On reconciling the "multidimensional" and "unitary" concepts of brain damage.
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Brain Damage, Chronic↗
Biomedical subjects
J Adams
Publications and source records attributed to J Adams.
Enhanced distress vocalization through selective reinforcement.
Eighteen Peking ducklings were imprinted and tested for their tendency to emit distress calls during the presentation and withdrawal of the imprinted stimulus. A subsequent arrangement in which each distress vocalization led to a 5-second presentation of the imprinted stimulus resulted in an enhanced tendency to emit distress calls.
Animals↗
The relationship of the Edwards personal preference schedule to the MMPI in a patient population.
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Adult↗
Tautomerism in N-acetyl sulfonamides. A clarification.
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Chemical Phenomena↗
Effect of hypothalamic lesions on histamine toxicity in the guinea pig.
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Anaphylaxis↗
26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer.
The 26S proteasome degrades proteins that regulate transcription factor activation, cell cycle progression, and apoptosis. In cancer, this may allow for uncontrolled cell division, promoting tumor growth, and spread. We examined whether selective inhibition of the 26S proteasome with PS-341, a dipeptide boronic acid analogue, would block proliferation and induce apoptosis in human pancreatic cancer. Proteasome inhibition significantly blocked mitogen (FCS) induced proliferation of BxPC3 human pancreatic cancer cells in vitro, while arresting cell cycle progression and inducing apoptosis by 24 h. Accumulation of p21(Cip1-Waf-1), a cyclin dependent kinase (CDK) inhibitor normally degraded by the 26S proteasome, occurred by 3 h and correlated with cell cycle arrest. When BxPC3 pancreatic cancer xenografts were established in athymic nu/nu mice, weekly administration of 1 mg/kg PS-341 significantly inhibited tumor growth. Both cellular apoptosis and p21(Cip1-Waf-1) protein levels were increased in PS-341 treated xenografts. Inhibition of tumor xenograft growth was greatest (89%) when PS-341 was combined with the tumoricidal agent CPT-11. Combined CPT-11/PS-341 therapy, but not single agent therapy, yielded highly apoptotic tumors, significantly inhibited tumor cell proliferation, and blocked NF-kappaB activation indicating this systemic therapy was effective at the cancer cell level. 26S proteasome inhibition may represent a new therapeutic approach against this highly resistant and lethal malignancy.
Adenocarcinoma↗
The arrival of a rival: maternal perceptions of toddlers' regressive behaviors after the birth of a sibling.
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Adult↗
Developmental neurotoxicity of anticonvulsants: human and animal evidence on phenytoin.
Most epileptic women delivering children each year take anticonvulsants throughout pregnancy. The teratogenic potential of anticonvulsants is most notable for phenytoin, trimethadione, valproic acid, and carbamazepine. This review focuses on the human and animal evidence for the teratogenicity of phenytoin, with emphasis on neurobehavioral end points. The Fetal Hydantoin Syndrome (FHS) consists of craniofacial defects and any two of the following: pre/postnatal growth deficiency, limb defects, major malformations, and mental deficiency. Available data suggest a prevalence of FHS of 10-30% in infants of women ingesting 100-800 mg/kg of phenytoin during the first trimester or beyond. Unfortunately, data on neurobehavioral development in FHS children is limited. Animal models of FHS have been developed and those focusing on neurobehavioral effects are reviewed. Phenytoin produces multiple behavioral dysfunctions in rat offspring at subteratogenic and nongrowth retarding doses. These behaviorally teratogenic doses produce maternal serum phenytoin concentrations in rats comparable to those found in humans. The dysfunctions in rats are dose-dependent and exposure-period-dependent, but independent of nutritional, maternal rearing, or seizure disorder confounds. Effects include vestibular dysfunction, hyperactivity and deficits in learning and memory. General comparability between the human and animal findings for phenytoin are apparent, however, difficulties with existing studies prevent precise comparisons. Animal studies have not dealt satisfactorily with the potential contribution of epileptic disease state to the FHS, with fetal brain drug concentration determinations, a complete dose-effect range, effects in multiple species (although limited nonhuman primate data exist), site of CNS injury, and the comparability of end points assessed. Human studies have not dealt satisfactorily with issues of the need for prospective study designs, separation of the effects of different anticonvulsants, or adequate long-term follow-up of cases, especially with attention to neuropsychological assessment.
Abnormalities, Drug-Induced↗
Structure-activity and dose-response relationships in the neural and behavioral teratogenesis of retinoids.
