Canine left ventricular hypertrophy predisposes to ventricular tachycardia induction by phase 2 early afterdepolarizations after administration of BAY K 8644.

OBJECTIVES: The purpose of this study was to test the hypothesis that the longer duration of ventricular action potentials in hypertrophied hearts predisposes to the development of early after-depolarizations and triggered ventricular tachyarrhythmias. BACKGROUND: For unknown reasons, the incidence of sudden death is greater in patients with myocardial hypertrophy. METHODS: We measured left ventricular monophasic action potentials in normal dogs and dogs with left ventricular hypertrophy before and after administration of the calcium agonist BAY K 8644 and the potassium channel blocker cesium. RESULTS: We demonstrated longer action potential durations in dogs with than in those without left ventricular hypertrophy. Also, BAY K 8644 produced phase 2 early afterdepolarizations and ventricular tachyarrhythmias more frequently in the dogs with than in those without left ventricular hypertrophy. Phenylephrine, an alpha agonist, further increased the action potential duration in hypertrophied hearts and the propensity to develop early afterdepolarizations and ventricular tachyarrhythmia after administration of BAY K 8644. Control and hypertrophied hearts developed early afterdepolarizations and ventricular tachyarrhythmia equally when exposed to cesium. CONCLUSIONS: Although in vitro studies have shown that fibers of hypertrophied ventricular myocardium can develop triggered activity as a result of both early and late afterdepolarizations, the present study is the first to show in vivo that the hypertrophied ventricular myocardium compared with the normal ventricle is predisposed to develop phase 2 early afterdepolarizations that appear to trigger ventricular tachyarrhythmia. It is possible that such a mechanism contributes to the development of ventricular tachyarrhythmia and sudden cardiac death in patients with left ventricular hypertrophy. If this is shown to be true, specific pharmacologic interventions can be suggested.

Progressive diaphyseal dysplasia: genetics and clinical and radiologic manifestations.

Progressive diaphyseal dysplasia was found in a three-generation family including 13 affected individuals, the largest family reported to date. Our study confirms that progressive diaphyseal dysplasia, also known as Engelmann's or Camurati-Engelmann disease, is an autosomal dominant disorder with variable osseous and muscular manifestations. Disease distribution among patients, within a given patient, or even in individual bones is unpredictable. The femur is the most commonly and severely affected bone and hence most useful for radiographic screening of possible patients. Radiographs provide a meaningful assessment of disease activity and extent. The severity of symptoms is generally proportionate to severity of involvement shown by roentgenography. Exophthalmos due to osteosclerotic dysplasia of the skull occurred in more than half of the patients with progressive diaphyseal dysplasia. Twelve-year follow-up of this family, with affected individuals ranging in age from 6 months to 12 years, indicates that progressive diaphyseal dysplasia may progress or become quiescent and be remarkably inactive despite advanced osteosclerosis and structural deformity.

Drug-induced tinnitus and other hearing disorders.

Tinnitus and hearing loss, both reversible and irreversible, are associated both with acute intoxication and long term administration of a large range of drugs. The mechanism causing drug-induced ototoxicity is unclear, but may involve biochemical and consequent electrophysiological changes in the inner ear and eighth cranial nerve impulse transmission. Over 130 drugs and chemicals have been reported to be potentially ototoxic. The major classes are the aminoglycosides and other antimicrobials, anti-inflammatory agents, diuretics, antimalarial drugs, antineoplastic agents and some topically administered agents. Prevention of drug-induced ototoxicity is generally based upon consideration and avoidance of appropriate risk factors, as well as on monitoring of renal function, serum drug concentrations, and cochlear and auditory functions before and during drug therapy. Ototoxicity, although not life-threatening, may cause considerable discomfort to patients taking ototoxic drugs, and in some cases drug discontinuation may be necessary to prevent permanent damage. Much research has been performed to investigate the causes and mechanisms of ototoxicity, to try to prevent this complication. Despite these efforts, ototoxicity still occurs, and there is much work to be done in order to understand the mechanism of ototoxicity of different drugs and to prevent hearing loss and tinnitus in the future.

Criteria to assess in vivo performance of sustained release products: application to diltiazem formulations.

