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Biomedical subjects

J D Miller

Publications and source records attributed to J D Miller.

At least 19 recordsLinked to original sources

Serotonergic phase shifts of the mammalian circadian clock: effects of tetrodotoxin and high Mg2+.

The mammalian circadian clock in the suprachiasmatic nuclei (SCN) can be phase-shifted in vitro by the serotonin agonist quipazine. Here we show that quipazine resets the SCN clock in the presence of tetrodotoxin or 10 mM Mg2+, treatments that block Na+ action potentials and Ca2+ channels, respectively. These results support the hypothesis that quipazine resets the clock by stimulating receptors located on clock elements rather than on cells afferent to the clock.

Animals

Progress in the management of head injury.

Three 1-year surveys of head injury management spanning a 9-year period in a single regional centre are presented. There was a reduction in total numbers of head injury admissions after guidelines for admission and referral were implemented. More liberal use of computed tomography resulted in detection of a greater number of intracranial haematomas with the majority detected in non-comatose patients. The early mortality rate in severe head injury fell from 45 per cent to 34 per cent despite referral of large numbers of patients with multiple injuries and a substantial proportion (12 per cent) of patients aged more than 70 years in whom outcome did not improve. Total occupied bednights and bednights occupied per surviving patient with severe head injury fell over the period of study. Care for patients with significant head injury should be based on regional neurosurgical units associated with trauma services.

Aged

The role of bradykinin in the etiology of vasogenic brain edema and perilesional brain dysfunction.

The feline infusion model of brain edema was used to evaluate the role of bradykinin in the etiology and pathophysiology of vasogenic brain edema. Bradykinin (3 or 90 ug in 600 microL saline) did not alter normocapnic regional cerebral blood flow (rCBF) nor induce specific changes in either the somatosensory (SEP) or motor (MEP) evoked potentials. The mean increases in ICP (from 4.5 to 16.1 mmHg) and peri-infusion white matter water content (from 69.4 to 79.8 ml/100 g tissue), mean decrease in lumped craniospinal compliance (from 0.040 to 0.014 ml/mmHg) and local histological changes were all similar to those after 600 microL saline infusion. The interstitial bradykinin infusion caused focal blood-brain-barrier (BBB) opening to Evans Blue dye and was chemotaxic for granulocytes. After the infusion there was a global loss of rCBF CO2 reactivity but there was no ischemia at normocapnia. These results show that bradykinin in brain edema fluid, at concentrations greater than those found in neuropathological conditions, can open the BBB of normal cerebral parenchymal capillaries and cause vascular dysregulation. In neuropathological conditions bradykinin may therefore potentiate formation of vasogenic brain edema but does not contribute to perilesional brain dysfunction.

Animals

Transcranial Doppler waveform differences in hyperemic and nonhyperemic patients after severe head injury.

Although increased cerebral blood flow velocity is readily measured by transcranial doppler ultrasonography (TCD), the causes of the velocity elevation may differ. After severe head injury, increased blood flow velocity can develop both in patients with global hyperemia (suggestive of vasodilation) and in those without hyperemia (suggestive of vasospasm). The present study attempts to determine whether TCD can differentiate these two mechanisms of velocity increase. Fourteen severely brain-injured patients who developed increased middle cerebral artery blood flow velocity (time-averaged mean velocity > 100 cm/s) were studied. Eight cases were nonhyperemic and six were hyperemic as defined by arterial-jugular venous oxygen content differences of more than 4 mL/dL and less than 4 mL/dL, respectively. The TCD waveform of all eight nonhyperemic cases showed a diastolic notch, which was absent in all six hyperemic patients (p = 0.00066). TCD waveform profile appears to provide a noninvasive means of differentiating at the bedside the two causes of increased flow velocity. If associated with raised intracranial pressure, these require different treatment.

Adolescent

Depot leuprolide versus danazol in treatment of women with symptomatic endometriosis. I. Efficacy results.

OBJECTIVE: We aimed to assess the efficacy of depot leuprolide versus danazol in the treatment of endometriosis. STUDY DESIGN: A double-blind randomized trial of 270 patients from 22 centers compared the pretreatment and posttreatment laparoscopic extent of endometriosis. Pretreatment and posttreatment endometriosis symptoms and signs were assessed with standardized methods. RESULTS: When compared with danazol, leuprolide depot caused a more rapid and profound suppression of estradiol. Leuprolide depot and danazol were similarly efficacious in decreasing the extent of endometriosis, as well as the pain and tenderness associated with endometriosis. CONCLUSION: Depot leuprolide is an effective alternative to danazol in decreasing the extent of endometriosis and endometriosis-related pain.

