Biomedical subjects

R W Hamill

Publications and source records attributed to R W Hamill.

At least 55 records · Page 3Linked to original sources

PubMed1987

Enkephalin fibers in autonomic nuclear regions: intraspinal vs. supraspinal origin.

The present studies in the rat employ spinal transections and hemisections, dorsal and/or ventral rhizotomies to determine whether enkephalin fibers in spinal sympathetic and parasympathetic nuclei are of supraspinal, intraspinal, or peripheral origin. Our results suggest enkephalin fibers in thoracolumbar sympathetic nuclei are of both supraspinal and intraspinal origin, whereas the enkephalin innervation of the sacral parasympathetic nucleus is primarily intraspinal in origin. Furthermore, the majority of descending enkephalin systems selectivity project to the intermediolateralis, pars principalis and pars funicularis, and the dorsal commissural sympathetic nuclei, whereas intraspinal enkephalin pathways appear to exist primarily in the intercalatus spinalis and intercalatus spinalis, pars paraependymalis sympathetic nuclei. These new observations suggest that specific patterns exist for supraspinal and intraspinal enkephalin pathways.

Animals↗

PubMed1987

Central neurotoxic effects of guanethidine: altered serotonin and enkephalin neurons within the area postrema.

This study reveals that the 5-HT and enkephalin cell body population of the area postrema (AP) is dramatically reduced via exposure to the peripherally circulating neurotoxin guanethidine. Efforts to restore cell body numbers to control levels, with colchicine and monoamine oxidase inhibitors, subsequent to guanethidine treatment are ineffective. However, 5-HT and enkephalin immunostaining of surrounding bulbar nuclei appears normal, implying that the neurotoxic effect of guanethidine is restricted to the AP. In addition, gamma-aminobutyric acid and neurotensin immunostaining within the AP appears normal, subsequent to guanethidine treatment, suggesting that the neurotoxic effect is restricted to specific AP cell populations.

Animals↗

PubMed1987

Catecholamines predict outcome in traumatic brain injury.

Activation of the sympathetic nervous system attends traumatic brain injury, but the association of the severity of neurological impairment and recovery with the extent of sympathetic nervous system stimulation is poorly defined. In this study, plasma norepinephrine (NE), epinephrine (E), and dopamine (DA) levels were measured serially in 33 patients with traumatic brain injury and compared with the Glasgow Coma Score (GCS), which was obtained concurrently. A catecholamine gradient that reflected the extent of brain injury was demonstrated within 48 hours of the injury. In patients with a GCS of 3 to 4, NE and E levels increased four- to fivefold and the DA level increased threefold above normal (NE, 1686 +/- 416 pg/ml; E, 430 +/- 172 pg/ml; DA, 236 +/- 110 pg/ml), while patients with mild brain injury (GCS, greater than 11) had slightly elevated or normal levels. Patients with marked (GCS, 5 to 7) and moderate (GCS, 8 to 10) traumatic brain injuries had intermediate levels. The prognostic value of determining admission levels of NE was shown in patients with an admission GCS of 3 to 4 1 week after injury. Patients with severe and unchanging neurological impairment 1 week after injury had markedly elevated initial NE levels (2,176 +/- 531 pg/ml), whereas initial NE levels (544 +/- 89 pg/ml) were only mildly elevated in patients who improved to a GCS of greater than 11. These data indicate that markedly elevated NE levels predict outcome in patients with comparable neurological deficits. Thus levels of circulating catecholamines are excellent endogenous and readily quantifiable markers that appear to reflect the extent of brain injury and that may predict the likelihood of recovery.

Adolescent↗

PubMed1987

Altered sympathetic-salivary gland development: delayed response to postnatal castration.

