Biomedical subjects

S A Ferguson

Publications and source records attributed to S A Ferguson.

106 records · Page 6Linked to original sources

PubMedDate not supplied

Functional effects of methylazoxymethanol-induced cerebellar hypoplasia in rats.

The behavioral effects of a series of methylazoxymethanol acetate (MAM) injections in neonatal rats were investigated. Pups were injected twice daily on days 5-8 after birth with 4 mg/kg MAM or saline. Similar treatment paradigms cause cerebellar hypoplasia, which is a result of a depletion of granule cells. MAM treatment reduced adult cerebellar weight to 92% that of control and was without effect on weight of other brain regions examined. Postweaning body weight gain in males was reduced. Nest odor preference and emergence (light/dark box) assessments indicated no significant effects. Complex maze assessments and performance in an operant test battery demonstrated no cognitive deficits. Indeed, MAM treated females performed better in a complex maze under lighted conditions than same-sex controls. Open field and running wheel activity levels in females were unaffected. Though not statistically significant, males exhibited a mild hyperactivity syndrome characterized by an increase in running wheel and open field activity, as well as a depressed startle response. Both sexes were hypersensitive to the locomotor-increasing effects of methamphetamine. These results suggest that the functional effects resulting from cerebellar hypoplasia produced by MAM treatment on PNDs 5-8 are milder than those resulting from MAM treatment beginning on the day of birth. The results are compared with other forms of cerebellar lesions and provide support for the hypothesis that early insult (day of birth or shortly after) produces hypoactivity whereas a later insult (day 4 or later after birth) produces a syndrome of hyperactivity.

Aging↗

PubMedDate not supplied

Maternal and offspring toxicity but few sexually dimorphic behavioral alterations result from nonylphenol exposure.

Nonylphenol ethoxylates are used in the production of surfactants and are found in numerous manufactured substances. para-Nonylphenol (NP) is a suspected endocrine disruptor, exhibiting estrogen-like activity and might cause alterations with developmental exposure. To evaluate such effects, pregnant Sprague-Dawley rats consumed diets containing 0 (n = 11), 25 (n = 10), 500 (n = 10), or 2,000 (n = 9) ppm NP beginning on gestational day (GD) 7. At postnatal day (PND) 21, offspring continued on the same maternal diets until PND 77 and were evaluated for behavioral alterations (open-field activity at PNDs 22-24, 43-45, 64-66, play behavior at PND 35, running wheel activity at PND 63-77, flavored solution intake at PND 69-75). During pregnancy and lactation, dams in the 25-, 500-, and 2,000-ppm groups consumed 9 to 25% less food, which was associated with a 17% less weight gain during GDs 1 to 21 in dams of the 2,000-ppm group, although this effect was not statistically significant. Gestation duration, birth weight, sex ratio of live pups, and number of live or dead pups per litter did not differ between treatment groups. Offspring body weight and food consumption were decreased in the 2, 000-ppm group beginning at PND 28; however, an effect of feed aversion could not be eliminated. Behavioral assessments of offspring indicated no consistent NP-related effects in open-field activity at PNDs 22-24, 43-45, and 65-67 nor in running wheel activity at PNDs 63-75. Play behavior at PND 35 and intake of a 0.3% saccharin-flavored solution at PNDs 69-71 did not differ with respect to treatment groups. However, intake of a 3% sodium-flavored solution at PNDs 73-75 was significantly increased in offspring of the 2,000-ppm group and intake of regular water during this same time was also significantly increased. These results indicate that developmental NP treatment results in maternal and offspring toxicity as evidenced by decreased food intake and weight gain. However, behavioral alterations were evident only in increased intake of a sodium solution.

Animals↗

PubMedDate not supplied

Retinoic acid exposure on gestational days 11 to 13 impairs swallowing in rat offspring.