Adolescent

Lower extremity fracture fixation in head-injured patients.

Compared with nonsurgical management or delayed repair, early fracture fixation can reduce the incidence of pulmonary complications in patients with long-bone fractures of the lower extremities. Blunt trauma victims often have multiple nonskeletal injuries that might influence the risk of pulmonary complications, and when head injuries are present it has been a common practice to delay nonemergent operations for several days to protect the injured brain. We conducted a retrospective review of 114 patients with multiple trauma whose injuries included head trauma and a fracture of the neck or shaft of the femur or shaft of the tibia to determine if delayed stabilization of lower extremity fractures increased the risk of pulmonary complications or reduced the risk of cerebral complications. Forty-six patients underwent surgical fixation of their fractures within 24 hours of injury (early fixation), 26 patients had their fractures repaired more than 24 hours after injury (late fixation), and 42 patients did not undergo surgical fracture fixation. The risk of pulmonary complications was not related to the timing of surgical fracture fixation but was strongly influenced by the severity of injuries to the head and to the chest (p less than 0.001). Furthermore, a delay in fracture fixation did not protect the injured brain; the risk of CNS events was determined by the severity of the head injury (p less than 0.0001). Early fracture fixation in patients with head injury may be appropriate because it simplifies patient care and does not seem to worsen the head injury, but it does not prevent pulmonary complications in these high-risk patients.

Adolescent

Protein synthesis rates in colon and liver: stimulation by gastrointestinal pathologies.

Rates of protein synthesis in vivo in normal and pathological tissues of the gastrointestinal tract, were measured using the 'flooding dose' technique with the stable isotope L-[1-13C] leucine. The rate of protein synthesis in normal colonic mucosa was 9.4 (1.2)% (mean (SEM)) per day but was significantly raised in benign and malignant colorectal tumour tissue, and in colonic mucosa from patients with inflammatory bowel disease (p less than 0.001). Furthermore, the rate of protein synthesis was significantly greater in benign colorectal tumour tissue, 36.7 (2.5)% per day, than that in either malignant tumour tissue, 21.7 (1.9)% per day, or in inflammatory bowel disease mucosa, 24.7 (2.5)% per day (means (SEM) p less than 0.001). Liver protein synthesis rates were also measured in separate groups of patients with benign disease of the gastrointestinal tract, in patients with colorectal carcinoma, and in patients with inflammatory bowel disease. The fractional rate of liver protein synthesis was 20.7 (1.9)% per day in patients with benign disease and 23.1 (1.6)% per day in patients with colorectal cancer. In patients with inflammatory bowel disease, however, liver protein synthesis was significantly increased to 35.4 (2.3)% per day (means (SEM) p less than 0.01).

Adult

Intracranial blood flow velocity after head injury: relationship to severity of injury, time, neurological status and outcome.

Middle cerebral artery (MCA) blood flow velocity was measured daily by transcranial Doppler ultrasonography in 121 patients with severe (50), moderate (16) and minor (55) head injury during their hospital stay, and the results compared with findings in control subjects. Admission MCA velocity was significantly lower after severe 35.8 (31.9-39.7) cm/s, mean (95% confidence limits), moderate 45.5 (40.0-51.0) cm/s and minor 51.7 (47.9-55.5) cm/s head injury when compared with normal controls 60.1 (56.9-63.3) cm/s. Initial mean velocity in severe head injury was significantly lower than in moderate and minor injury. At discharge, MCA velocity in severe injury remained below normal 46.2 (43.2-49.0) cm/s, whereas, in moderate and minor injury flow velocity had returned to normal. Correlation (r = 0.46, p less than 0.01) was found between MCA velocity and Glasgow Coma Score (GCS) on admission but not on discharge. Persistently low flow velocity was found in all 10 patients who died within 72 hours (early deaths). An admission MCA velocity of less than 28 cm/s correctly predicted 80% of the early deaths. Patients who made a good recovery or had only moderate disability at six months showed a significant increase in velocity from admission 36.2 (31.5-41.2) cm/s to discharge 47.8 (43.7-51.9) cm/s in contrast to those who were severely disabled, in whom velocity generally remained low.

Adolescent

Isoperiodic neuronal activity in suprachiasmatic nucleus of the rat.

A subpopulation of neurons in the suprachiasmatic nucleus (SCN) is shown here to exhibit isoperiodic bursting activity. The period of discharge in these cells may be lengthened or the periodicity may be transiently disrupted by photic stimulation. It is suggested that many, if not all, of these cells are vasoactive intestinal polypeptide (VIP) neurons. It is shown that the ultradian periodicity of these cells, estimates of the VIP neuron population size in the SCN, effects of partial lesions on tau (period), and estimates of the phase stability of SCN-driven circadian rhythms are consistent with a strongly coupled, multioscillator model of circadian rhythmicity, in which the oscillator population constitutes a restricted subset of the SCN neuronal population.

