Aerial measurement of radioxenon concentration off the west coast of Vancouver Island following the Fukushima reactor accident.

In response to the Fukushima nuclear reactor accident, on March 20th, 2011, Natural Resources Canada conducted aerial radiation surveys over water just off the west coast of Vancouver Island. Dose-rate levels were found to be consistent with background radiation, however a clear signal due to (133)Xe was observed. Methods to extract (133)Xe count rates from the measured spectra, and to determine the corresponding (133)Xe activity concentration, were developed. The measurements indicate that (133)Xe concentrations on average lie in the range of 30-70 Bq/m(3).

[Treatment of a serious autistic disorder in a child with Naltrexone in an oral suspension form]. / Traitement d'un enfant autiste par la naltrexone.

UNLABELLED: CLINICAL BACKGROUND: Autism is a developmental disorder that is usually diagnosed in early childhood. According to ICD-10 criteria, autism can be characterized by delays in language skills, by impaired social interaction, verbal or non-verbal communication and by repetitive, stereotyped or severely restricted activities and interests. The causes of autism are not yet elucidated, but both genetics and environment seem to play a role in 10 to 25% of autism cases. Several biochemical abnormalities, such as impairment of serotoninergic, catecholinergic, dopaminergic, and opioid systems have been reported. Autism therapies are designed to treat symptoms, and medication can be associated with psychoeducational and environmental interventions. Generally, the medications that are currently used are not intended for autism, and must be used with caution and selected according to the type and intensity of symptoms. The most common medication consists of psychotropic therapies by administration of dopaminergic and/or serotoninergic receptor antagonists (haloperidol, risperidone, clomipramine). Several drugs, such as anxiolytics (buspirone), mood stabilisers (lithium, sodium valproate), vitamins (vitamins B6, B12) or opioid antagonists (naltrexone) can be prescribed, in second intention, in cases of severe behavioural disorders. The prescription of opioid antagonists is based on the possible implication of an opioid system disorder observed in some cases. Nevertheless, several clinical studies reveal its variable effectiveness. Naltrexone is a competitive antagonist of opioid receptors OPRM1, OPRD1 and OPRK1. In France, this drug is prescribed for treating opioid and alcohol dependence. Moreover, several studies describe naltrexone as a possible treatment of autistic children in cases of developmental disorder and hyperactivity. CLINICAL CASE: In the Child and Adolescent Psychopathology Department of Sainte-Anne's Hospital, autistic children benefit from a multidisciplinary treatment program that sometimes includes the administration of psychotropic medication. One of these children presented with a severe autistic disorder according to the Childhood Autism Rating Scale (CARS). Considering ICD-10 criteria, he benefited from a multidisciplinary program, associating cognitive psychotherapy, psychomotor rehabilitation, speech therapy and educational intervention. However, persistent sleep disorder and motor instability led to successive prescriptions of several different psychotropic drugs. Initial treatment by thioridazine (10mg per day) followed by propericiazine (2.5mg per day) improved sleep, but was not efficient in reducing self-mutilating behaviour. A new treatment by risperidone (from 0.5mg to 1.5mg per day) was therefore chosen; however it lost its efficacy after five months. Finally, an anxiolytic (cyamemazine) and a thymoregulator (sodium valproate) were successively tried without yielding any clinical improvement. Owing to the persistence of communication difficulties, major instability, self-mutilating behaviour and heteroaggressiveness, treatment with naltrexone was subsequently chosen with parental consent. In France, naltrexone hydrochloride is only available in tablet form (Nalorex 50mg and Revia 50mg), which is not adapted to children at the efficient dose. Consequently, an oral suspension form marketed in Spain (Antaxone 50mg) was imported, having obtained the Afssaps' (the French drug administration) authorisation for its temporary use. The Connors and Nisonger scales were used as outcome measures of behavioural symptom change. The Conners scale is used to assess attention deficit and hyperactivity, whereas the Nisonger scale analyses social skills and behaviour disorders in children and adolescents with mental retardation. The onset of treatment, at a dose of 1mg/kg/day, led to a transitory increase in negative behaviour. However, a dose of 0.75mg/kg per day subsequently led to significant improvements, as shown by outcome measurements. Self-mutilating behaviour disappeared completely. Certain side effects were observed, namely transitory sedation at the beginning of treatment and moderate constipation. CONCLUSION: This clinical case confirms that treatment of a serious autistic disorder in children using Naltrexone in oral suspension form is a potentially interesting therapeutic alternative for treating behavioural symptoms resistant to classical drug therapy.