These studies defined the normal and hormonally altered development of activity for tyrosine hydroxylase (T-OH), the rate-limiting enzyme in catecholamine biosynthesis (Levitt et al., 1965), and choline acetyltransferase activity (CAT) in the male rat superior cervical ganglion (SCG). Additionally, salivary gland weight was monitored. Two distinct developmental plateaus for postsynaptic T-OH activity exist. The first plateau represents the prepubertal level, which is significantly lower than the second postpubertal plateau. In contrast, presynaptic CAT activity displayed only a single plateau, commencing at approximately 45 days of age. The effects of postnatal castration (at 10 or 11 days of age) on the submandibular gland and T-OH activity were delayed until after puberty. No change in T-OH activity was seen at two and four post-operative weeks between control and castrated animals; however, T-OH activity was significantly less in castrated animals at 12 and 16 post-operative weeks. Testosterone replacement reversed the effect of castration on T-OH activity. Conversely, CAT activity in the SCG was unchanged by postnatal castration for at least 16 post-operative weeks, the longest time point studied. The failure of castrated animals to display the normal developmental increase in T-OH activity following puberty was comparable with the effect of castration on the development of submandibular salivary gland weight. These results suggest that in postpubertal male rats, development of T-OH activity in the superior cervical ganglion is influenced by testosterone. The parallel effects of castration on submandibular gland weight imply that testosterone regulates T-OH activity via an indirect mechanism. In contrast to noradrenergic enzyme activity and target tissue size, the ontogeny of presynaptic CAT activity appears to be insensitive to testosterone levels.

Animals↗

PubMed1987

The predictive value of catecholamines in assessing outcome in traumatic brain injury.

Because of the central role of the sympathetic nervous system in mediating the stress response, plasma norepinephrine (NE), epinephrine (E), and dopamine (DA) levels were measured in 61 traumatically brain-injured patients to determine whether catecholamine (CA) levels obtained within 48 hours after injury provide reliable prognostic markers of outcome. Patient outcome was determined at 1 week using the Glasgow Coma Scale (GCS) and at the time of discharge using the Glasgow Outcome Scale (GOS). Levels of NE, E, and DA correlated highly with the admission GCS score (NE: r = 0.58, p less than 0.0001; E: r = 0.46, p less than 0.0025; DA: r = 0.27, p less than 0.04). Moreover, in the 21 patients with GCS scores of 3 or 4 on admission, NE levels predicted outcome at 1 week. All six patients with NE levels less than 900 pg/ml (normal level less than 447 pg/ml) improved to GCS scores of greater than 11, while 12 of 15 with NE values greater than 900 pg/ml remained with GCS scores of 3 to 6 or died. Levels of E and DA were not as useful. Catecholamine levels also increased significantly as the GOS score worsened. Levels of NE and E were significantly higher in patients who died or remained persistently vegetative than in those with better outcomes. In the 54 patients who survived beyond 1 week, significant correlations were present between the length of hospitalization and NE (r = 0.71, p less than 0.0001) and E (r = 0.61, p less than 0.0001) levels. Concentrations of NE (r = 0.61, p less than 0.0004) and E (r = 0.48, p less than 0.01) were also highly correlated with the duration of ventilatory assistance. Analysis of the interactions of CA levels and GCS scores, duration of ventilatory assistance, and length of hospitalization revealed that the CA's either enhanced the reliability of the GCS score or were independent predictors of outcome. Thus, these findings indicate that alterations in circulating CA levels reflect the severity of the neurological insult and provide support for the use of CA measurements as a physiological marker of patient outcome in both the acute and chronic phases of traumatic brain injury.

Adolescent↗

PubMed1987

The major pelvic ganglion: androgen control of postnatal development.

