Biomedical subjects

R W Hamill

Publications and source records attributed to R W Hamill.

At least 19 recordsLinked to original sources

PubMed1997

Central regulation of sympathetic ganglia development: heterogeneous response of paravertebral, prevertebral, and terminal ganglia.

These studies expand previous observations regarding the central control of neuronal maturation and indicate that paravertebral, prevertebral, and terminal ganglia are all under central influences, but in varying degrees. These variations are probably related to the relative contributions that central pathways exert on specific peripheral neuronal populations during growth and development as well as the various roles of more peripheral developmental modulators such as target organs and hormones, especially in the case of the HG. It is apparent, therefore, that during development central injury may result in heterogeneous deficits depending on the unique intrinsic and extrinsic environment that each ganglion population shares.

Adrenal Medulla↗

PubMed1996

Effect of buthionine sulfoximine, a synthesis inhibitor of the antioxidant glutathione, on the murine nigrostriatal neurons.

This study analyzed the effects of acute systemic treatment with buthionine sulfoximine (BSO), a synthesis inhibitor of the antioxidant reduced glutathione (GSH), on dopaminergic neurons of the murine nigrostriatal pathway. Part 1 of the study established a dose-response curve and the temporal pattern of GSH loss and recovery in the substantia nigra and striatum following acute BSO treatment. Part 2 of the study determined the effect of acute BSO treatment on the morphology and biochemistry of nigrostriatal neurons. We found that decreases in GSH levels had profound morphological effects, including decreased catecholamine fluorescence per cell, increased levels of lipid peroxidation and lipofuscin accumulation, and increased numbers of dystrophic axons in dopaminergic neurons of the nigrostriatal pathway. However, no measurable effects were observed in biochemical levels of either dopamine or its metabolites. These changes mimic those that have been reported to occur in the nigrostriatal system of rodents with advancing age. Our data suggest that reduction of GSH via BSO treatment results in the same types of nigrostriatal degenerative effects that occur during the aging process and consequently is a good model system for examining the role of GSH in protecting this area of the brain against the harmful effects of age-related oxidative stress.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

Glucocorticoid receptor mRNA in Alzheimer's diseased hippocampus.

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is a common finding in Alzheimer's dementia. Since there is a loss of hippocampal corticosteroid receptors in animal models of aging, and since hippocampal cell loss occurs in Alzheimer's disease (AD), it has been suggested that a loss of hippocampal glucocorticoid receptors (GR) may underlie some aspects of HPA axis dysfunction in patients with AD. Levels of corticosteroid receptor protein are not reliably determined in postmortem human brain due to rapid lability. In contrast, levels of mRNA coding for GR are stable in postmortem tissue. We report here initial observations from in situ hybridization experiments which indicate that regional levels of glucocorticoid receptor mRNA in hippocampus, as determined by film autoradiography, are significantly higher in AD hippocampus than in controls. While neuronal levels of GR mRNA in AD, revealed by emulsion autoradiography, were equal in control and AD tissue. Taken together these results suggest that adrenal dysfunction in AD may relate to defects in receptor function rather than corticosteroid receptor loss in the hippocampus.

Alzheimer Disease↗

PubMed1995

Calbindin D28k mRNA in hippocampus, superior temporal gyrus and cerebellum: comparison between control and Alzheimer disease subjects.

To further investigate the role of calbindin D28k in Alzheimer's disease (AD); hippocampus, superior temporal gyrus and cerebellum from control and AD cases were examined by quantitative in situ hybridization. We report here a decrease in CaBD28k mRNA in the CA2 region of AD hippocampus compared to control subjects. There were no significant differences between AD and control subjects in the other regions studied.

Aged↗

PubMed1995

Current diagnostic guidelines for Alzheimer's disease.

The pointers outlined recommend specific steps for the neurologic examination, assessment instruments for detecting physical and cognitive dysfunction and mood alteration, and relevant laboratory tests. When to use imaging studies is highlighted.

Alzheimer Disease↗

PubMed1995

Advances in Alzheimer's disease.

Investigations linking this disorder to numerous factors, such as neurotransmitters and apolipoprotein E, are leading to future drug therapy. Current patient care must be focused on finding and alleviating the causes of immediate behavioral concerns.

Alzheimer Disease↗

PubMed1994

Postmortem stability of mRNA for glucocorticoid and mineralocorticoid receptor in rodent brain.