Psychic tonus, body schema and the parietal lobes: a multiple lesion case analysis.

The psychic tonus model (Braun and colleagues, 1999, 2002, 2003, 2006) states that the left hemisphere is a "booster" of internal experience and behavior in general, and that the right hemisphere is a "dampener". Twenty-five patients with a "positive" extreme disturbance of body schema (somatoparaphrenia) and 37 patients with a "negative" disturbance of body schema (autotopagnosia or Gerstmann's syndrome), all following a unilateral parietal lesion, were found in the literature and were analyzed to test predictions from Braun's "psychic tonus" model. As expected, patients with a positive syndrome had a right hemisphere lesion significantly more frequently, and those with a negative syndrome had a left hemisphere lesion significantly more frequently. Thus the psychic tonus model of hemispheric specialization, previously supported with regard to psychomotor baseline, libido, talkativeness, memory, auditory and visual perceptual tonus, now incorporates the tonus of representation of the body (body schema) in the parietal lobes.

Outcomes of an ecological and participatory approach to prevent alcohol and other drug "abuse" among multiethnic adolescents.

This study presents outcomes related to adolescents' alcohol use from an evaluation study testing the effectiveness of The Coalition for Youth Quality of Life Project (Le Regroupement pour la qualité de vie des jeunes). This project is an ecological and participatory approach developed to prevent alcohol and other drug use and misuse among multiethnic youth. The intervention was implemented through four channels of program delivery: families, schools, community organizations, and local government. The study involved 411 sixth graders from eight elementary schools and 380 eighth graders from two junior high schools, in two school districts of the Island of Montreal (province of Quebec, Canada). All students were enrolled in regular classes. Follow-up data were collected 18 months and 30 months after pre-test using a school survey. The findings indicated that the program had no significant impact on alcohol use. The program was, however, capable of producing a significant effect on several hypothesized mediating variables. At first follow-up, the sixth graders showed a higher self-esteem, better peer pressure resistance skills, and a more positive relationship with their father than the controls. The eighth graders were also more inclined to get involved in community activities related to substance abuse prevention and to choose more alternatives to "substance abuse" in their leisure time than the controls. The results are discussed by examining attrition effects and also reasons for program failure. Issues are raised about the evaluation of an ecological and participatory approach.

Inhalation toxicology of urban ambient particulate matter: acute cardiovascular effects in rats.