Previously we reported the effects of postnatal castration on the postorganizational development of the sympathetic hypogastric ganglion (Hamill and Guernsey, 1983; Melvin and Hamill, 1986). "Postorganization" implies an activational role for gonadal hormones, in contrast to the permanent organizing effects that occur perinatally. We now report results that suggest that the major pelvic ganglion (PG), a mixed parasympathetic and sympathetic ganglion, is similarly regulated by testosterone during development. Choline acetyltransferase (CAT) and tyrosine hydroxylase (T-OH) activities were used to examine normal PG ontogeny. The normal development of these biochemical indices occurs primarily after day 10. Postnatal castration at 10-11 d of age completely prevented the postorganizational developmental increase of T-OH activity. At 12 postoperative weeks T-OH activity in castrates was approximately 6% that of the control animals (control, 2880 +/- 127 pmol/ganglion X hr; castrated, 161 +/- 16 pmol/ganglion X hr; p less than 0.001). In fact, by only 1 postoperative week, T-OH activity was already significantly reduced in castrated animals (control, 480 +/- 69 pmol/ganglion X hr; castrated, 179 +/- 6 pmol/ganglion X hr; p less than 0.001). CAT activity and total ganglion protein were also significantly reduced by 1 postoperative week. In contrast to T-OH activity, however, these indices continued to develop at diminished rates. By 12 postoperative weeks CAT activity and total ganglion protein in castrates were 30 and 50% of control values, respectively, resulting in a significant developmental abnormality in CAT-specific activity. Testosterone replacement reversed the castration-induced developmental deficits of T-OH and CAT activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens↗

PubMed1986

Gonadal hormone regulation of neurotransmitter synthesizing enzymes in the developing hypogastric ganglion.

The effects of postnatal castration at 10-11 days of age were examined in the sympathetic hypogastric ganglion (HG). Assays for choline acetyltransferase (ChAT) activity, a biochemical marker for presynaptic cholinergic maturation, and the activity of tyrosine hydroxylase (T-OH), the rate limiting enzyme in postsynaptic catecholamine biosynthesis and an index of noradrenergic development, were employed to monitor HG ontogeny. After 1 postoperative week ChAT activity and T-OH activity were significantly reduced in castrated animals as compared to sham operated controls. Over the 12 week postoperative observation period T-OH activity never varied significantly from the day 10 precastration value; thus, by 12 postoperative weeks T-OH activity in the castrated animals was 3% of the control value. In contrast, ChAT activity and total ganglion protein continued to mature in the castrated animals, but at diminished rates, so that by 12 postoperative weeks both indices were approximately 40% of the control values. Testosterone replacement therapy restored both ChAT and T-OH activities to control levels. Additionally, testosterone replacement restored the control level of activity for DOPA decarboxylase, a catecholamine synthetic enzyme which is differentially regulated from T-OH. The failure of enzyme activities to develop normally subsequent to castration on postnatal day 10 suggests that testosterone regulates the postorganizational maturation of postsynaptic noradrenergic enzyme activities and presynaptic ChAT activity.

Animals↗

PubMed1986

Immunohistochemical demonstration of serotonin neurons in autonomic regions of the rat spinal cord.

The immunohistochemical distribution of serotonin neurons in normal and transected spinal cords of rats was examined. Intraspinal serotonin neurons were immunostained as far rostral and caudal as T3 and Co1, respectively. All serotonin neurons were located in lamina VII and X, and most were located in spinal autonomic areas. Both bipolar and multipolar neurons were observed with many of the neurons oriented longitudinally to the long axis of the cord. Spinal neurons immunostained for serotonin were visible with and without L-tryptophan and monoamine oxidase inhibitor pretreatment.

Animals↗

PubMed1986

Effect of misonidazole on neurotransmitter systems.