We have previously reported that exposure to 10 mg/kg of all-trans-retinoic acid (RA) daily on the 11th, 12th, and 13th days of rat gestation is lethal to all fetuses so exposed, due to an inability to suckle [R.R. Holson et al., Neurotoxicol Teratol 19 (1997) 347-353]. Because this lethal RA effect could be due to any of a variety of causes, from olfactory problems in locating the nipple to a motor problem in sucking or swallowing, we performed the following experiment. Albino dams were exposed to 10-mg/kg RA or vehicle daily over gestational days (GDs) 11 to 13. On the afternoon of GD 21 all pups were delivered by c-section. Tongue cannulae were inserted into the oral cavity of these offspring, and used to infuse a solution of condensed milk directly into the mouth. During and after each of four infusions, the behavioral response to the infusion (typically rolling and curling) was recorded. Controls responded well to this procedure, typically swallowing all milk so infused. In contrast, almost no RA-exposed neonates were able to swallow milk infused into the oral cavity. In such cases the milk simply dribbled out of the mouth, while the stomach was found to be empty at autopsy. However, the RA-treated animals did seem aware that milk was entering their mouths, because they showed a normal behavioral response to milk infusion. We conclude that GD 11-13 retinoid lethality is due to motor not sensory problems in the control of swallowing.

Animals↗

PubMedDate not supplied

Attention deficit/hyperactivity disorder: characteristics, interventions and models.

An epidemiological study of Attention Deficit/Hyperactivity Disorder (ADHD) suggests that the prevalence may be two to three times higher than the figure of 3-5% often cited. In addition, the data suggest that both underdiagnosis and overdiagnosis occur frequently. Rodent animal models of ADHD, like the Spontaneously Hypertensive Rat (SHR) and other rat models such as those with chemical and radiation-induced brain lesions and cerebellar stunting, and the Coloboma mouse model exhibit clear similarities with several aspects of the human disorder and should prove useful in studying specific traits. Operant behavioral tasks that model learning, short-term memory and simple discriminations are sensitive to ADHD and methylphenidate has been shown to normalize ADHD performance in a short-term memory task. Recent findings challenge not only the current postulate that response inhibition is a unique deficit in ADHD, but also the concepts of ADHD and its treatment, which presume intact perceptual abilities. Time perception deficits may account, in part, for the excessive variability in motor response times on speeded reaction time tasks, motor control problems and motor clumsiness associated with ADHD. The Multimodality Treatment Study of ADHD (MTA) provided data suggesting that pharmacological interventions that included systematic and frequent follow-up with parents and teachers, with or without psychosocial interventions, are superior to psychosocial interventions or standard community care alone. Additionally, the MTA was one of the first studies to demonstrate benefits of multimodal and pharmacological interventions lasting longer than 1 year. Imaging studies have demonstrated differences in brain areas in children with ADHD: anterior corpus callosum, right anterior white matter, and cerebellar volumes are all decreased in children with ADHD and there is less brain asymmetry in ADHD subjects. Additionally, functional imaging studies, coupled with pharmacological manipulations, suggest decreased blood flow and energy utilization in prefrontal cortex and striatum and the dysregulation of catecholamine systems in persons with ADHD.

Animals↗

PubMedDate not supplied

Neonatal dexamethasone on day 7 in rats causes behavioral alterations reflective of hippocampal, but not cerebellar, deficits.

Developmental glucocorticoid treatment in rats has been shown to cause body and brain weight decrements concurrent with behavioral alterations. Here, Sprague-Dawley rats were treated with the synthetic glucocorticoid, dexamethasone (DEX), on postnatal day (PND) 7 (1.5 mg/kg, sc, injected in the morning and afternoon). Behavioral assessments of negative geotaxis, locomotor activity (open field, maze exploration, residential running wheel, residential figure 8 maze), open-field activity response to amphetamine, acoustic startle, prepulse inhibition (PPI) of acoustic startle, juvenile play behavior, anxiety (emergence tests), motor coordination (rotarod performance), spatial learning (Morris water maze and food-reinforced complex maze), and operant performance (time estimation and response inhibition) were assessed in male rats. Body weight was decreased beginning at PND 43 until sacrifice on PND 127. Whole and regional brain weights were less, especially hippocampus, cerebellum, brainstem, and cortical remnant. Indications of delayed development were apparent; specifically, DEX-treated rats took significantly longer to turn on PND 8, but not PND 9, in the negative geotaxis test. DEX treatment induced deficits in the Morris water maze that were similar to hippocampal deficits. Open-field activity changes were inconsistent; however, DEX-treated rats were hyperactive during the dark period in running wheel tests. There were no indications of changes in reactivity or emotionality.

