Biomedical subjects
Publications and source records attributed to P D Thompson.
We administered testosterone, with or without the aromatase inhibitor testolactone, to determine the effects of testosterone and its aromatization to estradiol on Lp(a) levels in normal men. Average Lp (a) values decreased by 37% during testosterone alone and by 28% when testosterone and testolactone were combined, suggesting that testosterone reduces Lp(a) in men primarily by an androgenic effect and not by its conversion to estradiol.
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The nucleocapsid protein (N, 525 amino acids) of measles virus plays a central role in the replication of the viral genomic RNA. Its functions require interactions with itself and with other viral components. The N protein encapsidates genomic RNA, a function reflected in its ability to self-assemble into nucleocapsid-like particles in the absence of other viral proteins. The substrate for the packaging of nascent RNA during RNA replication is a complex between the N and phosphoprotein (P). The domains on the N protein that promote binding to P protein and self-assembly have been identified utilizing a series of N protein deletions. Two noncontiguous regions, amino acids 4-188 and 304-373 of N protein, are required for the formation of the soluble N-P complex, while deletion of amino acids 189-239 did not affect N-P binding. Amino acids 240-303 appear to be necessary for the stability of the protein. The N-terminal 398 amino acids are all required for the formation of organized nucleocapsid-like particles, since deletion of the central region from amino acids 189-373 completely abolished N-N interaction, and deletion of amino acids 4-188 and 374-492 caused the formation of unstructured aggregates.
We used H2 15O positron emission tomography (PET) to investigate the effect of ethyl alcohol on regional cerebral blood flow in 6 patients with alcohol-responsive essential tremor and 6 age-matched control subjects. The patients were scanned while at rest and during involuntary postural tremor of the extended right arm. Normal control subjects were scanned at rest and during passive wrist oscillation of the right arm at tremor frequency. Regional cerebral blood flow associated with these conditions was measured before and after oral administration of 2 to 3 units of alcohol. The mean blood alcohol level was 35.3 +/- 20.0 mg/dl in the patient group and caused marked suppression of tremor; it was 33.9 +/- 12.9 mg/dl in the control group. Similar to previous PET studies on essential tremor patients, tremor compared with rest was associated with bilateral cerebellar activation including the cerebellar vermis. This pattern of activation differed from passive wrist oscillation where ipsilateral cerebellar activation was observed. Ethanol ingestion led to bilateral decreases of cerebellar blood flow in both tremor patients and normal subjects, and this was associated with suppression of tremor in the patients. Alcohol-associated increases of regional cerebral blood flow were observed in the inferior olivary nuclei in the patients but not in the control subjects. We conclude that alcohol-induced suppression of essential tremor is mediated via a reduction of cerebellar synaptic overactivity resulting in increased afferent input to the inferior olivary nuclei.
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We examined the effects of moderate physical activity on serum luteinizing hormone (LH), sex hormone-binding globulin (SHBG), and testosterone levels in seven sedentary but otherwise healthy men aged 66 to 76 years (mean +/- SD, 70 +/- 4). Blood samples were obtained at 10-minute intervals for 4 hours before, during, and 4 hours after 60 minutes of cycle ergometry. Blood samples were also obtained every 10 minutes for 9 hours during a separate day to control for normal diurnal variation in serum testosterone levels. Serum testosterone increased 39%, SHBG 19%, total serum protein 13%, and the free testosterone index 23% during exercise (P < .01 for all). Testosterone and SHBG levels during the 4-hour sampling period after exercise were similar to values obtained before exercise and on the morning and afternoon of the control day. LH concentrations were unaltered during or after exercise. The change in SHBG levels during exercise correlated positively with the change in testosterone concentrations (r = .74, P = .09). We conclude that short-term exercise produces a transient elevation in serum testosterone levels in elderly men, which is partly due to an increase in serum SHBG concentrations. The concomitant increase in total protein and the rapid return of total protein and SHBG to baseline values after exercise indicate that hemoconcentration partly contributes to the exercise-associated increase in circulating testosterone levels.