This study examines the effect of chronic administration of misonidazole on four neurotransmitter pathways (norepinephrine, dopamine, acetylcholine, and GABA) of the central nervous system (CNS). Biochemical assays examined the neurotransmitter synthesizing enzymes tyrosine hydroxylase (TOH) for catecholamines and choline acetyltransferase (CAT) for acetylcholine. An immunocytochemical stain for glutamic acid decarboxylase (GAD) was used as an enzymatic marker for GABAergic neurons. In drug-treated mice, enzymatic activity for TOH as well as the total concentration of enzyme was significantly increased in the locus coeruleus (LC), a principal norepinephrine-containing nucleus of the brainstem, but not in other brain regions. Correlative histofluorescence examination of the LC also showed an increase in the fluorescence intensity of noradrenergic neurons of the nucleus. In contrast, CAT activity was not different from controls in any of the areas examined. In the brainstem, immunocytochemical staining for GAD showed a significant reduction in the number of immunoreactive varicosities juxtaposed to neurons of the lateral vestibular nucleus suggestive of a loss of afferent GABAergic input from the cerebellum. These data suggest that both norepinephrine and GABAergic systems may be altered in selective nuclei of the CNS by chronic administration of misonidazole, and that drug related changes in NE and GABA may underline some of the neurotoxic side effects of MISO and/or exacerbate a patient's pre-existing cardiovascular or neurological problems.

Animals↗

PubMed1986

Transient hypogonadotrophic hypogonadism after head trauma: effects on steroid precursors and correlation with sympathetic nervous system activity.

Transient hypogonadotrophic hypogonadism commonly occurs after major medical insults. Because data on testosterone precursors are sparse and because little is known about the aetiology of these changes, we studied the interactions of traumatic brain injury with gonadal steroidogenesis and with sympathetic nervous system activation. Patients were divided into two groups based upon the severity of neurological dysfunction using the Glasgow Coma Score (GCS); Group 1 less than 8, Group 2 greater than or equal to 8. Group 1 was further divided into those patients treated (Group 1b) and those not treated with dexamethasone (Group 1a). Plasma levels of testosterone, androstenedione, 17-hydroxyprogesterone, DHEA sulphate, cortisol, LH, FSH, and the catecholamines noradrenaline (NE), adrenaline (EPI) and dopamine were measured in 31 acutely brain injured men, aged 18-95, shortly after their accident and 4 days later. In all patients, NE and EPI were elevated on admission (NE: 841 +/- 105 (SEM) pg/ml; EPI: 191 +/- 32 pg/ml and there were highly significant inverse correlations between admission NE (r = -0.52, P less than 0.003) and EPI (r = 0.44, P less than 0.02) levels and day 4 testosterone concentrations. Testosterone fell 53% (P less than 0.001) in 13 Group 1a men, but only 25% (P = NS) in the less severely injured. Similar reductions occurred in cortisol and the steroid precursors. However, only testosterone, 17-hydroxyprogesterone, and DHEA sulphate levels were significantly lower than normal on day 4. LH and FSH levels were also significantly reduced from elevated admission levels. In the eight men treated with dexamethasone (8-40 mg/ml) (Group 1b), the decrease in testosterone, LH and FSH concentrations were similar to those present in Group 1a. Thus, severe traumatic brain injury leads to hypogonadotrophic hypogonadism which affects testosterone and its precursors. The magnitude of the hormonal dysfunction is dependent upon the severity of the neurological insult. Finally, the decrease in testosterone is significantly correlated with admission catecholamine levels, which may suggest a role for the sympathetic nervous system (SNS) in mediating this response in men.

Adolescent↗

PubMed1985

Dopamine-stimulated adenylate cyclase and tyrosine hydroxylase in diabetic rat retina.

The effects of streptozotocin-induced diabetes on the retinal dopaminergic system have been examined in Long-Evans (pigmented) rats. Tyrosine hydroxylase activity was significantly decreased while dopamine-stimulated adenylate cyclase was increased in 2-month-diabetic rats. The observed increase in dopamine-stimulated adenylate cyclase activity in diabetic retinae may be related to neurotransmitter receptor changes because postreceptor activation of adenylate cyclase by guanylyl imidodiphosphate was not altered.

Adenylyl Cyclases↗

PubMed1985

Spinal parasympathetic enkephalin fibers: patterns and projections.

