Biomedical subjects
D O'Donnell
Publications and source records attributed to D O'Donnell.
Regulation of glucocorticosteroid receptor expression in rat hippocampal cell cultures by nerve growth factor.
Dispersed hippocampal cells cultured in serum-free conditions were used to study the effects of nerve growth factor (NGF) on the expression of type I (mineralocorticosteroid or MR) and type II (glucocorticosteroid or GR) corticosteroid receptors. Cells, plated at a density of 1.2 x 10(6) cells/ml in 60 mm Petri dishes, were mainly identified as neurons (90-95%) and maintained for at least 2 weeks. A 7-day treatment with 10-50 ng NGF/ml induced a concentration-dependent decrease of GR binding (40% decrease) compared to untreated cells. In contrast, MR density was unaffected by a 7-day treatment with 50 ng NGF/ml. Data are discussed as possible direct and/or indirect effects of NGF at the level of both neuronal and glial cells.
Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle.
OBJECTIVE: To evaluate the scope of the available therapeutic armamentarium in attention-deficit hyperactivity disorder (ADHD). METHOD: The literature of medication trials in ADHD was systematically reviewed, with attention to issues of psychiatric comorbidity, age, gender, and ethnic background. RESULTS: One hundred fifty-five controlled studies of 5,768 children, adolescents, and adults have documented the efficacy of stimulants in an estimated 70% of subjects. The literature clearly documents that stimulants not only improve abnormal behaviors of ADHD, but also self-esteem, cognition, and social and family function. However, response varied in different age groups and with certain comorbid conditions. In addition, there is an impressive body of literature documenting the efficacy of tricyclic antidepressants on ADHD in more than 1,000 subjects. Studies of alternative antidepressants, antipsychotics, antihypertensives, and other compounds were also reviewed. CONCLUSIONS: The available literature indicates the important role of psychopharmacological agents in the reduction of the core symptoms of ADHD and associated impairments. More research is needed on alternative pharmacological treatments and to further evaluate established therapeutics beyond school-age Caucasian boys. In addition, more research is needed on the efficacy of treatment for comorbid ADHD, use of combined medications, and the combination of medication and psychosocial treatment.
Growth deficits in ADHD children revisited: evidence for disorder-associated growth delays?
OBJECTIVE: To reevaluate the hypothesis that stimulants cause growth deficits in children with attention-deficit hyperactivity disorder (ADHD). METHOD: Growth deficits in height and weight were examined in 124 children and adolescents with ADHD and 109 controls, using appropriate correction by age and parental height measures and attending to issues of pubertal stage, treatment, and psychiatric comorbidity. RESULTS: Small but significant differences in height were identified between ADHD children and controls. However, height deficits were evident in early but not late adolescent ADHD children and were unrelated to use of psychotropic medications. There was no evidence of weight deficits in ADHD children relative to controls, and no relationship between measures of malnutrition and short stature was identified. CONCLUSIONS: ADHD may be associated with temporary deficits in growth in height through mid-adolescence that may normalize by late adolescence. This effect appears to be mediated by ADHD and not its treatment.
Treatment of a palatally impacted canine accompanied by root resorption of incisors: a case report.
This case report describes a simplified orthodontic system for the management of a palatally impacted canine accompanied by root resorption of incisors. The anchorage for this system is the transpalatal arch and a heavy buccal segment arch wire with two loops soldered to stainless steel bands. This type of stationary anchorage provides stability by uniting both molars across the palatal vault and thus avoids the need for bonding of adjacent mobile teeth. With this system an impacted canine can be extruded, moved distally, jumped over the occlusion, and derotated. The efficiency of this appliance makes it a safe method for moving teeth through simple manipulation and with minimal esthetic inconvenience.
Ingestion of fluoride dentifrice by a group of mentally handicapped children during toothbrushing.
The purpose of this study was to determine the amount of fluoride dentifrice ingested by mentally handicapped children during toothbrushing. A group of 24 mentally handicapped children, aged between 3 and 12 years, were used in the study. There were encouraged to brush in their usual way with a sodium fluoride dentifrice from a preweighed tube. Rinsings and excess dentifrice were collected, and fluoride analyses were performed on the rinsings and controls. The amount of fluoride retained was in the range of 14 to 269 micrograms, with a mean of 87 micrograms, equivalent to a mean retention of 23.5% of dentifrice. This is similar to findings of studies of children of normal intelligence. Thus, fluoridated dentifrices should be used by mentally handicapped children, but, as with all young children, small amounts of dentifrice should be used, preferably under direct adult supervision.