The relative postmortem stability of the mRNA's for glucocorticoid (GR) and mineralocorticoid (MR) receptor in rodent brain was determined using semi-quantitative in situ hybridization (ISH). Rats were killed by CO2 asphyxiation and their brains removed immediately (0 h) or following 12 h or 24 h delays. Specific hybridization of GR and MR anti-sense [35S]RNA-probe to tissue mRNA encoding these receptors was detected using film and emulsion autoradiography. The most intense labeling for GR mRNA was in the dentate gyrus followed by the CA1 hippocampal region. Lower, but still detectable signal, was apparent over CA3-CA4 pyramidal cell regions. MR mRNA was detected throughout the CA1-4 pyramidal cell fields of the hippocampus and the granular cells of the dentate gyrus. Film images demonstrated that even in the 24 h postmortem delay group intense specific signal was present in sections hybridized with both anti-sense GR and MR probes, although there was some diminution in signal intensity in cortical areas at this later postmortem delay. These initial experiments with rat brain demonstrate that the mRNA's for both GR and MR, as detected with ISH, are stable for up to 24 h following death.

Animals↗

PubMed1993

Increased levels of truncated nerve growth factor receptor in urine of mildly demented patients with Alzheimer's disease.

OBJECTIVE: In Alzheimer's disease, cholinergic basal forebrain neurons, which have receptors for nerve growth factor (NGF), degenerate, while NGF receptors increase in some areas of the neocortex. Levels of the truncated, extracellular portion of the NGF receptor (NGF-Rt) are elevated in urine of patients with peripheral neuropathies and in animals with peripheral-nerve injury, but it has not been determined whether urine levels of NGF-Rt are altered by the presence and/or progression of dementia-related neuropathologic changes in patients with Alzheimer's disease. In this study, we developed an enzyme-linked immunosorbent assay to determine whether urine levels of NGF-Rt are altered in patients with Alzheimer's disease. DESIGN: Survey of urine NGF-Rt levels in neurologically normal (n = 19), mildly demented (n = 31), and moderately to severely demented (n = 31) patients. SETTING: Subjects were participants in the Rochester Alzheimer's Disease Project and mildly demented patients about to begin a clinical drug study. PATIENTS: All patients met established criteria for a clinical diagnosis of probable Alzheimer's disease. Aged, nondemented, neurologically normal controls were selected from the families of the demented subjects. RESULTS: Urine NGF-Rt levels were substantially elevated in mildly demented patients relative to those of nondemented controls. CONCLUSIONS: These results suggest that an enzyme-linked immunosorbent assay on urine samples may provide an antemortem measure of dementia-related neuropathologic changes, but further study is needed to determine the source and potential clinical utility of increased NGF-Rt levels in urine of mildly demented patients.

Aged↗

PubMed1993

End-stage Alzheimer's disease. Glasgow Coma Scale and the neurologic examination.

OBJECTIVE: To characterize the cognitive and neurologic features of patients with end-stage Alzheimer's disease using a standard neurologic examination and the Glasgow Coma Scale. DESIGN: Case series. SETTING: Local community nursing homes. PATIENTS: Forty patients with Alzheimer's disease were drawn from previously enrolled subjects in the Rochester Alzheimer's Disease Project with Clinical Dementia Rating scores of 3, 4, or 5. MAIN OUTCOME MEASURES: Scores on the Glasgow Coma Scale and cognitive screening examinations and the prevalence of neurologic manifestations such as primitive reflexes and extrapyramidal signs were compared across the Clinical Dementia Rating groups. RESULTS: When compared with patients in the Clinical Dementia Rating stages 3 and 4, patients with a stage 5 scored significantly lower on the Glasgow Coma Scale, with the discriminating subscales being verbal and motor responses. Primitive reflexes, myoclonus, and dyskinesia were increasingly prevalent in the more terminal stages. Cognitive screening assessments did not discriminate between groups. CONCLUSIONS: Rudimentary neurologic functions can be readily assessed and, when viewed together with the Glasgow Coma Scale, may circumvent the "floor effect" frequently encountered when using the currently available cognitive and functional scales and, thereby, better define patients with end-stage Alzheimer's disease.

Aged↗

PubMed1993

Acetylcholinesterase staining and choline acetyltransferase activity in the young adult rat spleen: lack of evidence for cholinergic innervation.