Amphetamine↗

PubMedDate not supplied

Gestational retinoic acid exposure: a sensitive period for effects on neonatal mortality and cerebellar development.

This is the first in a series of studies investigating the developmental stage-specific neurobehavioral effects of all-trans retinoic acid (RA) exposure. Because high doses of this compound are known to be lethal to the developing organism, we first conducted a dose-response study to identify RA doses that produce low enough levels of gestational/postnatal mortality to make a behavioral analysis possible in survivors. Secondarily, at doses found to produce sufficient survivors on PND 28, effects on body and regional brain weights were examined. Finally, at these doses, effects on somatic malformations were evaluated. Four separate exposure periods were analyzed: gestational days (GD) 8 through 10, 11 through 13, 14 through 16, or postnatal days (PND) 3 through 5. In the postnatal exposure period rat pups were injected (s.c.) with three consecutive daily doses of 0, 5, 10, or 20 mg/kg RA on PND 3 through 5. This postnatal exposure had no detectable effect on survival, body or brain weight. In contrast, there was a marked sensitivity to RA in the GD 11-13 group. Many pups from dams given 10 mg/kg RA PO on GD 11-13 were found dead in the cage on the day of birth, and all surviving pups died within 4 days of birth. Examination of milkbands revealed no evidence of effective suckling in these short-term survivors. The same 10 mg/kg dose at GD 8-10 or GD 14-16 produced much lower mortality and pups appeared to suckle normally. To produce adequate PND 28 survival in the GD 11-13 group, it was necessary to reduce dosage to 2.5 mg/kg daily. Even this lower exposure produced effects on PND 28 body and brain weight, significantly lowering weights of body (84% of control), whole brain (94%), and cerebellum (90%). Cerebellar weight was also depressed as percent of whole brain weight, suggesting an effect focused specifically on this region. RA at 10 or 12.5 mg/kg over GD 14-16 also reduced cerebellar weight (92% and 91% of control, respectively). Thus, exposure on GD 14-16 had effects similar to those seen at GD 11-13, but only at considerably higher doses. In contrast, exposure to RA on GD 8-10 did not affect whole body or brain weight, and of eight brain regions examined, only brain stem weight was reduced (91% of control). The GD 8-10 exposure also differed substantially from later exposures in that it was the only treatment to produce substantial malformations, including exencephaly, eye and skeletal defects. We conclude that gestational exposure to RA produces lethality and regional brain stunting that is dose and developmental stage specific, with a pronounced sensitive period on GD 11-13. In contrast, the GD 8-10 period is most sensitive for production of malformations, albeit at somewhat higher doses.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

A behavioral and neuroanatomical investigation of the lethality caused by gestational day 11-13 retinoic acid exposure.

In a companion article, we report that there is a sensitive period for all-trans retinoic acid (RA) lethality on gestational days (GD) 11-13. When dams were given 10 mg/kg RA daily for 3 consecutive days on GD 11-13, a number of pups were found dead in the home cage on the day of birth, and the remainder inevitably died due to an apparent inability to nurse. Here we report a set of experiments further investigating these effects. Dams were exposed PO to 10 mg/kg RA or oil vehicle on GD 11-13. Fetuses were removed by Cesarean section on the afternoon of GD 21, culled, and fostered to non-treated dams that had given normal vaginal delivery a day earlier. Maternal behavior was observed for the first 6 h after fostering. The next morning all surviving pups were given a brief behavioral evaluation, including the ability to attach to the nipple of anesthetized foster dams. At the time of C-section, culls were killed and brains were quickly removed and placed in fixative. A series of paraffin-embedded, cresyl-violet-stained serial sections of a representative brain stem from each litter was prepared. RA exposure did not increase fetal mortality. Treated litters were as large as controls, and virtually all treated fetuses were alive in utero. However, unlike controls, some treated fetuses appeared to have difficulty in initiating spontaneous breathing when delivered by C-section, and considerable physical stimulation was required before normal breathing began. As in the previous report, RA-exposed pups did not have milk in their stomachs after 18 h on the foster dam; further, they did not attach to the maternal nipple, and they had greater difficulty than controls in maintaining an upright posture. Examination of serial sections of the medulla indicated that the hypoglossal nucleus appeared grossly normal in the RA-exposed pups. In contrast, the inferior olive and the area postrema were affected by RA exposure. Both nuclei were normally located, but exhibited reduced cell density and/or intensity of staining. In the inferior olive the dorsal and principal nuclei were primarily affected, to the degree that about one quarter of treated brains had no identifiable principal nucleus. We conclude that RA exposure on GD 11-13 causes abnormal development of cell-dense regions of the medial medulla, and these abnormalities may account for the difficulty these animals experience in beginning spontaneous breathing and in nursing. These breathing and nursing problems in turn almost certainly account for the high mortality seen during natural birth and for the subsequent failure to thrive, respectively.