Animals

Elevated growth hormone secretory rate in premature infants: deconvolution analysis of pulsatile growth hormone secretion in the neonate.

Premature infants have higher circulating concentrations of growth hormone (GH) than term infants. Previous investigations of these differences have used sampling frequencies of every 30 min with subsequent application of pulse detection algorithms, such as the CLUSTER program, to assess serum GH pulse parameters. To determine differences in GH secretory rates or GH t1/2 values between premature and term infants, we have sampled 11 neonates at 15-min intervals. We performed deconvolution analysis of the resultant plasma GH values to estimate GH secretory and clearance parameters. Five premature infants (gestational age range 24-34 wk) and six term infants (gestational age range 38-42 wk) were sampled every 15 min for 6 h. All subjects had indwelling arterial catheters. GH was measured (in duplicate) by RIA using 10 microL of plasma. Premature infants had higher secretory burst amplitudes (2.2 +/- 0.13 micrograms/L/min versus 1.4 +/- 0.27 micrograms/L/min, p = 0.02), higher production rates (product of the total number of bursts and the mean mass of GH secreted per burst, 811 +/- 173 micrograms/L/6 h versus 283 +/- 77 micrograms/L/6 h, p = 0.03), and a higher mass of GH per secretory burst (106 +/- 25 micrograms/L versus 38 +/- 11 micrograms/L, p = 0.049) than term infants. The integrated plasma GH concentration exhibited a strong trend toward a higher value in the premature infants (18,100 +/- 800 micrograms/L versus 10,200 +/- 2,700 micrograms/L, p = 0.067).(ABSTRACT TRUNCATED AT 250 WORDS)

Female

Spontaneous and stimulated growth hormone release in adolescents with type I diabetes mellitus: effects of metabolic control.

Abnormalities in GH release have been found in adults with poorly controlled type I diabetes mellitus. During puberty, circulating GH concentrations transiently increase. To investigate in pubertal diabetic adolescents, the physiological relationship between metabolic control and GH release, we compared spontaneous and GH-releasing hormone (GHRH)-stimulated GH release in six pubertal subjects during poor (study A) and improved (study B) metabolic control. The subjects included two females and four males (mean age +/- SE, 15.5 +/- 1 yr; duration of diabetes, 8.6 +/- 0.9 yr; Tanner stages II-V). Serum samples for glucose and GH determinations were obtained at 20-min intervals over a 24-h period. Significant pulses of GH release were identified using a pulse detection algorithm (Cluster). Fourier expansion time series was used to document the occurrence of significant periodicities in the GH concentration-time data series. All subjects received 1.0 microgram/kg GHRH-44, iv, at 0800 h on the day after the 24-h monitoring for GH. After GHRH administration, samples were taken for glucose and GH determinations over 90 min. The overall mean glucose level (+/- SE) during the 24-h monitoring was 11.5 +/- 0.2 mmol/L during study A and 7.2 +/- 0.2 during study B (P = 0.0001). During the 4 weeks of improved control, glycated hemoglobin fell from 13.9 +/- 1.4% to 11.7 +/- 0.8% (mean +/- SE; P < 0.025). All subjects had significant pulses of GH release during poor or improved metabolic control. Relative to that at night, the daytime pulse frequency was higher in study A (P < 0.025). The overnight pulse frequency increased during study B (P < 0.01). Other pulse parameters, including maximal and incremental pulse amplitudes, pulse width, and interpulse valley mean, did not change during improved control. The mean +/- SE 24-h GH concentration was 4.1 +/- 0.7 micrograms/L during study A and 4.3 +/- 0.8 during study B. The amplitude of the circadian GH rhythm was not different by Fourier analysis. The overall mean glucose +/- SE after GHRH administration was 15.3 +/- 0.2 mmol/L in study A and 6.8 +/- 0.1 in study B. In spite of the marked hyperglycemia during study A, the GH responses were similar during studies A and B. Maximal GH levels were obtained at 15-30 min (mean +/- SE) and were 36.0 +/- 16.9 micrograms/L in study A and 38.7 +/- 18.9 in study B.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent

Spontaneous pulsatile growth hormone release in male and female premature infants.