Wistar rats were exposed for 4 hours by nose-only inhalation to clean air, resuspended Ottawa ambient particles (EHC-93*, 48 mg/m3), the water-leached particles (EHC-93L, 49 mg/m3), diesel soot (5 mg/m3), or carbon black (5 mg/m3). Continuous data for physiologic endpoints (heart rate, blood pressure, body temperature, animal's activity) were captured by telemetry before and after exposure. Blood was sampled from jugular cannulas 1 to 3 days before exposure and at 2 and 24 hours after exposure, and by heart puncture on termination at 32 hours (histology group) or 48 hours (telemetry group) after exposure. Lung injury was assessed by 3H-thymidine autoradiography after the rats were killed. We measured endothelins (plasma ET-1, big ET-1, ET-2, ET-3) to assess the vasopressor components; nitric oxide (NO)-related metabolites (blood nitrate, nitrite, nitrosyl compounds, and plasma 3-nitrotyrosine) to assess the vasodilator components; and catecholamines (epinephrine, norepinephrine, L-DOPA, dopamine) and oxidative stressors (m- and o-tyrosine) for additional insight into possible stress components. Lung cell labeling was uniformly low in all treatment groups, which indicates an absence of acute lung injury. Inhalation of EHC-93 caused statistically significant elevations (P < 0.05) of blood pressure on day 2 after exposure, plasma ET-1 at 32 hours after exposure, and ET-3 at 2, 32, and 48 hours after exposure. In contrast, the modified EHC-93L particles, from which soluble components had been extracted, did not affect blood pressure. The EHC-93L particles caused early elevation (P < 0.05) of the plasma levels of ET-1, ET-2, and ET-3 at 2 hours after exposure, but the endothelins returned to basal levels 32 hours after exposure. Exposure to diesel soot, but not carbon black, caused an elevation (P < 0.05) of plasma ET-3 at 36 hours after exposure; blood pressure was not affected by diesel soot. Our results indicate that inhalation of the urban particles EHC-93 can affect blood levels of ET-1 and ET-3 and cause a vasopressor response in Wistar rats without causing acute lung injury. Furthermore, the potency of the particles to influence hemodynamic changes appears to be modified by removing polar organic compounds and soluble elements. Because the pathophysiologic significance of elevated endothelins has been clinically established in humans, our observations suggest a novel mechanism by which inhaled particles may cause cardiovascular effects. These findings in rats contribute to the weight of evidence in favor of a biologically plausible epidemiologic association between ambient particulate matter and cardiovascular morbidity and mortality in human populations.

Utility of cardiac catheterization in pediatric cardiac patients on ECMO.

Cardiac catheterization has been utilized rarely in children on extracorporeal membrane oxygenation (ECMO). We performed a retrospective review of 15 children with congenital heart disease who had undergone catheterization while on ECMO from December 1990-December 1995. The procedures, including four interventions, were successful in all patients with adequate evaluation of clinical questions. Unexpected diagnostic information of clinical importance was obtained in 40%, and clinical management of patients was significantly altered in 73%. All patients tolerated the procedure and transport well. The only significant complication was a retroperitoneal hemorrhage in one patient after approximately 12 hr. Although no patients died at catheterization, overall survival was poor, with 50% weaning from ECMO, 29% surviving to discharge, and 14% surviving at follow-up. We conclude that diagnostic and interventional catheterization may be performed in patients on ECMO with acceptable morbidity and mortality; however, long-term survival in this population is poor.

Ross procedure with aortic root tailoring for aortic valve replacement in the pediatric population.

BACKGROUND: Aortic valve replacement with a pulmonary autograft (Ross procedure) is being applied more commonly in children. Although indications for this procedure have been expanded, the presence of a dilated aortic annulus has remained a relative contraindication. In this condition, the use of an undersized autograft in an enlarged aortic annulus may result in significant aortic regurgitation. METHODS: Among 68 children and young adults undergoing the Ross procedure, 15 (age range, 8 to 24 years) with severe aortic regurgitation or stenosis and an aortic annulus diameter that was at least 2 mm larger than the pulmonary annulus had aortic root tailoring. In this group, the diameter of the aortic annulus measured 26.6 +/- 1.3 mm (mean +/- standard error of the mean), whereas that of the pulmonary annulus was 22 +/- 0.9 mm. The mean annular difference was 4.6 +/- 0.7 mm (range, 2 to 12 mm). The aortic annulus was reduced by excising a triangular wedge of tissue posteriorly from the aortic valve annulus at the level of the commissure between the left and noncoronary cusps extending into the anterior leaflet of the mitral valve. The edges were reapproximated over a calibrated dilator to adjust the final size of the aortic annulus to 2 mm smaller than that of the pulmonary autograft. Circumferential felt strips were not used in any patient. RESULTS: All patients survived and morbidity was limited to one reoperation for bleeding. Doppler echocardiographic examination performed at discharge demonstrated that no patient had more than trace to 1+ aortic regurgitation and none had evidence of aortic stenosis. Over a mean follow-up period of 6.3 +/- 1.5 months (range, 1 to 16 months) there has been no late morbidity or mortality and no progression of aortic regurgitation. CONCLUSIONS: Aortic root tailoring further extends the use of the Ross procedure to patients with excessive aortic annular dilation while maintaining the potential for growth, which is particularly important in the pediatric population.