The immunocytochemical distribution of enkephalin (Enk) was examined in the sacral spinal cord of the rat. Enk fibers are found interspersed among preganglionic parasympathetic neurons in the sacral parasympathetic nucleus. In addition, Enk fibers parallel the localization of primary visceral afferents found in the pelvic nerve. These findings provide a morphological substrate for enkephalin interactions with parasympathetic functions and with primary visceral inputs to the sacral cord.

Animals↗

PubMed1985

Transient hypogonadotropic hypogonadism caused by critical illness.

The effects of acute severe illness on pituitary-gonadal function were determined in 35 men and 19 women, including 12 who were postmenopausal. Seventeen men and 5 women had traumatic brain injury which resulted in coma. Twelve postmenopausal and 2 premenopausal women had intracranial vascular accidents. Eleven men had myocardial infarctions, while 7 men underwent elective surgery. Serial plasma samples were examined for testosterone (men), percentage of ultrafiltrable testosterone (men), estradiol (women), sex hormone-binding globulin, LH, and FSH. In men, mean testosterone levels fell by 271 +/- 72 (+/- SE), 202 +/- 63 and 195 +/- 75 ng/dl within 24 h of brain injury, myocardial infarction, or elective surgery, representing decreases of 55%, 43%, and 58%. Further declines occurred in the first and third groups to mean nadirs of 93 +/- 16 and 117 +/- 5 ng/dl, respectively. During recovery of neurological function there was no correlation between the testosterone level and the degree of neurological impairment; testosterone levels eventually returned to normal (627 +/- 77 ng/ml). The percentage of ultrafiltrable testosterone and sex hormone-binding globulin did not change in any group. Although significant decreases in mean immunoreactive LH and FSH levels were found after head trauma, and decreases in FSH were found in the men after surgery, these changes occurred after the decline in testosterone. Despite the fall in basal gonadotropin levels in the head trauma group, there were no significant differences in the gonadotropin responses to GnRH (100 micrograms) in 4 patients during their acute illness or recovery. LH, FSH, and estradiol levels in the premenopausal women were significantly lower on the second day of brain injury (LH, 10.3 +/- 4.7 vs. 3.5 +/- 0.6 mIU/ml; FSH, 3.8 +/- 1.9 vs. 1.4 +/- 0.8 mIU/ml, estradiol, 200 +/- 41 vs. 102 +/- 16 pg/ml) and remained suppressed for 7 days. Gonadotropin levels also fell in the postmenopausal women within 24 h; reductions in LH of 74% and in FSH of 62% were present by day 7 of study. We conclude that both men and women who are critically ill uniformly develop temporary hypogonadotropic gonadal insufficiency regardless of their illness. In men, it is manifested by low testosterone levels, while a comparable decrease in estradiol is present in women. The low testosterone concentrations are not due to reduced sex hormone-binding capacity. Based upon our data in postmenopausal women, hypogonadotropism also occurs in the presence of nonfunctioning gonads. Although our studies do not completely establish the pathophysiology of this disorder, they suggest a suprapituitary origin.

Adolescent↗

PubMed1984

Spinal sympathetic pathway: an enkephalin ladder.

Enkephalin distribution was examined in autonomic areas of the rat thoracic spinal cord. The localization of enkephalin fibers coincided with nuclear regions containing sympathetic preganglionic neurons. Horizontal sections revealed a pattern for enkephalin fibers resembling Laruelle's description of the localization of sympathetic preganglionic neurons as rungs of a ladder.

Animals↗

PubMed1984

Hormonal regulation of adult sympathetic neurons: the effects of castration on tyrosine hydroxylase activity.