Acetylcholinesterase (AChE) staining in spleens from young adult Sprague-Dawley rats was examined following several denervation paradigms to determine the source of splenic AChE+ nerve fibers. In spleens from all control groups, AChE+ neural-like profiles were present along the vasculature and in the trabeculae. AChE+ reactivity also was present in lymphoid and reticular cells in the spleen, and in neuronal cell bodies in the superior mesenteric-coeliac ganglion (SM-CG). Neurochemical analysis revealed no significant choline acetyltransferase activity in spleens from control animals. Surgical removal of the SM-CG resulted in a total loss of both noradrenergic (NA) and AChE+ nerve profiles, as well as a loss of AChE staining in nonneural compartment in the spleen. On Days 1 and 3 after treatment, chemical sympathectomy with 6-hydroxydopamine also resulted in a loss of both NA and AChE nerve profiles in the spleen, except for a few resistant fibers in the hilar region. AChE reactivity in nonneural compartments also was diminished in chemically denervated regions of the spleen. AChE staining in both neural and nonneural profiles progressively increased from 10 to 56 days after chemical sympathectomy, with a time course and distribution pattern similar to NA fibers reinnervating the spleen. AChE+ staining was preserved following bilateral vagal nerve transection. The miniscule splenic levels of choline acetyltransferase suggest that at best, only a small density of cholinergic nerves distribute to the rat spleen. Further, what cholinergic innervation is present does not arise from the vagus nerve as suggested in the earlier literature. Collectively, the overlapping distribution of AChE+ and NA nerve profiles in spleen and parallel loss of both population of nerve fibers following surgical and chemical sympathectomy support the presence of AChE in NA nerves colocalized with norepinephrine, and thus make AChE+ staining an inappropriate marker for cholinergic innervation in the rat spleen.

Acetylcholinesterase↗

PubMed1993

Clinicopathologic correlates in Alzheimer disease: assessment of clinical and pathologic diagnostic criteria.

The neuropathologic findings from a group of 123 patients who have come to autopsy from the Rochester Alzheimer Disease Project (RADP) are presented. Among these 123 cases, there were 94 demented subjects who met the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) clinical criteria for the diagnosis of "probable Alzheimer disease," and 29 normal elderly controls. Autopsy confirmation of Alzheimer disease (AD) was based on the age-graded National Institutes of Health (NIH) consensus conference pathologic criteria. Using the NINCDS-ADRDA clinical criteria and the NIH pathologic criteria, the diagnostic accuracy was 88%, the sensitivity was 98%, and the specificity was 69%. Additional strict clinical and pathologic criteria developed by the RADP were applied in the final review of these cases to exclude all confounding causes of dementia, including cerebral infarcts. After applying these additional criteria, a subset of 62 cases of "pure" AD and "pure" control subjects was identified for a more detailed examination of neuritic plaques (NP) and neurons containing neurofibrillary tangles (NFT). The NP and NFT were counted in three subfields of hippocampus and two areas of association neocortex. The density of diffuse plaques (plaques lacking dystrophic neurites) was estimated on a semiquantitative basis. Results show that the AD patients and control groups could be distinguished from each other easily on the basis of mean NP and NFT counts, but there was sufficient overlap in the counts to present difficulty in diagnosing any individual case. Abundant diffuse plaque involvement and NFT in the neocortex were, however, seen only in AD cases.

Aged↗

PubMed1992

Molecular aspects of the regulation of tyrosine hydroxylase by testosterone.

Previous studies have demonstrated that the sympathetic hypogastric ganglia (HG) are dependent upon the continued presence of testosterone for normal development and maintenance of tyrosine hydroxylase (TH) activity. The regulation of TH by testosterone has been examined further to determine whether the reduction in TH activity following castration is associated with changes in levels of TH protein and mRNA. TH protein was measured by immunotitration of HG homogenates using a TH-specific antibody, and TH-specific mRNA was detected by hybridization of dot blots of total RNA isolated from HG with a cDNA probe coding for TH. The results show that tyrosine hydroxylase activity, protein and mRNA are coordinately reduced in a graded fashion at 1, 2 and 4 weeks following castration. Testosterone replacement therapy immediately following castration prevents the decrease in TH levels. The results indicate that gonadal steroids regulate the biosynthesis of TH in the HG. Testosterone may control TH either directly by interacting with neurons of the HG, or indirectly by altering levels of trophic factors in the target tissues.

Animals↗

PubMed1992

Traumatic brain injuries: predictive usefulness of CT.