The special needs patient. Treatment in general dental practice: is it feasible?
Special needs patients often have difficulty in obtaining dental treatment. This paper highlights these problems and discusses, specifically, how these problems relate to the special needs patient in Hong Kong.
Increased levels of statin, a marker of cell cycle arrest, in response to hippocampal neuronal injury.
Injured neurons in the CNS are known to synthesize high levels of proliferation related oncogene products and heat shock proteins without dividing. Statin is a cell cycle regulated nuclear phosphoprotein, selectively associated with the non-proliferative state in a wide variety of cell types. In the present study, neuronal statin was examined following lethal or sublethal neuronal injuries in the hippocampus of Alzheimer's disease patients, in rats receiving kainate lesions to the dorsal hippocampus and in entorhinal cortex lesioned rats. Immunolabelling of nuclear statin showed that statin immunoreactivity increased preferentially in CA1 pyramidal neurons of the hippocampus in Alzheimer's disease. In kainate lesioned rats, statin immunoreactivity was markedly induced in the CA3 hippocampal region in association with neuronal loss. Entorhinal cortex lesioned rats showed a transient induction of statin between 2 and 6 days post lesion in CA1 neurons. However, cell counts in entorhinal cortex lesioned rats remained unaltered in the CA1 and granule cell layers during the entire 30 day time course, indicating that increased statin levels are not secondary to neuronal degeneration and are not necessarily accompanied by irreversible neuronal death. It is concluded that, in addition to proliferation related gene products, neuronal injury induces an increase in levels of statin, a nuclear marker of cell cycle arrest. Furthermore, statin may be a potentially useful marker of injurious neuronal stress, even under conditions that do not necessarily lead to irreversible cell death.
Effects of adrenalectomy and corticosterone replacement on glucocorticoid receptor levels in rat brain tissue: a comparison between western blotting and receptor binding assays.
A sensitive Western blotting technique, using a commercially available antibody, was developed herein to study glucocorticoid receptor (GR) autoregulation in brain tissue. A prominent immunoreactive band at approximately 94 kDa, representing the GR, was observed in soluble fractions prepared from rat hippocampus whereas two bands (approximately 97 and 94 kDa) were detected in frontal cortex preparations. Four-day adrenalectomy significantly increased immunoreactive GR levels in both brain regions. In contrast, adrenalectomized animals implanted with corticosterone pellets of varying concentrations displayed dose-dependent decreases in immunodetectable GR levels. Radioligand binding assays ([3H]dexamethasone +/- RU 28362), performed on these same tissue preparations, revealed a similar pattern of GR response to that measured by Western blotting. However, changes in GR binding capacity were generally greater in magnitude than corresponding changes in immunoreactive GR levels. This discrepancy was most pronounced in adrenalectomized animals administered a bolus of corticosterone 1 h prior to sacrifice where a 60-70% reduction in receptor binding sites occurred, in sharp contrast to the 25-30% decrease in immunoreactive GR levels. Taken together, our findings suggest that Western blotting can be used to study GR regulation in brain tissue and that changes in steroid-binding capacity may not necessarily reflect changes in receptor protein levels.
Gastrointestinal absorption of pravastatin in healthy subjects.
The bioavailability of pravastatin, a hypocholesterolmic agent, may be enhanced by decreasing its exposure to stomach contents, where it may be converted nonenzymatically to a relatively inactive metabolite. The pharmacokinetics of pravastatin and its metabolite were determined after infusion of pravastatin directly into the stomach (locus for greatest bioavailability for the metabolite), duodenum (greatest bioavailability for pravastatin), jejunum, or ileum. An enterically coated formulation of pravastatin may increase its bioavailability.
Environmental regulation of the development of glucocorticoid receptor systems in the rat forebrain. The role of serotonin.
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Aldosterone modulates glucocorticoid receptor binding in hippocampal cell cultures via the mineralocorticoid receptor.
