Biomedical subjects

M W Church

Publications and source records attributed to M W Church.

At least 19 recordsLinked to original sources

PubMed1998

Effects of prenatal cocaine on hearing, vision, growth, and behavior.

The illicit use of cocaine has increased dramatically over the last 10-12 years. There has been a corresponding increase in cocaine abuse among obstetric patients and in the number of "cocaine babies." According to some estimates, these children make up more than half of the drug-associated births. This problem is therefore a major public health concern. Consequently, our laboratory investigated the effects of prenatal cocaine exposure on hearing, vision, growth, and exploratory/stress behavior. This chapter summarizes the literature on animals and humans on these topics and presents new observations from our laboratory. In terms of maternal toxicity, prenatal cocaine exposure causes hypertension, placental abruption, spontaneous abortion, poor pregnancy weight gain, and undernutrition secondary to appetite suppression. Some offspring effects include in utero growth retardation, cephalic hemorrhage, fetal edema, altered body composition, congenital malformations, and even pre- and postnatal death. The offspring can also exhibit a variety of behavioral, visual, hearing, and language disorders. Differential effects of animal strain and late gestational cocaine exposure are discussed. Comparisons are made between prenatal cocaine, the fetal alcohol syndrome, and the effects of prenatal undernutrition. Recommendations for clinical assessment and intervention are made.

Abnormalities, Drug-Induced↗

PubMed1998

Prenatal cocaine, alcohol, and undernutrition differentially alter mineral and protein content in fetal rats.

Alcohol exposure and undernutrition during pregnancy have been associated with altered fetal body composition. Recent observations suggest that cocaine exposure during pregnancy may impair delivery of nutrients to the fetus and could thereby alter body growth and composition. Such effects are important because they can adversely influence physical and neural development. Consequently, we investigated the dose-dependent effects of cocaine on fetal body composition in an animal (rat) model and compared such effects with those caused by prenatal alcohol exposure and undernutrition. Pregnant Sprague-Dawley rats received either 20, 30, 40, or 50 mg/kg cocaine HCl (SC) twice daily from gestation days 7 through 19. Pair-fed (undernutrition) and untreated control groups and a group receiving 3.0 g/kg alcohol (PO) twice daily served as comparison groups (n = 11 to 14/group). Females were sacrificed on gestation day 20. One male and one female fetus was removed from each dam. The fetuses were minced, dehydrated, defatted, and analyzed for content of protein and the minerals Zn, Ca, Fe, Mg, K, and Na. In terms of concentration per unit of fat-free dry solids, male fetuses in the cocaine groups showed significant decreases in protein compared to untreated controls (15+/-3 to 20+/-2 mg/g vs. 24+/-4 mg/g, p = 0.01). There was a significant treatment effect for Ca (p < 0.05), reflecting a trend for decreased Ca concentrations in the fetuses of the cocaine and undernutrition groups. Male fetuses in the alcohol group had significantly elevated Mg levels compared to male fetuses in the other groups (3.0+/-0.8 vs. 1.0+/-0.2 to 2.3+/-0.7 mg/g, p < 0.05). There were some sex differences, with female fetuses having significantly lower concentrations of Mg, Fe, K, and higher protein concentrations than male fetuses. Although the effects were few and modest, these results suggest that prenatal cocaine, alcohol, and undernutrition can differentially alter fetal body weight and composition and, therefore, adversely influence fetal development.

Animals↗

PubMed1998

Fetal alcohol syndrome. Hearing, speech, language, and vestibular disorders.

Fetal alcohol syndrome (FAS) refers to a pattern of anomalies that include craniofacial, CNS, growth, and various sensory anomalies. We have observed that FAS is associated with four kinds of hearing disorders: (1) developmentally delayed auditory function, (2) sensorineural hearing loss, (3) intermittent conductive hearing loss owing to recurrent serous otitis media, and (4) central hearing loss. As is the case with other syndromes associated with craniofacial anomalies and hearing impairments, speech and language pathologies also are common in FAS patients. Although auditory and vestibular systems arise from similar embryological tissue, vestibular dysfunction is variable in FAS. Early identification and intervention to treat hearing, language, and speech problems should improve the functional level of FAS in children.