Although premature infants have high umbilical cord GH levels, little is known about spontaneous GH release in these individuals. The purpose of our study was to investigate spontaneous 12-h GH release in appropriate for gestational age male and female premature infants. We studied 22 premature infants (15 males and 7 females) of appropriate length and weight for age. Gestational ages, birth weights, birth lengths, and ages at the time of study were similar in male or female infants. All infants were biochemically euthyroid. Blood was taken every 30 min over a 12-h period from an indwelling umbilical catheter; no stress occurred during the blood withdrawal. GH was determined by a double antibody RIA, using 0.01 mL plasma. GH pulse detection was undertaken using Cluster, a computerized pulse detection algorithm. Total insulin-like growth factor-I and -II (IGF-I and -II) levels were measured after separation of the IGFs from the serum binding proteins. Spontaneous pulsatile GH release was observed in all infants studied. No differences were found between males and females in the pulse characteristics of frequency, maximal amplitude, incremental amplitude, width, or area. The GH pulse frequency per 12 h was 3.2 +/- 0.3 (mean +/- SE) in males and 3.0 +/- 0.7 in females. The maximal pulse amplitude was 50.7 +/- 6.2 micrograms/L in males and 44.7 +/- 9.0 micrograms/L in females. The incremental pulse amplitude was 24.3 +/- 3.2 micrograms/L in males and 20.2 +/- 3.9 micrograms/L in females. The mean 12-h GH level was 37.1 +/- 4.8 micrograms/L in males and 35.8 +/- 8.5 micrograms/L in females; the average GH nadir was 26.1 +/- 4.0 micrograms/L in males and 24.4 +/- 8.3 micrograms/L in females. Both IGF-I and IGF-II concentrations were similar in males and females. The mean IGF-I levels were 10.7 +/- 1.5 ng/mL in males and 7.5 +/- 1.1 ng/mL in females; IGF-II levels were 96.0 +/- 12.0 ng/mL in males and 115.4 +/- 17.1 ng/mL in females. These results demonstrate similar pulsatile GH release in male and female premature infants at a mean age of 32-33 weeks. Compared with previously reported values for mean GH concentration and average GH nadir in older children, the values in these premature infants were much higher. We speculate that the higher GH levels in premature infants may result from decreased negative feedback associated with low IGF-I levels. The premature infant's somatotrophs may also not fully respond to the GH inhibitory action of somatostatin.

Blood Glucose

Carbon dioxide reactivity in the evaluation of cerebral ischemia.

Carbon dioxide reactivity, as measured by transcranial Doppler, has been determined in a group of patients with carotid artery disease and compared to a control group. CO2 reactivity was readily evaluated using transcranial Doppler by having the patients breathe 5% CO2 via a rebreathing circuit. There were significant differences (P less than 0.01) between the symptomatic patients and asymptomatic controls, as well as between symptomatic and asymptomatic hemispheres (P less than 0.05) in the patients with carotid artery disease. Five patients had revascularization procedures with all showing improved CO2 reactivity in the symptomatic and asymptomatic hemispheres. The improvement occurred early in patients after carotid endarterectomy. Two patients demonstrated improved reactivity at 6 to 13 months after extracranial-to-intracranial bypass. Transcranial Doppler has proven to be an easily performed and repeatable method of evaluating CO2 reactivity and its response to treatment.

Administration, Inhalation

Interstitial white matter brain oedema does not alter the electroencephalogram.

An experimental study was performed to determine the effects of interstitial white mater oedema on the electroencephalogram (EEG). Using both rodent and feline infusion models of focal brain oedema no difference was found between the EEG waveforms recorded epidurally from the infused and control hemispheres. It is concluded that where focal slow-wave EEG abnormalities overlie oedematous brain the EEG abnormalities are not primarily related to the brain oedema but arise from either local biomechanical or other pathophysiological mechanisms.

Animals

Transient glucose hypermetabolism after acute subdural hematoma in the rat.

Ischemic brain damage occurs in most patients with acute subdural hematoma, yet many aspects of the distribution and extent of this damage remain unexplained. Previous studies in rat model, which produces a region of infarction under the hematoma, have implicated an "excitotoxic" mechanism, suggesting that high concentrations of excitatory amino acids may exacerbate ischemic damage. A study is described in which local glucose utilization is measured 2 or 4 hours after induction of acute subdural hematoma in the rat. These changes are compared to those produced by introducing the same volume of inert silicone gel into the subdural space. Massive increases (up to 142%) in glucose utilization occurred throughout both hippocampi and in a variable zone around the ischemic core, but these had normalized by 4 hours after blood injection. Hippocampal hypermetabolism was not seen after introduction of the silicone mass, suggesting that diffusible substances from the clotted blood may be responsible for these changes. This transient hypermetabolism accords with an excitotoxic process, which may amplify brain damage after acute subdural hematoma.

Acute Disease