Animals↗

PubMedDate not supplied

Behavioral effects of low-dose gestational day 11-13 retinoic acid exposure.

In a comparison article we report that maternal PO exposure to 2.5 mg/kg all-trans retinoic acid (RA) daily for 3 consecutive days over gestational days (GD) 11-13 produces a 10% reduction in weight of cerebellum at 4 weeks of age, not accompanied by other malformations. Here we report the results of a preliminary behavioral analysis of offspring exposed gestationally to RA as above. Exposed dams were allowed to deliver normally, and litters were culled to eight pups (4 +/- 1 of each sex) at birth. Both male and female offspring were tested prior to weaning on GD 21. Thereafter females were killed on postnatal day (PND) 28 for verification of RA effects on regional brain weight, and all subsequent behavioral testing was conducted on males. Preweaning tests were restricted to negative geotaxis (PND 8-9) and open field activity (PND 22). Postweaning tests included open field activity (PND 43), auditory startle response (three times, on PNDs 22, 43, and 84), 2-week activity in residential running wheels (PNDs 62-76), complex maze performance for 5 consecutive days (PND 83-87), emergence latency (PND 106), and assessment of the behavioral response to an amphetamine challenge (PND 107). Males were then killed on PND 108 for verification of RA effects on regional brain weights. In this study, RA reduced weight of cerebellum but not striatum. Cerebellar weight was 92% of control values in PND 28 females, and this weight difference had diminished to 95% of control weight by PND 108 in males. There were no treatment effects on negative geotaxis, activity in a small open field, auditory startle amplitude, or latency to enter an illuminated alley from a dark chamber. Maze learning occurred at levels equal to or slightly better than controls. Running wheel activity was enhanced by RA exposure, whereas activity in response to an amphetamine challenge was reduced by such exposure. We conclude that RA doses low enough to produce mild weight reductions in cerebellum, without attendant malformations, can alter behavior. The precise nature of these alterations remains to be elucidated, but the findings reported here suggest that effects may be more pronounced on activity than on learning.

Animals↗

PubMedDate not supplied

Minimal behavioral effects from moderate postnatal lead treatment in rats.

Developmental lead exposure continues to be a worldwide problem. This study investigated the behavioral effects resulting from developmental lead treatment in rats with corresponding physiological measures of lead exposure. Sprague-Dawley rats were treated with 350 ppm lead acetate from birth to weaning via the dam's drinking water. Behavioral measures assessed in the offspring included residential activity tests, complex maze performance, acoustic startle response, emergence behavior (light/dark preference), prepulse inhibition, and ethological assessments of play, dominance, and burrowing. Pb blood levels averaged 53 microg/dl in the dam at the time of offspring weaning and 46 microg/dl in weanling female offspring. Pb levels averaged 277 ng/g and 32 microg/g in the brain and bone, respectively, of female offspring at weaning. No behavioral assessment indicated any lead-related functional alterations nor were there any statistically significant differences when the lead-treated group was restricted to rats in those litters that were above the median Pb blood lead level at weaning. These results indicate that any lead-related functional alterations at this dose may be subtle and require a sufficient demand on the system for detection.

Animals↗

PubMedDate not supplied

Neonatal dexamethasone on day 7 causes mild hyperactivity and cerebellar stunting.