The computed tomographic (CT) scans from 72 patients with traumatic brain injury were reviewed to determined whether a specific type, location, or size of lesion correlated with changes in neurologic function (assessed with the Glasgow Coma Scale [GCS]), patient outcome (assessed with the Glasgow Outcome Scale [GOS]), or catecholamine levels. The lesions were classified as focal or diffuse. GOS changed as a function of lesions size (P = .00004) in the 48 patients with focal hemorrhages, regardless of whether the lesions were intra- or extraaxial, and in the 19 patients with normal CT scans. Patients with lesions larger than 4,100 mm3 had a twofold greater risk of a poor outcome than patients with smaller lesions (100% vs 50%). Patients with normal CT scans were significantly more likely to have mild neurological dysfunction or none than patients with abnormal CT scans (P = .03), but lesion location, skull fracture, and pineal shift were not significant predictors of GCS or GOS scores. A positive relationship existed between lesion size and both plasma norepinephrine and epinephrine levels (P less than .02); a significant relationship existed between lesion size and GCS score (P = .02).

Adult↗

PubMed1991

Effects of intoxication on the catecholamine response to multisystem injury.

In patients suffering isolated head trauma, we have previously shown that levels of circulating catecholamines obtained within 48 hours of trauma correlate with the severity of brain injury and predict outcome and that intoxication blunts this response. The effects of alcohol on the increase in catecholamines in systematically injured patients, however, have not been well defined. From 1983 to 1990, 78 patients (74% male; median age 30 years) with blunt head and multisystem injury, who also had alcohol levels measured within 5 hours of injury, were studied. Norepinephrine and epinephrine levels were assayed by a radioenzymatic technique. Injury severity was assessed by the admission Glasgow Coma Scale (GCS) score (4-15; median, 12), the Injury Severity Score (ISS) (13-50; median, 25) and the volume of blood products administered within the first 24 hours (0-14.4 L; median, 0.5 L). The impact of alcohol on the norepinephrine response to injury was analyzed using multiple linear regression models, including polynomial interaction terms. Norepinephrine levels significantly (p less than 0.0001) correlated with the GCS score and ISS. However, alcohol significantly lowered the norepinephrine response to decreasing GCS score (R = 0.49, p less than 0.002) and to increasing ISS (R = 0.51, p less than 0.0006). The blunting of the catecholamine response was most marked in those severely injured. The rise in norepinephrine concentrations seen with increasing volume of blood replacement was not affected by intoxication. An association between injury severity and epinephrine levels was also present, but not as consistently. Epinephrine concentrations rose with falling GCS score and with increasing ISS values, but unlike norepinephrine, there were no apparent effects of alcohol on changes in epinephrine levels. Thus, in patients suffering head and multisystem injury, catecholamine changes reflect the severity of injury using three different scalers. Furthermore, intoxication blunts only the norepinephrine component of this important biologic response.

Adolescent↗

PubMed1991

Brainstem enkephalinergic projections to spinal autonomic nuclei.

The present studies in the rat employed a combined retrograde transport-immunocytochemical technique to determine the origin in the brainstem of enkephalin (Enk) projections to spinal sympathetic nuclei, including the intermediolateralis nucleus, pars principalis (ILp). We found that Enk projections to the ILp nucleus are found in such serotonergic-containing areas as the raphe obscurus; raphe pallidus; gigantocellular reticular nucleus, pars alpha; paragigantocellular lateral nucleus; raphe magnus; and the rostral extension of the raphe magnus nucleus. The adrenergic-containing rostroventrolateral reticular nucleus as well as the noradrenergic-containing areas A5, A7, ventral locus coeruleus, subcoeruleus, and fiber pathway linking the locus coeruleus and A5/A7 send Enk projections to ILp. In the pons, a large contralateral Enk projection to spinal sympathetic nuclei was found medial to the facial nerve and medial to the motor nucleus of the trigeminal nerve. These observations show the existence of a large number of Enk brainstem regions that can influence spinal autonomic centers via descending supraspinal projections.

Amidines↗

PubMed1990

Hormonal regulation of adult sympathetic neurons: the effects of castration on neuropeptide Y, norepinephrine, and tyrosine hydroxylase activity.

Previous studies utilizing the hypogastric ganglia (HG) have indicated that gonadal steroids exert organizational and activational effects on noradrenergic biochemistry. Bilateral castration of male rodents at birth prevents the normal maturation of tyrosine hydroxylase (T-OH) activity in the HG; castration during adulthood results in a progressive decline in T-OH activity. Testosterone replacement corrects both the ontogenetic and adult functional alterations in the neurotransmitter-synthesizing enzyme. The present studies in adult male rats extend these previous observations and asked the question whether gonadal steroids regulate the neurotransmitters neuropeptide Y (NPY) and norepinephrine (NE) in the HG. Adult rodents were castrated and ganglia T-OH, NPY, and NE were examined at various time points after surgery. All three indices of sympathetic neuron biochemistry declined following castration, but they exhibited different profiles. It appears that hormones may affect enzyme activity and neurotransmitter pools differently within neurons. Testosterone replacement therapy fully restored T-OH activity, and NPY and NE levels in the HG. These studies extend the activational role of testosterone in regulating sympathetic neuron neurotransmitter and neuropeptide levels as well as neurotransmitter-synthesizing enzymes.