Animals↗

PubMed1997

Cocaine's lethality increases during late gestation in the rat: a study of "critical periods" of exposure.

OBJECTIVE: Cocaine-associated morbidities in pregnant women (e.g., abruptio placentae, hypertension, seizures) occur mostly during the final stages of gestation. The purpose of our study was to determine whether cocaine's toxicity and blood levels varied as a function of "critical periods" of exposure during gestation. STUDY DESIGN: To evaluate mortality rates, pregnant Long-Evans rats received subcutaneously 30, 40, or 50 mg/kg cocaine hydrochloride twice daily (C30, C40, and C50 groups) either during gestational days 7 to 13 (midgestation) or gestational days 14 to 20 (late gestation) (n 9 to 20 per group). Serum levels of the cocaine metabolite benzoylecgonine were examined in other groups of rats on either gestational day 13 (mid) or day 20 (late) in the C30 treatment condition (n = 5 and 10 per group). RESULTS: There were no maternal mortalities in the midgestation groups at any dose. In contrast, the late-gestation groups showed a dramatic dose-dependent effect, with maternal mortality rates of 0%, 40%, and 72% in the C30, C40, and C50 groups. The late-gestation group had higher benzoylecgonine levels than the midgestation groups did. CONCLUSIONS: Late gestation was associated with higher maternal mortality rates and higher benzoylecgonine levels, indicating that some underlying physiologic change enhanced cocaine's toxicity as pregnancy progressed. This increased sensitivity to cocaine may be mediated by estrogen or progesterone, suggesting that the cocaine-abusing woman is at increased risk for cocaine-induced morbidities whenever levels of these hormones are elevated, such as during the final stages of pregnancy or possibly when taking oral contraceptives.

Animals↗

PubMed1997

Comparison of five agents in protecting the cochlea against the ototoxic effects of cisplatin in the hamster.

The purpose of this investigation was to study the ameliorating effects of four agents on cisplatin-induced ototoxicity. Hamsters were given a series of five cisplatin injections either alone or in combination with sodium thiosulfate (STS), diethyldihydrothiocarbamate (DDTC), and S-2(3-aminopropylamino) ethylphosphorothioic acid (WR-2721), or fosfomycin. Ototoxicity was assessed anatomically by quantifying the extent of cochlear damage with the scanning electron microscope and physiologically with measures of the auditory brain stem response. When administered alone, cisplatin induced widespread loss of outer hair cells (OHCs) along much of the cochlea in the hamster, especially in the basal and middle turns, with an average survival of only 56% of the OHC population. In contrast, inner hair cells resisted cisplatin ototoxicity in the hamster. Thus the ameliorative effects of the different test agents were assessed by counting the number of surviving OHCs in each treatment group and comparing with cisplatin-treated controls. STS provided the most effective protection against the ototoxic effects of cisplatin, yielding 91% survival of OHCs. DDTC also reduced the ototoxic effects of cisplatin, yielding 68% survival of OHCs. Cotreatment with WR-2721 and fosfomycin yielded 45% and 52% OHC survival, respectively, and thus did not provide any chemoprotection. The results closely paralleled those based on auditory brain stem response recordings in that the magnitude of threshold shift was proportional to the amount of OHC loss; also, the amount of threshold shift at each frequency was in good agreement with the pattern of hair cell loss along the cochlear spiral. Thus both histologic and physiologic results suggest that STS and DDTC hold promise for ameliorating the ototoxic effects of cisplatin chemotherapy.

Amifostine↗

PubMed1997

Hearing, speech, language, and vestibular disorders in the fetal alcohol syndrome: a literature review.