The three classical pharmacokinetic parameters used to assess bioequivalence, AUC (total area from zero to infinity), Cmax (peak plasma concentration), and tmax (time to reach Cmax), are suitable to determine the extent and rate of absorption of immediate-release drug products. However, they may fail to evaluate the pharmacokinetic performance, particularly the rate of absorption of sustained-release (SR) formulations, which yield flat plasma curves with multiple peaks. This paper evaluates the inclusion of the following criteria for bioequivalence assessment of diltiazem SR formulations: MRT (mean arithmetic time), Cmax/AUC, peak occupancy time (POT), t(apical) (the arithmetic mean of the times associated with the concentrations within 25% of Cmax), C(apical) (the arithmetic mean of the concentration within 25% of Cmax), percent fluctuation and flatness of the curve as assessed by the coefficient of variation of the Css (steady state concentration) values obtained during a dosing interval at steady state. The above proposed criteria, as well as the classical parameters AUC, Cmax, and tmax were utilized in a recent pharmacokinetic study of a new SR product of diltiazem, Dilapress 240 (formulation A). Formulation A was analyzed following single (240 mg) and multiple (240 mg qd for 6 days) dosing at steady state (day 6) in comparison to Cardizem CD (formulation B). The bioavailability of formulation A relative to that of formulation B following single and multiple dosing was 92 +/- 28% and 90 +/- 24%, respectively. The 90% confidence intervals (Cl) over a mean AUC ratio of 89% were 78-101% (single dose, SD) and 77-101% (multiple dose, MD). following the administration of formulations A and B, identical mean values of the peak plasma concentration were obtained: 84 ng/mL (SD) and 132 ng/mL (MD). The 90% Cl over a mean Cmax ratio of 100% were 83-115% (SD) and 86-115% (MD). In the SD study, subject 8 had a relative bioavailability value of 24%, which deviated by 7.5 standard errors (SE) from the mean AUC ratio. Consequently, we repeated the single dose analysis without subject 8. The mean bioavailability data was 97 +/- 37% with a 90% Cl of 80-114% over a mean AUC ratio of 92%. ANOVA analysis did not show any formulation or period effect in all tested pharmacokinetic parameter s. On the basis of these results, these two formulations were judged to be bioequivalent. In contrast to the AUC and Cmax ratio, the 90% Cls associated with the ratio of the proposed criteria, with the exception of C(apical), did not fall within the acceptable limits. In the current study, a discrepancy was found between the above pharmacokinetic parameters, which were examined concerning their ability to detect differences in bioequivalence between SR products and the classical parameters regularly used for bioequivalence assessment. Although the parameters examined are theoretically more attractive than the single point parameters Cmax and tmax for rate of absorption assessment, their utility in bioequivalence would require further examination.

Plasmacytoma arising in the vicinity of a foreign body in the nasal cavity.

The development of a plasmacytoma in the vicinity of a long residing metallic foreign body in the nasal cavity is presented. In spite of the multitude of reports concerning neoplasma associated with trauma, most of which arise in chronic scars, this presentation is very rare. It is speculated that the plasma cell proliferation, occurring nearby the foreign body, roots from an immunologic and granulomatous reaction. This case is discussed in light of the vast data on foreign body tumorigenesis obtained from laboratory animals, and the implications of this data are outlined. Further attention should be drawn to the clinical associations of malignant processes co-existing with long-standing foreign bodies.

Brainstem auditory evoked potentials with increased stimulus rate in patients suffering from systemic lupus erythematosus.

Central nervous system involvement in systemic lupus erythematosus is frequently occult, may be the presenting sign, and is a bad prognostic indicator. At present, there is no reliable, sensitive laboratory test for the evaluation and diagnosis of subclinical central nervous system involvement of the disease. Brainstem auditory evoked potentials with and without increased stimulus rate have been used to diagnose ischemic lesions in the central nervous system. Brainstem auditory evoked potentials, with and without increased stimulus rate, was used to investigate 15 systemic lupus erythematosus patients, 20 normal participants, and 5 patients receiving corticosteroids for bronchial asthma. A significant statistical difference was found in the net effect of increased stimulus rate in comparisons of the systemic lupus erythematosus patients with the normal group. Brainstem auditory evoked potentials, with increased stimulus rate, demonstrated subclinical involvement of the central nervous system in systemic lupus erythematosus, reinforcing the notion that increased stimulus rate measures are sensitive to ischemic changes, in this case, even in neurologically asymptomatic patients.

Computerized dynamic posturography and seasickness susceptibility.