The regulation of corticosteroid receptor expression in the rat brain by adrenal steroids remains controversial. The results of in vivo studies [Brinton and McEwen, 1988; Luttge et al., 1989] suggest that activation of type I receptors can modulate both mineralocorticoid (MR; type I) and glucocorticoid (GR; type II) receptor binding in selected brain regions. The present study utilized primary hippocampal cell cultures from rats sacrificed at E19-20 days of gestation to examine the effects of RU 28362, corticosterone (CORT) and aldosterone (ALDO) on GR binding ([3H]dexamethasone +/- RU 28362). Four days of exposure to 10 nM RU 28362, a highly selective GR agonist, resulted in a robust (approximately 70%) decrease in GR binding. Similar exposure to 10 nM of either CORT or ALDO also produced a significant (50-55%) decrease in GR binding capacity. Scatchard analyses confirmed that the diminished GR binding capacity in response to ALDO was due to a decrease in total number of binding sites (Bmax for Control = 112 +/- 25 fmol/mg vs. ALDO = 48 +/- 12 fmol/mg) with no significant change in the affinity constant. The calculated EC50 from the ALDO concentration response curve was 3.5 nM. Competition studies demonstrated that such low nM concentrations of ALDO were unable to displace specific [3H]dexamethasone +/- RU 28362 binding. Spironolactone, a highly specific MR antagonist, inhibited the ALDO-induced down-regulation of GR binding. These findings support the hypothesis that MR activation can modulate GR binding in hippocampal cells.
Statin, a marker of cell cycle arrest, is overexpressed during the early phase of delayed NMDA toxicity in hippocampal cell cultures.
Statin is a 57-kDa protein exclusively expressed in nuclei of nonproliferating mammalian cells. Recent studies have suggested that statin may play a role in the maintenance of growth arrest. Several lines of evidence also support the notion that a variety of genes and gene products are modulated during cell proliferation and cell death. The present study examined the possibility that statin expression could be modulated during neuronal injury using N-methyl-Daspartate (NMDA)-induced toxicity to rat embryonic hippocampal cultures as a model. Immunocytochemical studies using a monoclonal antibody to statin revealed a prominent nuclear localization of statin in cultured hippocampal cells. Western blot analysis showed that this antibody recognizes a 57-kDa protein band, indicative of the presence of statin in this preparation. Brief exposure of hippocampal neurons to NMDA (500 microM) produced severe neuronal degeneration over the subsequent hours. NMDA-treated neurons markedly overexpressed statin. Both NMDA-induced neuronal toxicity and statin overexpression were prevented by the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohept-5,10-imine hydrogen maleate (MK-801). Interestingly, time course studies indicate that the increased expression of statin observed following NMDA exposure clearly preceded the appearance of the first signs of neuronal death as determined by vital staining. In addition, exposure of hippocampal neurons to the Ca2+ ionophore, A23187, produced a marked increase in statin immunodetection, indicating that statin expression is likely regulated in a Ca(2+)-dependent manner. Thus, these results show that statin, which is expressed at low levels in embryonic rat cultured hippocampal neurons, is rapidly overexpressed following a toxic insult produced by the activation of the NMDA receptor. The observation that statin overexpression occurs prior to neuronal death raises the possibility that the up-regulation of statin could be used as an early index of neuronal injury.
Postnatal handling alters glucocorticoid, but not mineralocorticoid messenger RNA expression in the hippocampus of adult rats.
Postnatal handling alters hypothalamic-pituitary-adrenal (HPA) responses to stress in the rat. Handling also increases hippocampal glucocorticoid receptor density, and this effect appears to form, in part at least, the basis for the effect of handling on HPA responsiveness to stress. In the present study we have used in situ hybridization techniques to examine the effect of postnatal handling on the expression of glucocorticoid and mineralocorticoid receptor mRNAs in various cell fields of the dorsal hippocampus in adult rats. Grain counting analysis over individual cells showed that postnatal handling significantly increased (40-50%) glucocorticoid receptor mRNA in all hippocampal cell fields. In contrast, handling had no effect on mineralocorticoid receptor mRNA expression. These findings are consistent with the results of receptor binding studies showing that handling increases hippocampal glucocorticoid receptor, but not mineralocorticoid receptor density. Thus, the increase in glucocorticoid receptor binding in handled animals is likely associated with altered rates of receptor biosynthesis. Moreover, the handling effect is quite specific, altering glucocorticoid receptor, but not mineralocorticoid receptor mRNA expression. The mechanism(s) whereby glucocorticoid receptor gene expression is permanently increased by postnatal handling remains to be determined.
Molecular basis for the development of individual differences in the hypothalamic-pituitary-adrenal stress response.