Fetal alcohol syndrome (FAS) is characterized in part by mental impairment, as well as craniofacial and ocular anomalies. These conditions are traditionally associated with childhood hearing disorders, because they all have a common embryonic origin in malformations of the first and second branchial arches, and have similar critical periods of vulnerability to toxic insult. A review of human and animal research indicates that there are four types of hearing disorders associated with FAS. These are: (1) a developmental delay in auditory maturation, (2) sensorineural hearing loss, (3) intermittent conductive hearing loss due to recurrent serous otitis media, and (4) central hearing loss. The auditory and vestibular systems share the same peripheral apparatuses (the inner ear and eighth cranial nerve) and are embryologically and structurally similar. Consequently, vestibular disorders in FAS children might be expected. The evidence for vestibular dysfunction in FAS is ambiguous, however. Like other syndromes associated with craniofacial anomalies, hearing disorders, and mental impairment, FAS is also characterized by a high prevalence of speech and language pathology. Hearing disorders are a form of sensory deprivation. If present during early childhood, they can result in permanent hearing, language, and mental impairment. Early identification and intervention to treat hearing, language, and speech disorders could therefore result in improved outcome for the FAS child. Specific recommendations are made for intervention and future research.

Animals↗

PubMed1997

Hearing, language, speech, vestibular, and dentofacial disorders in fetal alcohol syndrome.

Fetal alcohol syndrome (FAS) is characterized by congenital anomalies traditionally associated with hearing disorders. The present study sought to (a) evaluate possible central hearing loss; (b) verify and extend previous observations on sensorineural and conductive hearing losses; (c) evaluate possible vestibular disorders; (d) examine the relationships between hearing, speech, language, vestibular, and dentofacial disorders in FAS patients; and (e) evaluate the influence of patient age, race, and gender on the expression of these morbidities. A biracial group of 22 FAS patients (aged 3 to 26 years) were evaluated by standard hearing, speech, language, and vestibular tests. Dentofacial and other malformations were also assessed. Of the 22 FAS patients, 17 (77%) had intermittent conductive hearing loss due to recurrent serous otitis media that persisted from early childhood into adulthood, whereas 6 (27%) had sensorineural hearing loss in addition to the conductive hearing loss. Among the 12 patients tested for central hearing function, all (100%) were significantly impaired. Among the patients tested for speech and language ability, 18 of 20 (90%) had speech pathology, 16 of 21 (76%) had expressive language deficits, and 18 of 22 (82%) had receptive language deficits. Hearing, speech, and language deficits were not influenced by age, race, or gender. On the vestibular tests, all performed within normal limits with the possible exception of one child (n = 6). High incidences of dentofacial, temporomandibular joint, ocular, cardiac, and skeletal disorders were observed. Race and gender tended to influence dental malocclusion class. Two subjects exhibited autistic tendencies. In conclusion, new and important findings included a high prevalence of sensorineural, conductive, and central hearing deficits, the persistence of otitis proneness into adulthood, the existence of temporomandibular joint disorders, and the possible influence of gender or race on dental malocclusions. Such disorders can contribute to the learning, behavioral, and emotional difficulties seen in FAS patients and warrant early, aggressive intervention.

Adolescent↗

PubMed1996

Differential effects of prenatal cocaine and retinoic acid on activity level throughout day and night.

Prenatal cocaine exposure is associated with disrupted state control and lowered activity levels. Prenatal retinoic acid excess also influences activity levels in laboratory rats. Activity level is usually monitored during a brief period in young offspring. The effects of these drugs on pup activity levels throughout the day is unknown. There is also little information on the long-lasting effects of these teratogens in adult animals. We compared the daily activity of rats which were prenatally exposed to cocaine or retinoic acid (RA). Appropriate control groups were also used. The offspring were evaluated for activity levels in a neophobic situation and for a 22-h period in same-sex groups of 3 littermates. As both pups and adults, the cocaine groups were hypoactive while the RA group was hyperactive when first placed into the testing cage (neophobic situation). Similarly, during the remainder of the 22-h testing period, the pup and adult cocaine animals exhibited reduced activity levels while the RA animals exhibited elevated activity levels. Thus, prenatal cocaine and retinoic acid exposures affected offspring activity levels differently, both drugs have long-lasting neurobehavioral effects that persist into adulthood, and effects are influenced by time-of-day. Strain-dependent differences and mechanisms of action are discussed.