OBJECTIVE/HYPOTHESIS: The neural mismatch theory emphasizes the role of conflicting multimodal sensory interactions in producing both motion sickness and the rearrangement process that finally leads to habituation to the adverse motion conditions. If this theory is, indeed, correct, the patterns of the response to the integrated signal from simultaneous multisensory stimulation, characterized by unusual relationships between the senses responsible for spatial orientation, should differ according to motion sickness susceptibility. Computerized dynamic posturography (CDP) provides the opportunity to simultaneously change the interactions between visual, somatosensory, and vestibular inputs, thus giving an indication of the relative importance of these senses in maintaining balance. The objective was to investigate balance strategies in naval crew members with differing susceptibility to sea conditions using CDP. STUDY DESIGN: Cross-sectional, parallel-group design. METHODS: Twenty subjects susceptible to seasickness (SS) and 20 nonsusceptible subjects (NSS), healthy male volunteers aged 18 to 25, were tested using the EquiTest system (NeuroCom, Inc., Clackamas, OR). RESULTS: The SS group exhibited significantly less stability than the NSS group in condition 5 of the sensory organization test (SOT). The ratio of the SOT scores of conditions 5 to 1 (the vestibular organization pattern) was also found to be significantly lower in the SS group. CONCLUSIONS: The results suggest that SS might be more dependent on somatosensory and visual inputs and less on vestibular inputs for maintenance of balance compared with NSS. Higher susceptibility to seasickness might reflect abnormal weighting of sensory modalities during the integration process. This would result in disruption of the integration process required to maintain balance and a sense of orientation in space in conditions producing conflicting sensory inputs.

Chronic otitis media treated topically with ciprofloxacin or tobramycin.

OBJECTIVE: To evaluate the efficacy of ciprofloxacin compared with tobramycin and placebo ear drops in the treatment of chronic suppurative otitis media without cholesteatoma. DESIGN: Sixty ears (in 51 patients) were randomly divided into 3 treatment groups: ciprofloxacin hydrochloride, tobramycin, and placebo interventions. SETTING: The otolaryngology department of a university teaching hospital. INTERVENTION: All ears were treated topically for 3 weeks. MAIN OUTCOME MEASURES: Each patient received a small, numbered bottle and was instructed to instill 5 drops 3 times daily for 3 weeks. The final clinical and bacteriologic assessment was made after 3 weeks. RESULTS: The organism most commonly isolated from the ear discharge was Pseudomonas aeruginosa. Its sensitivity to ciprofloxacin and tobramycin was 94.2% and 70.6%, respectively. The clinical response was 78.9%, 72.2%, and 41.2% in the ciprofloxacin, tobramycin, and placebo groups, respectively. The bacteriologic response rate was 66.7% for the ciprofloxacin and tobramycin groups and 20% for the placebo group. Treatment with ciprofloxacin ear drops seemed to be as effective as treatment with tobramycin. CONCLUSION: While the lack of ototoxicity of ciprofloxacin was not tested in our study, this treatment may be considered as a potential topical therapy for cases of chronic suppurative otitis media.

Prediction of atrial and ventricular fibrillation complicating myocardial infarction from admission data: a prospective study.

This study set out to examine prospectively two logistic formulae based on admission clinical data to predict ventricular or atrial fibrillation complicating acute myocardial infarction. A prospective study of 87 consecutive patients with acute transmural myocardial infarction was conducted. The formula for predicting ventricular fibrillation from the diastolic blood pressure, degree of ST-segment elevation, and QTc had a sensitivity of 93%, specificity of 83%, and a predictive value for an abnormal test of 62% (13 of 14 patients who developed ventricular fibrillation were identified). The formula for predicting atrial fibrillation from the age of the patient, a history of heart failure, systolic blood pressure, and four electrocardiographic parameters had a sensitivity of 78%, specificity of 85%, and a predictive value of 67% (14 of 18 patients identified). Our study shows that patients with myocardial infarction who are liable to develop ventricular or atrial fibrillation can be identified on admission from simple clinical data.

Is the vestibular system affected by middle ear effusion?

The association between middle ear effusion (MEE) and vestibular pathology is controversial. To investigate this point, 50 children with MEE scheduled for myringotomy and grommet, and 20 normal hearing children without MEE scheduled for adenotonsillectomy, underwent vestibular investigations by craniocorpography and rotatory chair, preoperatively and postoperatively. Most of the correlations, preoperative vs. postoperative, and study vs. control groups, were nonsignificant. Assuming that serous labyrinthitis is responsible for vestibular involvement in MEE, the lack of significant vestibular pathology in our study could probably be explained by the fact that no children with acute otitis media episodes or otalgia were included.

Cat-scratch disease of the parotid gland: an often-misdiagnosed entity.

A case of cat-scratch disease involving the parotid area in a young adult is presented. Thanks to meticulous history-taking, the correct diagnosis was suggested and later established, thus preventing unnecessary surgery. The pertinent literature is discussed.