Effect of aging on the basal expression of c-Fos, c-Jun, and Egr-1 proteins in the hippocampus.

In the present study the effect of aging on the basal expression of three different immediate early genes (IEGs) was investigated. The protein products of c-fos, c-jun, and egr-1 genes were visualized immunohistochemically in the rat hippocampus of young adult (4-month-old) and old rats (20-month-old). Astrocytes were quantified by GFAp immunostaining to determine whether changes in the expression of IEGs were correlated with modifications in this marker of degenerative changes. In the young adult rat brain, basal levels of c-Jun and Egr-1 but not c-Fos were detected within the hippocampal formation. Whereas very high basal levels of c-Jun were found in the dentate granule cells and in the pyramidal cells of the ventral hippocampus, Egr-1 was highly expressed in the CA1 pyramidal cells of the dorsal hippocampus. Aging was accompanied by a decrease in Egr-1 expression, by a decrease in total cell density, as well as by a loss of astrocytes in CA1 subfields. In contrast, basal expression of c-Fos and c-Jun as well as astrocyte density within the dentate gyrus were not affected by aging. No difference in these markers was observed in aged rats with or without impairment in spatial learning in a water maze. It was concluded that although these changes may reflect senescence-induced decline of brain function, they do not constitute the defect underlying the age-associated reduction in mnesic capability.

Changes in striatal immediate early gene expression following neonatal dopaminergic lesion and effects of intrastriatal dopaminergic transplants.

To evaluate the functional integration of neonatal dopaminergic transplants within host brain we studied the postsynaptic effects induced by their stimulation by following the expression of immediate early genes c-fos, c-jun and egr-1. This study was conducted nine months after the intrastriatal implantation of embryonic mesencephalic neurons to rat pups having sustained a unilateral lesion of the nigrostriatal dopaminergic system. We examined whether, when challenged with d-amphetamine: (1) dopaminergic grafts transplanted into the previously denervated neonatal neostriatum lead to a normal activation of postsynaptic striatal neurons in term of immediate early genes activation; and (2) whether this activation is related to the action of the dopamine released from the grafts using a dopaminergic D1 antagonist. Following a mild stress-injection of saline-c-fos expression was high in the lesioned neostriatum when compared with control animals. This effect was only partially counteracted by a pre-treatment with the D1 antagonist SCH 23390, but was abolished by the graft. Administration of d-amphetamine increased c-fos expression in the neostriatum and the globus pallidus of the control group. This activation was partially blocked by the lesion. The transplant reversed the effect of the lesion and, moreover, led to a c-fos over-expression in the dorsolateral neostriatum and the globus pallidus. These overcompensations positively correlated with the abnormal rotation induced by d-amphetamine in the same animals. Pre-treatment with SCH 23390 blocked the effect of d-amphetamine on c-fos expression in control and grafted animals. Similar results were found for egr-1 but not c-jun expression. It is concluded that the neonatal lesion of the nigrostriatal dopaminergic pathway, in contrast to the adult-stage lesion, modifies the reactivity of c-fos in the neostriatum to stress, presumably in relation with compensatory reorganizations occurring following the neonatal lesion. Grafts made into neonates, when challenged with amphetamine, induce an abnormal c-fos expression which can predict the degree of overshoot observed for rotation activity. This over-expression, which depends upon the stimulation of D1 receptors, indicate an abnormal activation of postsynaptic target cells by the grafts.

Convergence or divergence of male and female physicians' hours of work and income.

This article verifies if the increase in the percentage of women in the medical profession led to the convergence of male and female physicians' hours of work as well as income. Active physicians in Quebec in 1978 were compared to the ones in 1988. Data were obtained from the computerized files of the Quebec Corporation of Physicians and the Régie d'assurance-maladie du Quebec. Despite the increasing representation of women in the medical profession, gender differences in hours worked and income remained. However, results also showed a tendency toward a convergence in total hours of work, more behavioral variation among women physicians and some behavioral change among men. The experience of the past should thus not be used as the basis for projections of future physician productivity or for medical manpower planning purposes without a careful analysis of trends in behavioral changes.