Activity Cycles↗

PubMed1996

Effects of prenatal alcohol exposure and aging on auditory function in the rat: preliminary results.

This study investigated select aspects of peripheral and central auditory dysfunction, as well as the pathological effects of aging, In an animal model of fetal alcohol syndrome (FAS). Pregnant rats consumed liquid alcohol diets containing 0, 17.5, or 35% ethanol-derived calories, from gestation day 7 to parturition. A fourth group was untreated. Offspring of these mothers were tested for auditory and neurological function, using the auditory brainstem response at 6, 12, and 18 months of age. Some animals in the alcohol-exposed groups showed a peripheral auditory disorder in the form of congenital sensorineural hearing loss. This was correlated with punctate lesions and malformed stereocilia on the auditory sensory receptor cells of the inner ear. Alcohol-exposed animals also showed a central auditory processing disorder characterized by prolonged transmission of neural potentials along the brainstem portion of the auditory pathway. Animals in the highest dose group also showed an augmentation in the age-related deterioration of auditory acuity. Thus, increased peripheral and central auditory dysfunctions and pathological deterioration of auditory function in old age may be sequelae of FAS. Such morbidities have important implications for the long-term clinical assessment and management of FAS patients.

Age Factors↗

PubMed1995

The comparative effects of sodium thiosulfate, diethyldithiocarbamate, fosfomycin and WR-2721 on ameliorating cisplatin-induced ototoxicity.

The efficacies of four agents in ameliorating cisplatin-induced ototoxicity were investigated. Hamsters were given a series of 5 cisplatin injections (3 mg/kg/injection once every other day, i.p.) either alone or in combination with 1600 mg/kg/injection sodium thiosulfate (STS), 300 mg/kg/injection diethyldithiocarbamate (DDTC), 18 mg/kg/injection WR-2721, or 300 mg/kg/injection fosfomycin (n = 10/group). Ototoxicity was assessed electrophysiologically by auditory brainstem responses (ABRs) and anatomically by cochlear histology. The greatest auditory protection was given by STS, followed by DDTC. WR-2721 and fosfomycin did not provide any protection. All of the animals in the STS and DDTC groups survived, while some fatalities occurred in the fosfomycin, WR-2721, and cisplatin-only groups. Thus, the agents that were protective against ototoxicity were also protective against mortality. The ABRs also provided evidence of cisplatin-induced neuropathy. In summary, STS and DDTC hold promise for ameliorating the ototoxic effects of cisplatin chemotherapy and the hamster proved to be an excellent model of cisplatin ototoxicity.

Amifostine↗

PubMed1995

X-linked dominant cone-rod degeneration: linkage mapping of a new locus for retinitis pigmentosa (RP 15) to Xp22.13-p22.11.

Retinitis pigmentosa is the name given to a heterogeneous group of hereditary retinal degenerations characterized by progressive visual field loss, pigmentary changes of the retina, abnormal electroretinograms, and, frequently, night blindness. In this study, we investigated a family with dominant cone-rod degeneration, a variant form of retinitis pigmentosa. We used microsatellite markers to test for linkage to the disease locus and excluded all mapped autosomal loci. However, a marker from the short arm of the X chromosome, DXS989, showed 0% recombination to the disease locus, with a maximum lod (log-odds) score of 3.3. On the basis of this marker, the odds favoring X-linked dominant versus autosomal dominant inheritance are > 10(5):1. Haplotype analysis using an additional nine microsatellite markers places the disease locus in the Xp22.13-p22.11 region and excludes other X-linked disease loci causing retinal degeneration. The clinical expression of the retinal degeneration is consistent with X-linked dominant inheritance with milder, variable effects of Lyonization affecting expression in females. On the basis of these data we propose that this family has a novel form of dominant, X-linked cone-rod degeneration with the gene symbol "RP15."