In vivo measurement of human nasal mucociliary motility using a laser light scattering instrument.

The mucociliary system is one of the most important airway defense mechanisms, and knowledge of the mucociliary wave frequency (MWF) is important in the understanding of this system. Employing a laser light scattering technique and a thin, flexible fiberoptic probe, we developed and tested a simple and practical device for real-time in vivo measurements of mucociliary activity in the human nose. The laser instrument is user-friendly and does not produce any discomfort to the patient. The mean +/- SE of MWF of 36 measurements in 16 normal subjects was 7.7 +/- 0.5 Hz. The mean MWF of 17 measurements in 7 patients with allergic rhinitis was 5.5 +/- 0.2 Hz (p < .005), and the mean MWF of 56 measurements in 17 patients with septum deviation was 5.8 +/- 0.2 Hz (p < .001). The instrument presented in this study might provide a new and convenient method of studying the mucociliary activity in the respiratory tract.

Vestibular findings associated with chronic noise induced hearing impairment.

Histological and functional derangements of the vestibular system have been reported in laboratory animals exposed to high levels of noise. However, clinical series describe contradictory results with regard to vestibular disturbances in industrial workers and military personnel suffering from noise induced hearing loss (NIHL). The purpose of the present study was to evaluate vestibular function in a group of subjects with documented NIHL, employing electronystagmography (ENG) and the smooth harmonic acceleration (SHA) test. Subjects were 22 men suffering from NIHL and 21 matched controls. Significantly lower vestibulo-ocular reflex gain (p = 0.05), and a tendency towards decreased caloric responses were found in the study group. No differences in the incidence of vertigo symptoms, spontaneous, positional and positioning nystagmus, directional preponderance and canal paresis in the ENG, or the SHA test phase and asymmetry parameters were observed between the groups. These results demonstrated a symmetrical centrally compensated decrease in the vestibular end organ response which is associated with the symmetrical hearing loss measured in the study group. Statistically significant correlations were found between the average hearing loss, the decrement in the average vestibulo-ocular reflex gain (p = 0.01), and ENG caloric lateralization (p = 0.02). These correlations might indicate a single mechanism for both cochlear and vestibular noise-induced injury. The results imply subclinical, well compensated malfunction of the vestibular system associated with NIHL.

Eosinophilic granuloma of the temporal bone.

Involvement of the temporal bone by eosinophilic granuloma is rare. Four cases are presented here and the pertinant literature is reviewed. This disease must be kept in mind by the otolaryngologist because of the diagnostic and therapeutic problems that may arise. Direct injection of methyl-prednisolone sodium succinate is suggested as a treatment of eosinophilic granuloma in the temporal bone.

Perilymphatic fistula--the value of diagnostic tests.

Perilymphatic fistula (PLF) remains one of the most challenging problems in otological practice. Fifty-two consecutive patients (53 ears) who underwent explorative tympanotomy for suspected PLF between 1985-1992 were included in this study. The clinical picture, history, patients' complaints and laboratory tests were analysed and compared with the operative findings. The conclusions of our work are that the diagnosis of PLF is based mostly on the clinical picture and a battery of laboratory diagnostic tests, but no one test is truly diagnostic for PLF.

Auditory brain stem evoked potentials in patients suffering from peripheral facial nerve palsy and diabetes mellitus.

Forty-two patients affected by acute idiopathic peripheral facial palsy (AIPFP) underwent auditory brainstem evoked potential (ABEP) investigation in order to further our understanding of the nature of facial palsy. Twenty-two of these patients suffered from diabetes mellitus. Our results indicate that the AIPFP of the diabetic person may be considered as a preliminary sign of diabetic peripheral neuropathy.

Ototoxicity of ear drops in patients suffering from chronic otitis media.

The sensorineural hearing loss in 150 patients with chronic otitis media who were treated in the Haifa Medical Center (Rothschild) during a ten year period was studied. There were 124 patients treated with a mixture containing neomycin, polymyxin B and dexamethasone and a control group of 26 patients with dexamethasone only. All patients were followed up for a period of 1-2 years. Patients with hearing loss due to factors such as previous ear surgery, family history, exposure to noise etc., have been excluded. The conclusions reached were that there is a relationship between the period of disease and the sensorineural hearing loss and that the local treatment with a mixture containing neomycin + polymyxin B appears to contribute to the worsening of the sensorineural hearing loss in patients with chronic otitis media. Our numbers are small and further studies must be done, but the fact that currently used ear drops may produce a sensorineural hearing loss should not be ignored.

