomy for patients with FAO.

Children tend to select novel objects over familiar ones as the likely referents of novel nouns. This finding is of central importance to several accounts of early word learning. In the current studies, 2-year-olds were shown pairs of videotaped actions, one familiar and one novel, and were asked to select the referents of novel verbs. For actions that did not involve objects, children tended to select the novel action over the familiar one in each of four experiments. For example, they chose the woman who was turning in circles while leaning backwards as "the one who is glarving" more often than the woman who was running. For actions involving objects, novel actions (e.g., shuffling balls) were chosen more often than familiar ones (e.g., kicking balls) in only two of the four experiments. An object-name-blocking mechanism was proposed to account for this last result. The preference for novel actions was also found to be strengthened by preexposing both actions from a test pair, but to be unaffected by preexposing just the novel actions.

Clinical records were reviewed to examine the effectiveness of stapedectomy in patients 70 years and older. A total of 154 patients was studied, including 11 with profound hearing loss with long-standing otosclerosis. Ages at the time of surgery ranged from 70 to 92 years (mean, 76.3 years). The mean pure-tone average (500, 1,000, 2,000, and 4,000 Hz) improved 30.6 dB after surgery for the 143 patients in the main otosclerotic group and 26.8 dB for the patients in the profound-hearing-loss group. The rate of successful stapedectomies for the 70(+)-year-old patients (90.9%) and the younger comparison group (90.0%) were similar. These findings extend the documented range of stapedectomy as a safe and effective procedure through the eighth decade of life.

A new word-learning phenomenon is demonstrated and a new word-learning principle is proposed to account for it. In Study 1, 60 3-year-olds were shown a pair of objects and heard a novel label used repeatedly for one, but not for the other. In a forced-choice test of generalization of the label, the latter object was selected less often by the children than one that had not been present during training. This so-called Nominal Passover Effect was the same whether the speaker had completely ignored the comparison object during training or had referred to it with pronouns. The performance of a no-word control group (N = 24) indicated that the effect was not due to a preference for the less exposed of the two choice objects. The effect is consistent with the Exhaustive Reference Principle, which stipulates that whenever a new generic word is used to name something, expect it to be extended to all entities in a situation that the speaker perceives and believes to be exemplars of the name. In Study 2 (N = 48), the Nominal Passover Effect was replicated with 3 new sets of objects and with training language that contained only indefinite forms of reference. The passover experience was often sufficient to counteract children's tendency to generalize a novel label on the basis of perceptual similarity. The passover effect was not evident in free-choice name generalization tests in either study.