It has been claimed that patients with cerebellar pathology are impaired at associative learning. Patients with cerebellar ataxia (n = 7) were taught a visual-motor associative task. The task was chosen so as to allow comparisons with data currently being collected on the effects of cerebellar lesions on associative learning in monkeys. As a group the patients were as impaired at learning the task as a group of 8 patients with Huntington's disease. When each patient was individually matched with a control of the same age and IQ, some patients with cerebellar ataxia were found to be clearly impaired, but 2 were not. Of the 4 patients who were most clearly impaired, 2 had brainstem pathology and 2 did not. The relevance of these findings is discussed in relation to views concerning the functions of the cerebellum.
Epilepsia partialis continua (EPC) is defined clinically as a syndrome of continuous focal jerking of a body part, usually localized to a distal limb, occurring over hours, days or even years. The anatomical and physiological origin of EPC has been the subject of much speculation. It has been argued that EPC is a form of focal cortical myoclonus, but subcortical mechanisms have also been proposed. We describe a series of 36 patients ascertained over a period of 1 year in the UK using the British Neurological Surveillance Unit. The commonest aetiologies identified were Rasmussen's syndrome (n = 7; 19%) and cerebrovascular disease (n = 5; 14%). Rasmussen's syndrome was the most common diagnosis in patients under 16 years. In seven patients the cause remained unknown. Eight patients (22%) had focal epileptiform scalp EEG abnormalities, and 56% had generalized background scalp EEG disturbances. Lesions on MRI or CT were found in 20 cases (56%), half of whom showed predominant cortical involvement. The muscle jerking resolved in four patients (with no treatment in one), with a partial response to treatment in seven (19%) patients. A cognitive or neurological decline had been noted retrospectively in 13 (36%) patients (and in all of the patients with Rasmussen's syndrome). We personally saw 16 patients who underwent detailed clinical and neurophysiological assessments. Only six of the patients had EEG and EMG evidence for a cortical origin of their jerks; five others had indirect evidence for a cortical origin, from EMG, magnetic stimulation, and other investigations. Two patients did not have myoclonus of cortical origin, but some other source (brainstem and basal ganglia). The origin in the remaining three patients was uncertain. The clinical appearance of the muscle jerks was similar in all patients despite the different origins. We propose that the definition of EPC is best restricted to "continuous muscle jerks of cortical origin'. Continuous muscle jerking that arises from other sites in the nervous system should be termed "myoclonia continua'.
In normal subjects the execution of single rapid one-joint movements is characterized by an electromyographic (EMG) pattern composed of three discrete bursts of activity; two bursts (first and second agonist bursts, or AG1 and AG2) are present in the agonist muscle separated by an almost complete period of electrical silence. During this pause, another burst (antagonist burst, or ANT) occurs in the antagonist muscle. If a rapid movement is executed during tonic activation of the agonist muscle, tonic activity is inhibited just prior to AG1 onset (agonist inhibition). Similarly, if the movement is performed during tonic activation of the antagonist muscle, such activity is also inhibited prior to AG1 onset (antagonist inhibition). Antagonist inhibition also starts prior to AG1 onset and lasts until ANT onset. A general descriptor of the kinematic features related to the EMG pattern described above is a symmetrical and unimodal velocity profile that is bell-shaped and shows an acceleration time roughly equal to the deceleration time. This holds true for movements performed under low accuracy constraints; as accuracy demands become stricter and stricter, the peak velocity decreases but, as long as the movement is made with one continuous trajectory, the velocity profile remains roughly symmetrical. In general terms, the function of AG1 is to provide the impulsive force to start the movement; the function of ANT is to halt the movement at the desired end-point; and the function of AG2 is to dampen out the oscillations which might occur at the end of the movement. The timing and size of the bursts vary according to the speed and amplitude of the movement. The origin of the EMG pattern is a central programme, but afferent inputs can modulate the voluntary activity. In this paper, we also review the EMG and kinematic abnormalities that are present during the execution of single-joint, rapid arm movements in patients with Parkinson's disease, Huntington's disease, Sydenham's chorea, dystonia, athetosis, cerebellar deficits, upper motor neuron syndrome, essential tremor and large-fibre sensory neuropathy. The data from these studies lead us to the following conclusions: (i) the basal ganglia have a role in scaling the size of AG1, reinforcing the voluntary command and inhibiting inappropriate EMG activity; (ii) the cerebellum has a role in timing the voluntary bursts and probably in implementing muscle force phasically; (iii) the corticospinal tract has a role in determining spatial and temporal recruitment of motor units; (iv) proprioceptive feedback is not necessary to produce the triphasic pattern but it contributes to the accuracy of both the trajectory and the end-point of rapid movements.