Comparative cardiac effects of milrinone and sodium nitroprusside in conscious rats.

The rat has been shown to be resistant to the inotropic action of milrinone. We compared in conscious rats, the effects of an i.v. infusion of milrinone (0.3 mg/kg/min), a phosphodiesterase (PDE) inhibitor to those of nitroprusside (50 micrograms/kg/min), a pure vasodilator, on blood pressure and dP/dtmax to determine whether or not an inherent positive inotropic effect of milrinone is offset by its powerful hypotensive action. For the first 10 min of infusion, we found no differences in dP/dtmax, (the first derivative of the left ventricular pressure (LVP), an index of contractility) for equihypotensive doses of milrinone or nitroprusside. A second objective of this study was to determine if milrinone-induced ventricular fibrillation (VF) is due to cardiac ischemia which could be associated with the profound hypotension induced by the drug. Milrinone infusion was accompanied by a significant QTc interval (QT corrected for heart rate) prolongation. VF and death occurred in 5/6 rats at total doses varying from 3.6 to 20.1 mg/kg infused over 12 to 67 min respectively. Premature ventricular contractions (PVCs) were noted in all 6 milrinone infused rats during the first min. of infusion. No arrhythmias were noted during the 2 hour i.v. infusion with nitroprusside. A direct action on the heart is postulated to explain, at least partially, the milrinone-induced VF since nitroprusside had a similar hypotensive action but no effect on the ECG. We conclude that the rat, in analogy to patients with severe cardiac failure, might be resistant to the inotropic action of milrinone but is sensitive to its vasodilatory and arrhythmogenic effects.

Peripheral leukocyte count and leukocyte indexes in healthy newborn term infants.

PURPOSE: This study was designed to determine normal values for the peripheral leukocyte count and leukocyte indexes in healthy term neonates at a specific time after birth. METHODS: We prospectively enrolled 193 healthy term-gestation neonates with no identifiable perinatal risk factors for sepsis. At 4 hours of age a blood sample was collected by warmed heel stick. An automated Coulter complete blood cell count and a 100-cell manual differential leukocyte count were performed on each sample. The differential count was performed by a single hematopathologist unaware of the clinical status of each infant. Perinatal factors were identified by review of the mothers' and infants' hospital records. RESULTS: The mean ratio of immature to total neutrophils was 0.16 (SD 0.10), and the 10% to 90% range was 0.05 to 0.27. The mean leukocyte count was 24.06 x 10(9)/L (24,060/mm3), and the 10% to 90% range was 16.2 to 31.5 x 10(9)/L (16,200 to 31,500/mm3). Neutropenia, < 1.5 x 10(9)/L (1500/mm3) segmented plus band form neutrophils, was not observed. Of all the perinatal factors studied, only the duration of stage 1 labor was found to be associated with significant elevations in the leukocyte and absolute neutrophil counts. CONCLUSIONS: Previously published normal ranges for leukocyte indexes in healthy newborn infants during the early neonatal period are too restrictive; reference standards should be broadened.

Validation of a human atrial trabecular preparation for evaluation of inotropic substances.

Assessment of cardioactive substances is usually performed using animal tissue, with the effects being extrapolated to humans, thereby potentially introducing errors due to species differences. In order to validate the use of human atrial tissue, known positive and negative inotropic agents were tested on trabeculae obtained from patients' atrial appendages at the time of cardiac surgery requiring, cardiopulmonary bypass. Trabeculae were selected according to strict criteria: cross-sectional area less than 1.0 mm2, resting force (RF) less than 0.7 g, and developed force (DF) greater than 0.8 g. Each trabecula received only one drug in a cumulative dose manner. Where necessary, the vehicle used to dissolve or stabilize the drug solution was also tested. In addition, the relative DF of "no-drug," "time-only" controls were measured during the same time period. After adjusting for the effect of time on the preparation, relative DF was increased to 157% by dobutamine (1.5 x 10(-5) M), to 136% by amrinone (5.6 x 10(-4) M), and to 117% by ouabain (2 x 10(-7) M). The relative DF decreased with nifedipine and propranolol, with 50% inhibition for both drugs being 1.5 x 10(-7) M. Although human ventricular muscles might be more appropriate to use in order to determine the effects observed with the whole heart, they are extremely difficult to obtain on a regular basis. The results of this study show that the atrial trabecular preparation offers an acceptable alternative.