To investigate the effects of glucocorticoid treatment on central nervous system development, rats were injected with dexamethasone (DEX) (1-3 mg/kg) on postnatal day (PND) 3 or 7. DNA and protein content and concentration were measured in the cerebellum and hippocampus on PND 28 and 112. Whole and regional brain weights were measured at PND 28, 84, and 112. Nest odor preference (PND 10-11), open field activity (PND 18-21), running wheel activity (PND 50-56), and complex maze performance (PND 60-63) were measured in rats treated twice with 1.5 mg/kg DEX on PND 7. DEX treatment on PND 7 resulted in reductions in PND 28 whole brain and regional weights (frontal cortex, cerebellum, and brain stem) and, by PND 112, all except whole brain and cerebellar weights had recovered. A mild syndrome of hyperactivity (increased open field rearing and activity) was apparent in rats treated with DEX on PND 7. These results are discussed in terms of the developmental stage specificity in production of brain, and, specifically, cerebellar insults and their resulting effects.

Animals↗

PubMedDate not supplied

Gestational stage-specific effects of retinoic acid exposure in the rat.

Although, or perhaps because, retinoids are among the earliest known behavioral teratogens, there is still little agreement about the behavioral effects of stage-specific exposure to these compounds. In these studies, pregnant albino rats were gavaged once daily with retinoic acid (RA) for 3 consecutive gestational days (GD), GD 8-10), GD 11-13, or GD 14-16. Dose levels were maximal levels compatible with survival (10, 2.5, or 12.5 mg/kg RA, over GD 8-10, 11-13, and 14-16, respectively). Two studies were conducted. The first assessed the effects of RA exposure on GD 8-10 or 14-16 on regional brain weight and on a large behavioral test battery. The second study assessed the effects of RA exposure on GD 11-13 or GD 14-16 on many of the same variables. Taken together with an earlier study of the behavioral effects of GD 11-13 RA exposure, these studies permit the following conclusions. 1) RA exposure at the above doses at any of the three exposure periods produced an apparent reduction in amphetamine-induced open field activity. 2) RA exposure on GD 14-16 but not earlier produced a robust, replicable rotarod deficit in exposed offspring. 3) RA exposure on GD 11-13, but not earlier or later, increased daytime activity in residential running wheels. 4) RA exposure on GD 11-13 or GD 14-16 but not GD 8-10 reduced weight of cerebellum. 5) No RA effect at any exposure period was seen on maze learning, activity in novel open fields, or on auditory startle.

Amphetamine↗

PubMedDate not supplied

Minimal behavioral effects from developmental cerebellar stunting in young rats induced by postnatal treatment with alpha-difluoromethylornithine.

Postnatal treatment with alpha-difluoromethylornithine (DFMO), a potent inhibitor of ornithine decarboxylase, reduces polyamine levels in rats. Because polyamines are critically involved in growth and development, body and/or brain weights are often decreased by DFMO treatment. Here, rats were injected subcutaneously with 0, 250, 500, or 750 mg/kg of DFMO on postnatal days (PNDs) 5-10. Behavioral assessments included righting reflex, negative geotaxis, forelimb hanging, open field activity, and rotarod performance. Additionally, day of eye opening was recorded and on PND 28, whole and regional brain weights were measured. Cerebellar/whole-brain ratio was decreased in a dose-dependent manner whereas frontal cortex/whole-brain ratio was increased. Eye opening was delayed to a similar extent in all treated groups whereas body weight was unaffected. alpha-difluoromethylornithine treatment had no significant effects on the assessed behaviors. These results indicate that 6 days of DFMO treatment can substantially impact cerebellar development, but this appears to have few effects on these early assessed behaviors. However, potential behavioral alterations may not be apparent until adulthood. Published by Elsevier Science Inc.

Animals↗

PubMedDate not supplied

Predicting recovery using continuous low back pain outcome measures.

BACKGROUND CONTEXT: There is a lack of research evaluating multiple follow-up visits, specifically when using continuous outcome measures. Continuous outcome measures with several follow-up assessments would allow us to evaluate rate of recovery. PURPOSE: To predict low back pain outcomes based on the quantification of initial conditions. STUDY DESIGN/SETTING: This was a prospective study where patients were enrolled within the first month of low back pain symptoms and evaluated for 3 months. Patients were recruited from several primary care facilities. PATIENT SAMPLE: Thirty-two patients with local low back pain symptoms were recruited for the study. OUTCOME MEASURES: There were four major outcome measures, including functional performance probability, symptom intensity, impairment of activities of daily living, and a summary outcome measure. METHODS: Regression models were constructed using the initial conditions, including psychological, psychosocial, physical workplace, and personal factors, to predict the rate of recovery for each outcome measure. RESULTS: Twenty-eight patients completed the study. The r2 value for the rate of recovery regression models were 0.77 symptom intensity prediction, 0.85 activities of daily living prediction, 0.87 functional performance probability prediction, and 0.96 summary outcome measure prediction. Two functional performance patterns of recovery were found, including a steady improvement and a large jump in improvement. A discriminant function model identified the pattern of recovery in 91% of cases given initial conditions. CONCLUSIONS: Continuous outcome measures can be accurately predicted given the initial conditions.