Post-laryngectomy pharyngocutaneous fistula--a still unresolved problem.

Fifty-six total laryngectomy cases are presented with special reference to post-operative fistula formation. All these patients were operated upon at the Department of Otorhinolaryngology at the Bnai Zion Medical Centre by one surgeon over a 16-year period, from 1976-1992. The incidence of fistula was 12.5 per cent. This paper could not verify reports that any specific factors were significantly related to fistula formation, although there was a preponderance of fistulas in patients presenting with late stage tumours. No relationship was found with rate of infection, age, or between previous neck irradiation (ranging from 5500 to 7000 cGy) and fistula formation in the patient population. If a fistula occurs, the administration of oral solid food keeping the nasogastric tube in place for administration of fluids may lead to spontaneous closure of the fistula, with no need for secondary surgical repair.

Tympanoplasty in adults: a five-year survey.

In order to identify factors that could influence the success of tympanoplasties in adults, a retrospective study of 291 tympanoplasties performed on patients aged 15 years and older during the years 1984-1989 was carried out. Surgical success was defined as an intact membrane after two years follow-up and hearing improvement of at least 15 decibels. The success rate of the tympanoplasties was 90%. A functioning eustachian tube was found to be important for graft take. No difference was found in the rate of graft take regardless of whether fascia of the temporal muscle or tragal perichondrium was used or if fibrin glue was used. An audiological improvement was seen in 77% of the patients, and no significant difference regarding hearing gain was found between the different prostheses. It is concluded that tympanoplasty in adults is a simple operation with a high probability of success which can improve the quality of life of those operated upon.

Sonovestibular symptoms evaluated by computed dynamic posturography.

The investigation of stability under bilateral acoustic stimulation was undertaken in an attempt to mimic the real-life conditions of noisy environment (e.g., industry, aviation). The Tullio phenomenon evaluated by computed dynamic posturography (CDP) under acoustic stimulation is reflected in postural unsteadiness, rather than in the classic nystagmus. With such a method, the dangerous effects of noise-induced instability can be assessed and prevented. Three groups of subjects were submitted. The first (group A) included 20 patients who complained of sonovestibular symptoms (i.e., Tullio phenomenon) on the background of an inner-ear disease. The second group (B) included 20 neurootological patients without a history of Tullio phenomenon. Group C consisted of 20 patients with normal hearing, as controls. A pure-tone stimulus of 1,000 Hz at 110 dB was delivered binaurally for 20 seconds during condition 5 and condition 6 of the CDP sensory organization test. The sequence of six sensory organization conditions was performed three times with two intermissions of 15-20 minutes between the trials. The first was performed in the regular mode (quiet stance). This was followed 20 minutes by a trial carried out in quiet stance in sensory organizations tests (SOTs) 1 through 4, and with acoustic stimulation in SOT 5 and SOT 6. The last test was performed in quiet stance throughout (identical to the first trial). A significant drop in the composite equilibrium score was witnessed in group A patients upon acoustic stimulation (p < .0001). This imbalance did not disappear completely until 20 minutes later when the third sensory organization trial was performed. In fact, the composite score obtained on the last SOT was still significantly worse than the baseline. Group B and the normal subjects (group C) showed no significant change in composite score. As regards the vestibular ratio score, again, group A marked a drop on stimulation with sound (p < .004). This decrease contrasted once more with the other two groups. The leading sensory organization pattern was vestibular dysfunction (i.e., 40%, 10%, and 0% before acoustic stimulation in groups A, B, and C, respectively). The initial proportion of vestibular dysfunction increased on acoustic stimulation to 55% in group A, but this subsequently decreased in the third trial. The percentages of vestibular dysfunction remained constant during repeated trials in the other two groups. The positive medical history of sonovestibular symptoms was confirmed objectively by CDP with sound stimulation with a high statistical significance. This establishes the described method as a sensitive testing technique for validating the existence of the Tullio phenomenon in patients with a variety of disorders of the inner ear, especially chronic noise-induced hearing loss and acute acoustic trauma. All patients who suffered phonic trauma, chronic exposure to noise (e.g., aviation employees, industry and army personnel), or other neurootological disorders and who complain of sonovestibular symptoms should be tested for the presence of the Tullio phenomenon. This should be carried out preferably by means of CDP with acoustic stimulation for an objective corroboration of their complaint before continuing activity in a noisy environment, thus preventing dangerous loss of balance when exposed to noise.