Delay in hearing loss following drug administration. A consistent feature of amikacin ototoxicity.

The time course of threshold increase in the VIII nerve compound action potential was studied in guinea pigs following amikacin administration at four different constant infusion rates. Despite the wide range of dosing durations required to achieve drug ototoxicity (2-24 days), the full development of both high and low frequency hearing loss was invariably found to be delayed with respect to the time of drug removal. The greatest degree of delayed hearing loss generally occurred within the first 7 days after drug removal, with smaller losses occurring during later time intervals. The delay showed a tendency to decrease as the ototoxic dose was increased. Using the data from the two highest dosing rates, it was estimated that a minimum of 4 days had to elapse before any hearing loss could be detected, once an ototoxic amount of drug had been administered. These data suggest that hearing loss is always substantially delayed with respect to the receipt of an ototoxic dose of amikacin, and that this must be taken into account when conducting animal experiments and when monitoring hearing in patients for the early detection of ototoxicity.

Acute effects of milrinone on the electrocardiogram and the cardiac hemodynamics of rats with pressure overload-induced congestive heart failure.

The effects of i.v. bolus injections of milrinone on the electrocardiogram and cardiac hemodynamics were evaluated in old rats with chronic (82-93 weeks) pressure overload induced by aortic constriction. Based on the heart weight/body weight ratio and histopathological findings, the rats with aortic clips were divided into 2 groups: rats with (CHF group) or without (CLIP group) congestive heart failure (CHF). In CHF rats, the cardiac contractility, as measured by the peak of the first derivative of the left ventricular pressure (dP/dt max), was significantly lower than in CLIP rats, confirming the presence of heart failure in these rats. Three groups of anesthetized rats received boluses of milrinone of 0.1, 0.5, 1, 5 and 10 mg/kg: sham-operated rats (SHAM, n = 9), CLIP (n = 22) and CHF (n = 10). A control group of 3 CHF and 5 CLIP rats received only the vehicle. The major effect of milrinone at the 2 highest doses was the induction of ventricular fibrillation and death in approximately 25% of the rats (SHAM 2/9, CHF 1/10 and CLIP 7/22). A significant widening of the QRS complex (which includes ST segment) was also noted 3 min after each dose of milrinone in the SHAM group and at 5 and 10 mg/kg doses in the CHF group. These results were thought to be related to the marked hypotensive effect of milrinone possibly inducing myocardial ischemia. No positive inotropic effect, as indicated by the maximum rise of left ventricular pressure (dP/dt max) could be observed. This might have been because of (1) the marked vasodilating effect of milrinone on venous and arterial beds, negating a possible small positive inotropic effect, or (2) the lack of positive inotropic action of milrinone in rats. Our results thus indicate that, in anesthetized rats, milrinone is a powerful vasodilator but not a positive inotropic agent (or a very weak one).

Effects of milrinone treatment in cardiomyopathic hamsters (CHF 147) with severe congestive heart failure.