Activities of Daily Living↗

PubMedDate not supplied

Quantification of back motion during asymmetric lifting.

The objective of this study was to determine how trunk motion characteristics (in all three planes of the trunk) change as a free dynamic lifting task becomes more asymmetric. Trunk motion characteristics included range of motion, velocity (peak and average), and acceleration. Previous studies have shown that trunk motion characteristics affect trunk strength as well as the action of the trunk musculature. These trunk motion characteristics were quantified as a function of seven task asymmetries and three task weights. The experimental task required the subject to lift materials in positions commonly seen in the workplace. The range of motion, peak velocity, average velocity, and peak acceleration in each plane of the body were documented during the tasks. Generally, trunk motion characteristics in all three planes increased with an increase in task asymmetry. However, with an increase in task weight all the sagittal plane parameters and one transverse plane parameter decreased. Models were constructed to predict trunk motion characteristics given a task asymmetry and weight. When these motion components were compared to dynamic strength estimates from previous studies it was found that dynamic asymmetric lifts could reduce available strength up to 21% of maximum static strength. The results provide new insight into factors associated with the risk of developing low back disorders.

Adult↗

PubMedDate not supplied

Validity and reliability of sincerity test for dynamic trunk motions.

PURPOSE: Marras et al. developed a technique to evaluate sincerity of effort during dynamic trunk motion performance. The validity and reliability of the technique have not been evaluated. Therefore, the objective of this study was to first determine whether or not a sincerity of effort measure correctly identified those giving a sincere effort in a blinded randomized control trial and second to quantify inter-rater and test-retest reliability. METHODS: This article reports the findings of a two phase study. In phase one, the blinded evaluation, participants were randomly assigned to either a sincere or insincere performance condition. An examiner tested participants without knowledge of the participant's group membership. In the second phase, two examiners evaluated each participant twice to quantify inter-rater and test-retest reliability. RESULTS: In the blinded phase the specificity was 100% and sensitivity was 90% for identifying sincere and insincere effort, respectively. Phase two results showed no significant difference in probability of sincere effort between raters or between testing sessions. CONCLUSION: A performance criterion that accurately identifies sincere vs insincere group membership during functional evaluations was identified. There were no significant differences between raters or between testing sessions. These findings indicate that this test is reliable and possesses good predictive validity in assessing sincerity of effort.

Disability Evaluation↗

PubMedDate not supplied

Gender-based differences in rats after chronic dietary exposure to genistein.

Gender-based differences can be observed from pharmacokinetic, behavioral, or anatomical assessments. No single assessment tool will provide a complete answer, but the use of a variety of indices, each with known gender-related outcome differences, can reveal agent-induced gender-based alterations. In a series of initial range-finding studies in rats conducted at the National Center for Toxicological Research (NCTR), the effects of dietary exposure to the weak estrogen, genistein, have been assessed using a number of techniques with validated gender-related outcome measures. The findings indicated that (1) the internal dose of genistein was higher in females than males after equivalent dietary exposure and this was consistent with the faster rate of genistein elimination in males; (2) in behavioral assessments, males and females in the high-dose dietary genistein group consumed more of a sodium-flavored solution; however, no genistein-related changes were observed in open field or running wheel activity, play behavior, or intake of a saccharin-flavored solution; and (3) dose-related alterations of the volume of the sexually dimorphic nucleus of the medial preoptic area were observed in genistein-exposed male rats but not females. These observations describe the utility of a variety of gender-based assessment tools and indicate that dose-related effects of developmental and chronic dietary exposure to genistein can be observed in the rodent. Additional studies, perhaps in nonhuman primates, are necessary to further predict the effect(s) of genistein on human gender-based development.

Administration, Oral↗