The therapeutic use in the human teratogenic range of retinoid compounds (Accutane; Tigason) for the treatment of dermatologic disorders has refocused attention on the teratogenicity of vitamin A-related compounds. This article reviews rodent data on three retinoids: vitamin A (retinol), all-trans retinoic acid (tretinoin), and 13-cis retinoic acid (isotretinoin) with respect to effects on central nervous system (CNS) malformations and postnatal death, growth reduction, and behavioral dysfunction. All three retinoids have been shown to effect these endpoints in a dose-dependent manner whereby smaller doses are necessary to produce each consecutive endpoint at the same stage of gestation. Whereas gestation days (GD) 8-10 are the most sensitive for the induction of gross CNS malformation, GD 11-13 appear most sensitive in effecting postnatal endpoints in rats with normal gross morphology. With respect to structure-activity relationships, retinol appears to have less than 1/4 the potency of all-trans retinoic acid, and isotretinoin may have much less than 1/8 the potency of all-trans retinoic acid in disrupting development with respect to all endpoints. The systematic relationships across endpoints argue for common controlling variables. For these retinoids, all-trans retinoic acid and its metabolites are proposed as the active agents of developmental toxicity.
Animals↗
Event-related potentials in schizophrenia: their biological and clinical correlates and a new model of schizophrenic pathophysiology.
Evidence is growing that schizophrenic patients show significant structural damage in the temporal lobe limbic system. We review event-related potentials abnormalities (ERPs) in schizophrenia that may be related to dysfunction in this brain region or its inputs; ERPs discussed include the N100/P200, P300 and N400 components. Additional CT and clinical data have led our laboratory to a unifying working hypothesis of the presence of temporal lobe damage in schizophrenics that is evinced electrophysiologically as ERP alterations, structurally as tissue loss/derangement, and clinically as positive symptoms. The final section of this paper presents a new model of at least one form of schizophrenic pathology that, while speculative, incorporates experimentally based data from both our ERP work and from basic cellular physiology and pharmacology. The model proposes that positive symptoms of schizophrenia are related to limbic system pathology and in particular to a dysregulation of the NMDA form of excitatory amino acid transmission, potentiated by stress, and leading to cell damage and death due to 'excitotoxicity'.
Arousal↗
Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotropin releasing hormone.
By means of pelvic ultrasonography, a multifollicular ovarian appearance was observed in women with weight-loss-related amenorrhoea. Multifollicular ovaries (MFO) are normal in size or slightly enlarged and filled by six or more cysts 4-10 mm in diameter; in contrast to women with polycystic ovaries (PCO), stroma is not increased. Unlike PCO patients, women with MFO were not hirsute and serum concentrations of luteinising hormone and follicle stimulating hormone were normal and decreased, respectively. The uterus was small indicating oestrogen deficiency. In MFO, treatment with gonadotropin releasing hormone (LHRH) induced ovulation in 83% of cycles and there were seven pregnancies in 8 women; in PCO, only 40% of cycles were ovulatory and there were eleven pregnancies (8 women) but six of these aborted. In MFO ovarian morphology reverted to normal in ovulatory cycles, whereas in PCO the polycystic pattern persisted despite the presence of a dominant follicle. MFO may represent a normal ovarian response to weight-related hypothalamic disturbance of gonadotropin control.
Amenorrhea↗
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↗
Gestational retinoic acid exposure in the rat: effects of sex, strain and exposure period.
Effects of gestational exposure to all-trans retinoic acid (RA) were assessed in the Long-Evans (hooded) and Sprague-Dawley (albino) rat strains. Two exposure periods were evaluated against vehicle controls. Both involved three consecutive daily per os doses of either 2.5 mg/kg RA on gestational days (GD) 11 through 13 or 10 mg/kg RA on GD 14 through 16. All assessments were conducted on at least one male and one female per litter. Substantial main effects of sex, strain and treatment were obtained, but with few significant interactions. Main effects of strain were found on surface righting, neonatal mortality, litter weight and postnatal day (PND) 35 regional brain weight. Among strain effects, the most interesting was the finding that weights of whole brain, frontal cortex, brainstem and cerebellar vermis were lower in hooded than in albino rats. These strain effects seldom interacted with treatment. Among the treatment effects was the finding that GD 11-13 but not GD 14-16 RA exposure impaired the righting reflex in both strains. Moreover, GD 11-13 exposure reduced weight of the cerebellar vermis more than did GD 14-16 RA exposure, while GD 14-16 RA exposure had greater impact on the weight of the cerebellar hemispheres than did GD 11-13 exposure. Covariate analysis suggested that these effects were independent of reductions in body weight. It is concluded that there are few strain or sex differences in the effects of gestational RA exposure, at least for the rat strains evaluated in this study.
Animals↗
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↗
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↗
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↗
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↗
Nurse-managed clinics: a blueprint for success using the Covey framework.
This article describes the process from inception to successful operation of a university-based nurse managed clinic. The article includes information regarding the planning process, method of financing, political strategies for gaining approval, and on-going development of services. Covey's seven habits of highly effective people are used as a framework on which the development and evolution of the clinic are based. The habits are illustrated by relating how services/operation were enhanced and barriers and obstacles were overcome.
Community Health Centers↗