The effects of oral milrinone treatment in cardiomyopathic hamsters with severe congestive heart failure (CHF) were evaluated. Strict criteria based on increase in body weight were established to define day no 1 of treatment. Survival rate of non-treated hamsters (group 1) ranged between 9 and 16 d, mean 12.9 (SEM 0.8) d, after entering the study. Hamsters treated with milrinone in drinking water (group 2a: 0.3 mg.ml-1, or group 2b: 0.6 mg.ml-1) survived between 6 and 36 d, mean 15.0(2.1) d, NS, for group 2a, and between 6 and 47 d, mean 19.6(4.0) d, NS, for group 2b. There was a significant difference between the number of hamsters that survived longer than 16 d between untreated hamsters (group 1, n = 0/12) and hamsters treated with milrinone (groups 2a, b, n = 7/24). There was no significant correlation between survival duration and milrinone daily dose nor between survival and milrinone plasma concentration at death. Milrinone treatment also significantly decreased pulmonary congestion as measured by the number of pigment containing macrophages per alveolus. No other pathological findings were modified by milrinone. It was concluded that, in addition to exerting a beneficial effect on pulmonary congestion, milrinone improved survival in some CHF hamsters. However, more studies are needed to evaluate the possibility of an arrythmogenic potential that might explain why some treated hamsters died earlier than non-treated hamsters.

Incidence of amikacin ototoxicity: a sigmoid function of total drug exposure independent of plasma levels.

A sigmoid curve was found to closely describe the relationship between the incidence of amikacin ototoxicity (greater than or equal to 15 dB hearing loss at a given frequency) and either (1) total dose, or (2) the area under the curve (AUC) describing plasma drug concentration v time over the total period of amikacin administration (total AUC) in continuously infused guinea pigs. Total dose or total AUC estimates of the drug exposure required to produce ototoxicity in 50% of the animals (ED50s) were not significantly different over an eight-fold range of dosing rates or plasma concentrations. A theoretical explanation for this result is that ototoxicity occurs only when a critical amount of drug is accumulated at the ototoxic site by an essentially unidirectional process with a rate that is slow and linearly related to the extracellular drug concentration. The sigmoid relationships for pooled data were parallel in slope for all hearing frequencies from 2 to 32 kHz, and the ED50s showed a strong negative linear relationship to the log of the hearing frequency over this range. The magnitude of ototoxicity expressed as the number of octaves (frequency ratios of 2) for which hearing loss damage was continuous from 32 kHz downward, was correlated to both total dose (r = .605) and total AUC (r = 0.703). No relationship between ototoxicity and plasma level or dosing rate was found. The extreme steepness of the dose-effect curve for the incidence of ototoxicity greatly amplified the variability between individuals and offers an explanation for the unpredictability of aminoglycoside ototoxicity in human patients. The results indicate that either total dose or total AUC (in cases of highly unpredictable blood levels), and not peak or trough serum levels, should be used as an index of ototoxic risk and that the safety limits of drug exposure should be set conservatively.

A pressure overload model of congestive heart failure in rats.

Approximately 32% of the rats used as animal models showed an elevated heart weight/body weight ratio (0.432[SEM 0.022] g.100 g-1 compared to 0.293[0.009] g.100 g-1 for sham-operated rats), a hydrothorax, pulmonary and liver congestion, and specific histological changes 82-93 weeks after surgically induced aortic constriction. The histological changes were comparable to those observed in hearts of people suffering from long term hypertension. Cardiac failure was also confirmed by depressed contractility as measured by maximum and minimum dP/dt (first derivative of left ventricular pressure), which were 4604(346) and 3627(526) mm Hg.sec-1, respectively, compared with 9165(745) and 5835(268) mm Hg.sec-1 respectively in rats that did not develop left ventricular hypertrophy and failure (CLIP rats). Systolic and left ventricular blood pressures measured under anaesthesia were also decreased: 71.6(5.0) and 88.1(6.3) mm Hg respectively in rats with congestive heart failure, compared with 83.6(2.4) and 109.5(3.6) mm Hg in CLIP rats. Except for a prolonged mean PQ interval associated with a lower heart rate and for a slightly shorter QRS interval in the conscious state, the electrocardiograms of rats with congestive heart failure did not show any major abnormalities specific to ventricular hypertrophy and/or failure. This model could be useful for studying the pathology and adaptative mechanisms in compensated pressure overload induced congestive heart failure as well as in studies comparing pathological changes and means of treatment of congestive heart failure with different aetiologies encountered in the human population.