Adolescent↗

PubMed1994

Effect of alcohol on platelet-activating factor acetylhydrolase activity in pregnant and nonpregnant mice.

Platelet-activating factor (PAF) induces platelet aggregation and hypotension. It has been implicated in embryonic implantation, fetal lung maturation, and parturition. Alcohol abuse is associated with platelet dysfunction, chronic hypertension, and alcohol-related birth defects. We hypothesized that alcohol may cause, in part, these effects by increasing the activity of PAF-acetylhydrolase (PAF-AH), thereby decreasing PAF concentration. Pregnant mice were given 3.5 g/kg of alcohol orally twice daily from gestation days 7-17. PAF-AH was measured on gestation days 5, 14, and 19 in pregnant females. Nonpregnant females were treated and sampled at parallel time intervals. Pair-fed and untreated control groups were also used. The maternal plasma PAF-AH decreased with gestational age in the untreated controls. Alcohol significantly increased PAF-AH levels in both the pregnant and nonpregnant animals. PAF deficiency might contribute to the tocolytic action of alcohol, as well as some alcohol-related pregnancy complications.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed1993

The hamster's auditory brain stem response as a function of stimulus intensity, tone burst frequency, and hearing loss.

Young adult hamsters were evaluated for normal variations in the auditory brain stem response (ABR) and for the effects of hearing loss. Normal variations in the ABR's latencies and amplitudes were defined for both click and tone burst stimuli over a broad range of intensities. As stimulus intensity decreased from 100 to 15 dB pe SPL, the ABR latencies were prolonged, the P4-P1 interpeak latencies varied in a complex manner, and amplitudes decreased. As tone burst frequency decreased from 8000 to 4000 and then to 2000 Hz, ABR latencies were prolonged, amplitudes decreased, and thresholds increased. The P4-P1 interpeak latencies were also influenced by tone burst frequency, with the longest interpeak latencies occurring in response to the 2000 Hz tone bursts. Data from two hamsters with hearing loss were compared to the normal data to illustrate how the ABR can be used to describe experimentally induced hearing impairment. Hearing impairment was induced by rearing animals in ambient noise. These animals showed elevated ABR thresholds at all three frequencies and upward displacements in the ABR's latency-intensity profiles.

Acoustic Stimulation↗

PubMed1992

Effects of tone burst frequency and intensity on the auditory brainstem response (ABR) from albino and pigmented rats.

Young adult male Sprague-Dawley (SD) and Long-Evans (LE) rats were evaluated using the auditory brainstem response (ABR). ABRs were evoked by stimuli with intensities ranging from 15 to 100 dB peSPL. Stimuli were tone bursts of 2000, 4000 and 8000 Hz. As stimulus intensity decreased from 100 to 15 dB, the ABR peak latencies prolonged, interpeak latencies (IPLs) shortened and amplitudes decreased. As stimulus frequency decreased from 8000 to 2000 Hz, ABR latencies prolonged, amplitudes decreased and ABR thresholds increased. The longest IPLs were in response to the 4000 Hz tone bursts. SD rats had ABRs with shorter peak latencies, larger amplitudes and lower thresholds than LE rats. The IPLs usually did not show significant strain-dependent differences. Our observations on stimulus intensity and frequency are consistent with previous reports. Our observations also suggest that the SD (albino) rat has better auditory acuity than the LE (pigmented) rat over the frequency range of 2000 to 8000 Hz. This implies that previous concerns about the use of albino animals in audiological research are somewhat overstated.

Acoustic Stimulation↗

PubMed1992

Audiogenic seizure susceptibility and auditory brainstem responses in rats prenatally exposed to alcohol.