Animals↗

PubMed1990

Calcitonin gene-related peptide and somatostatin immunoreactivities in the rat lumbar spinal cord: sexually dimorphic aspects.

The immunohistochemical distribution of calcitonin gene-related peptide and somatostatin in rat lumbar spinal laminae VII-X was investigated using the peroxidase-antiperoxidase technique. Within L1,2 laminae VII and X, calcitonin gene-related peptide and somatostatin fibers demarcate the location of preganglionic sympathetic neurons in a similar fashion in either sex but somatostatin is distributed in a sexually dimorphic manner in the lumbosacral (L5-S2) spinal cord with the male rat containing more somatostatin fibers and neurons than females. Within the ventral horn (lamina IX), calcitonin gene-related peptide has a sexually dimorphic distribution. Calcitonin gene-related peptide varicose fibers are found within the sexually dimorphic male cremaster nucleus but are virtually absent in the female cremaster nucleus. Calcitonin gene-related peptide varicose fibers are nearly absent in the remainder of the male and female lamina IX: this area includes the other two known sexually dimorphic spinal motonuclei: the dorsomedial and dorsolateral nuclei. Virtually all motoneurons in the lumbosacral spinal cord which are not sexually dimorphic contain calcitonin gene-related peptide. However, calcitonin gene-related peptide containing motoneurons have a heterogeneous distribution within sexually dimorphic nuclei. Calcitonin gene-related peptide containing motoneurons within the male and female cremaster nucleus are extremely rare. Some motoneurons within the male and female dorsomedial and dorsolateral nuclei contain calcitonin gene-related peptide with the female dorsomedial and dorsolateral nuclei containing a greater percentage of calcitonin gene-related peptide-containing motoneurons (c. 50%) than males (c. 20%). Somatostatin fibers are preferentially located in sexually dimorphic nuclei of either sex and are distributed in a sexually dimorphic manner within these nuclei with males containing a greater amount of somatostatin fibers than females. The amount of somatostatin immunoreactivity is most dense in the medial aspect of the dorsolateral nucleus, dense in the dorsomedial nucleus, moderate in the cremaster nucleus, and sparse in the lateral portion of the dorsolateral nucleus. In addition, a small column of motoneurons, between the dorsomedial and dorsolateral nuclei at the L5 level, is outlined by somatostatin fibers in females but is absent in males. Somatostatin containing motoneurons were not observed within the lumbar sexually dimorphic nuclei of either sex.

Animals↗

PubMed1990

Alcohol intoxication blunts sympatho-adrenal activation following brain injury.

In 46 patients experiencing traumatic brain injury, we studied the interactions of alcohol intoxication and severity of neurologic dysfunction on the resulting sympathetic nervous system activation. Sixty percent of the variation in norepinephrine (p less than 0.0001) and more than 50% of the variation in epinephrine (p less than 0.0001) were due to the initial ethanol concentrations and extent of brain injury assessed by the admission Glasgow Coma Score (GCS). As brain function deteriorated plasma cathecholamines rose (p less than 0.0001), but ethanol qualitatively and quantitatively modified this observation. The magnitude of the sympathetic response to worsening neurologic function was progressively diminished in association with increasing ethanol levels, i.e., the inverse relationship of GCS values with both norepinephrine and epinephrine was flattened. In comatose patients (GCS less than 8) increasing ethanol levels was associated with progressively decreasing norepinephrine and epinephrine responses (p less than 0.04), such that catecholamines were reduced by 80 to 90% at ethanol concentrations approaching 400 mg/dl (87.0 mmol/l). However, the impact of ethanol on the degree of sympathetic nervous system activation depended upon the degree of injury; the apparent ethanol suppression was greatest in patients with the most severe neurologic dysfunction (GCS 3 or 4), but it diminished as neurologic function improved. We conclude that the presence of alcohol appears to modify the rise in catecholamine levels following traumatic brain injury in a dose-dependent manner and alters the relationship between neurologic dysfunction and SNS activation. These alterations may have profound effects on patient morbidity in the immediate post-accident period.

Adolescent↗