The effects of the hormone testosterone on neurotransmitter synthesis in peripheral sympathetic ganglia were examined in adult male Sprague-Dawley rats. Tyrosine hydroxylase (T-OH), the rate limiting enzyme in catecholamine biosynthesis was examined in the hypogastric (HG), coeliac (CG), and superior cervical ganglion (SCG) subsequent to castration. Initial studies indicated that 2 weeks after surgery, HG T-OH activity fell to approximately 30% of control. In order to more clearly define the pattern of testosterone effects, HG was examined 1, 2 and 4 weeks after surgery. T-OH activity was 67%, 50% and 11% of control at these 3 respective time points, and the observed alteration in T-OH activity appeared to parallel changes in the size of pelvic target organs. Similar hormonal effects did not occur in other peripheral sympathetic ganglia; T-OH activity was unchanged in SCG and CG when examined 1 month after castration. Enzyme activity was restored following replacement therapy with testosterone, whereas the neural metabolite 17-beta estradiol was without effect. The recovery in T-OH activity was associated with partial recovery of target organ size. These studies suggest that hormonal factors regulate neurotransmitter synthesizing enzymes in adult sympathetic neurons and may do so via consequences of alterations in target organs. These observations parallel similar events in the developing nervous system.

Animals↗

PubMed1984

Reserpine induction of tyrosine hydroxylase in paraplegia.

Reserpine induction of tyrosine hydroxylase (TH) activity reflects the biochemical adaptability of sympathetic neurons. Midthoracic spinal cord transection in adult animals precludes TH induction in the sixth lumbar (L6) ganglion, a ganglion innervated by spinal segments caudal to the lesion. However, in animals receiving lesions as neonates, an elevation in L6 ganglion TH activity occurred after reserpine. This retained biochemical adaptability indicates an increased recuperative capacity of developing neurons.

Animals↗

PubMed1983

Long-term effects of spinal transection on the development and function of sympathetic ganglia.

The long-term effect of interruption of descending central pathways on the biochemical development and function of sympathetic neurons was examined in the sixth lumbar (L6) sympathetic ganglia of the rat. Previous investigations had defined the normal maturation of presynaptic choline acetyltransferase (CAT) activity, postsynaptic tyrosine hydroxylase (T-OH) activity and total protein in L6 ganglia. Neonatal spinal cord transection prevented the normal ontogeny of CAT activity: enzyme activity was 40% of control one week and one year after surgery. Similarly, T-OH activity failed to develop normally after transection and was 22% of control one year postoperatively. Spinal transection at 30 days of age did not alter baseline CAT or T-OH activities in L6 ganglia when examined up to 6 months after surgery. Apparently during the first month of life descending central pathways exert critical facilitatory influences on sympathetic ganglia maturation; interruption of these influences results in long-lasting biochemical deficits. We also examined the role of central mechanisms in adult sympathetic function. Stressful stimuli, including reserpine treatment, normally induce adult T-OH through reflex sympathetic activation. This biochemical adaptability was studied by treating rats with reserpine after spinal transection. After motor and autonomic spinal reflexes returned in paraplegic animals, reserpine treatment was initiated. Spinal animals did not exhibit T-OH induction. These observations indicate that central rather than spinal mechanisms govern this biochemical adaptability of mature sympathetic neurons.

Aging↗

PubMed1983

Hormonal regulation of sympathetic neuron development. The effects of neonatal castration.

The effects of neonatal castration on neuronal ontogeny were examined in peripheral sympathetic ganglia in male Sprague-Dawley rats. Tyrosine hydroxylase (T-OH) activity, the rate-limiting enzyme in catecholamine biosynthesis and a marker of noradrenergic maturation, was examined in the hypogastric (HG) and superior cervical ganglion (SCG). Initial studies characterized the normal development of T-OH activity in HG ganglia. Neonatal castration at 10-11 days of age prevented the normal ontogeny of HG T-OH activity: T-OH activity failed to develop normally and was 17% of sham-operated littermate controls when examined at 8 weeks of age, and less than 5% when studied 10 weeks after surgery. In contrast to the effects in HG, there was no change in enzyme activity in the SCG. Replacement therapy with testosterone decanoate completely reversed the developmental alteration in enzyme activity. These observations suggest that hormonal factors modulate noradrenergic ontogeny in peripheral sympathetic ganglia but these effects appear restricted to ganglia whose targets include hormonally dependent sex organs.

Animals↗