Rats prenatally exposed to alcohol (0%, 17.5%, or 35% ethanol-derived calories) were tested for audiogenic seizure susceptibility on one of postnatal days 18 to 23, then retested 5 days later. Prenatal alcohol exposure did not influence audiogenic seizure susceptibility or severity. There was, however, a significant increase in seizure incidence on the retest day for all groups, suggesting a priming effect. Auditory brainstem response (ABR) data suggested that prenatal alcohol exposure and acoustic trauma (i.e., exposure to an alarm bell used for eliciting audiogenic seizures) induced measurable sensorineural hearing loss, and that the combined exposure to alcohol and acoustic trauma interacted additively to produce greater hearing loss than either alone.

Animals↗

PubMed1991

Sensorineural hearing loss as evidenced by the auditory brainstem response following prenatal cocaine exposure in the Long-Evans rat.

Prenatal cocaine exposure has been associated with a variety of adverse neurological effects. Three recent studies found evidence that prenatal cocaine exposure is associated with abnormal auditory electrophysiology, suggesting abnormal processing of auditory information. The present study used the auditory brainstem response to evaluate the effects of prenatal cocaine exposure on hearing in an animal model (Long-Evans rat). We report that prenatal cocaine exposure can cause elevated ABR thresholds and latency-intensity curves consistent with a recruitment-type sensorineural hearing loss.

Animals↗

PubMed1991

Long term effects of prenatal cocaine exposure on bone in rats.

Prenatal exposure to cocaine has been shown to produce a variety of effects on skeletal development and mineralization in humans, mice, and rats. The effects of cocaine on bone cell function and mineral metabolism pre- and postnatally are poorly understood. The present study examined the long term effects of prenatal cocaine exposure on femoral growth and mineralization in male rats. Pregnant rats were given 80 or 100 mg cocaine hydrochloride/kg during days 7-20 of gestation. At birth, body weights of pups born to these females were significantly decreased compared to normal and pair-fed controls. At the termination of the study (32 weeks), body weights of offspring from C100-treated females were still lower than normal. Long term effects of prenatal exposure to cocaine on femoral growth were most pronounced in offspring of C80-treated females. Femur dry weight, ash weight, organic matrix weight and density were significantly reduced in these animals compared to normal or pair-fed controls. The apparent osteopenic effects of prenatal exposure to cocaine suggests some long term postnatal impact on bone cell or mineral metabolism. Previous studies of cocaine use during pregnancy in humans and animals have focused primarily on physical and behavioral defects in offspring. The present findings indicate that prenatal exposure to cocaine may also have long term consequences to the skeleton.

Animals↗

PubMed1990

Maternal age and blood alcohol concentration in the pregnant Long-Evans rat.

Despite comparable alcohol consumption, not all women who drink excessively give birth to children with fetal alcohol effects or the fetal alcohol syndrome. Various maternal factors may be important in this regard. For example, two recent animal studies found that maternal age was an important risk factor in regard to alcohol's adverse effects on pregnancy. Specifically, alcohol produced greater maternal and fetal toxicity in older and middle-age mothers than in younger cohorts. An age-related difference in maternal blood alcohol concentrations (BACs), despite comparable alcohol administration, may have been the major factor. That is, older mothers may achieve higher BACs or take longer to eliminate alcohol from their blood, resulting in greater maternal and fetal toxicity. The present study was conducted to investigate this possibility. Dams were of three age groups: 2 1/4, 3 3/4 and 5 1/4 months old. Alcohol (3.5 g/kg p.o.) was administered twice daily at a 6-hr interval from gestation days 11 to 19. Blood samples were obtained on gestation day 19 at 1, 2, 4 and 6 hr after each injection. The data showed a progressive increase in peak BACs and a prolonged presence of alcohol with increasing maternal age. It was subsequently hypothesized that age-related differences in percent body water content might account for these effects, and we tested for this possibility. While age-related differences in body water content were found, administering alcohol doses on the basis of body water content did not equate BAC curves across the maternal age groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