1. Several years ago, investigators described the effects of infantile handling on the development of hypothalamic-pituitary-adrenal (HPA) responses to stress in the rat. Rat pups exposed to brief periods of innocuous handling early in life showed reduced HPA responses to a wide variety of stressors, and the effect persists throughout the life of the animal. These effects are robust and provide an excellent model for understanding how early environmental stimuli, which are external to the organism, alter neural differentiation and, thus, neuroendocrine responsivity to stress. 2. This paper reviews the endocrine mechanisms affected by early handling and our current understanding of the neural transduction of environmental events and their effects at the level of the target neurons (in the hippocampus and frontal cortex). 3. In brief, handling serves to increase glucocorticoid receptor gene transcription, increasing sensitivity to glucocorticoid negative feedback regulation and, thus, altering the activity within hypothalamic corticotropin-releasing factor/vasopressin neurons. Together these changes serve to determine neuroendocrine responsivity to stress.
Glucocorticoid receptor gene expression is unaltered in hippocampal neurons in Alzheimer's disease.
Excessive glucocorticoid levels increase the metabolic vulnerability of hippocampal neurons to a wide variety of insults. Since glucocorticoid hypersecretion occurs in Alzheimer's-type dementia it has been proposed that a primary reduction in hippocampal glucocorticoid receptor expression leads to failure of feedback, hypercortisolemia and hence further neuronal loss. However, we have recently found that lesions of the cholinergic innervation of the hippocampus--known to be severely affected in Alzheimer's disease--increase corticosteroid receptor gene expression in the rat hippocampus. We have now examined both glucocorticoid (GR) and mineralocorticoid (MR) receptor gene expression in individual neurons in human postmortem hippocampus, using in situ hybridization histochemistry in 5 patients with Alzheimer's disease (81 +/- 3 years) and 7 controls (81 +/- 7 years) without neurological disease. The distribution and intensity of MR and GR mRNA expression in the hippocampus of Alzheimer's disease were similar to that in control tissue, with high expression in dentate gyrus and CA2-4, but significantly lower expression in CA1. In a separate group of patients with Alzheimer's disease we found significantly increased 24 h integrated plasma cortisol levels (59% greater than age-matched controls) and reduced cortisol-binding globulin (21% lower). These data do not suggest a primary deficiency of biosynthesis of hippocampal corticosteroid receptors in Alzheimer's disease. The maintenance of hippocampal GR and MR gene expression, in the face of an increased glucocorticoid feedback signal, may reflect loss of the cholinergic innervation.
Entorhinal cortex lesions transiently alter glucocorticoid but not mineralocorticoid receptor gene expression in the rat hippocampus.
Entorhinal cortex lesions destroy an important hippocampal input and lead to axonal sprouting in the dentate gyrus. Glucocorticoids are known to inhibit this reinnervation process. In the present study, we examined changes in hippocampal glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) mRNA expression using in situ hybridization following unilateral entorhinal cortex lesioning (ECL) in the rat. As early as 1 day postlesioning, a 33% bilateral decrease in GR mRNA expression was observed in the dentate gyrus. By contrast, a 36% bilateral increase in GR mRNA expression was detected in the CA1 cell field. GR mRNA levels in both regions returned to those of control animals 2 days postlesioning, indicating that these effects were transient. Adjacent sections hybridized with probes to MR mRNA revealed no changes in hippocampal MR gene expression as a result of ECL. The selective decrease in GR mRNA expression observed in the dentate gyrus following ECL is specific to the hippocampal subregion targeted for reactive synaptogenesis and thus may serve to attenuate the inhibitory actions of circulating glucocorticoids.
Educational computer simulation of malignant hyperthermia.
An educational graphic simulator was developed to provide an interactive learning environment to practice the diagnosis and treatment of malignant hyperthermia. The program incorporates a set of dynamically interacting models to present the physiologic changes associated with malignant hyperthermia and the simulated patient's response to management. Cardiovascular, respiratory, and temperature changes are presented through a graphic display of the operating room monitors. Mouse-driven input is used to manage the airway, control ventilation, manage cardiovascular and rhythm disturbances, and control fluids, electrolytes, and temperature. Medications, including dantrolene, antidysrhythmics, diuretics, and sodium bicarbonate, can be administered. Four simulated patients with different presentations of malignant hyperthermia are included to illustrate variations in the syndrome. Two of these patients are described in detail.