The clinical and neurophysiological features of six patients with action tremor of the upper limbs associated with IgM paraproteinaemic neuropathy are described. Symptomatic tremor was confined to the upper limbs and was broadly symmetrical. The frequency of associated rhythmic muscle activity ranged from 2.8 to 5.5 Hz in abductor pollicis brevis and from 3.7 to 5.5 Hz in the forearm flexor muscles. Magnetic brain stimulation, somatosensory evoked potentials (SEPs) and stretch reflex studies did not provide evidence for delayed conduction within central pathways. There was marked slowing of the maximum motor conduction velocities in peripheral nerves. Forearm stretch reflexes were present but their latencies were prolonged. Somatosensory evoked potentials were obtained in the majority of patients, but were delayed. Wrist tremor could be modulated by mechanical perturbations or median nerve electrical shocks. Simple voluntary wrist movements were of normal duration and peak velocity, but the kinematic profile was asymmetric. Each movement was associated with a triphasic EMG pattern in agonist-antagonist-agonist muscles but the durations of the bursts were prolonged and the onset of the second agonist was delayed. These results support the hypothesis that distorted, mistimed peripheral inputs reach a central processor (probably the cerebellum) which although intact is misled into producing tremor in certain parts of the body.
Few studies have examined the effect of prolonged exercise training on left ventricular diastolic function in previously sedentary subjects. We performed M-mode, 2-D, and Doppler echocardiography on 16 previously sedentary men before and after 1 yr of exercise training. Six men served as controls. Exercise subjects participated in four 1-h supervised sessions weekly at 60-80% of their measured maximal heart rate. Maximal oxygen uptake, maximal exercise cardiac output, and resting left ventricular systolic and diastolic function were determined before and after training. Maximal oxygen uptake and peak cardiac output increased 27.3% and 8.5% in the trainers (P < 0.001 for both) and 1.3% and 1.0% in the controls. Left ventricular diastolic and systolic dimensions changed slightly in both groups. Maximal early inflow velocity decreased in both trainers (-9.9 +/- 14.0 cm.s-1, mean +/- SD, P < or = 0.01) and controls (-7.2 +/- 10.2 cm.s-1). Maximal atrial inflow velocity decreased (-7.8 +/- 10.9 cm.s-1, P < or = 0.01) only in the trainers possibly because of a reduction in resting heart rate (-6 +/- 11 beats.m-1, P < or = 0.05). Acceleration and deceleration times were unchanged in both groups. These results demonstrate that substantial increases in exercise performance and exercise cardiac output can occur without detectable changes in resting cardiac dimensions or left ventricular systolic and diastolic function.
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Axial motor impairments are a common cause of disability in patients with Parkinson's disease, become more prominent with longer disease duration, and have been said to be less responsive to levodopa replacement therapy. The ability to turn in bed while lying supine before and after dopaminergic stimulation was studied in a group of 36 patients with Parkinson's disease; 23 were in Hoehn and Yahr stages 3-5 when "off", and 13 were in stages 1-2. Turning was also compared with postural stability and gait before ("off") and after ("on") dopaminergic stimulation. Failure to turn in bed was noted in 19 of the 36 patients in the "off" state, with significant associations between disturbances of gait, postural stability, rising from a chair, whole body bradykinesia, and axial rigidity. Gait, postural stability, rising from a chair, whole body bradykinesia, and axial rigidity were significantly correlated in the "off" state. Disorder of axial movement, gait, and postural stability were not dependent on age at onset of Parkinson's disease, but did relate to duration of disease. After a levodopa challenge, turning in bed returned to normal in all but one patient, and gait, postural stability, rising from a chair, whole body bradykinesia, and axial rigidity also improved in nearly all. It is concluded that in the later stages of Parkinson's disease at least some aspects of axial motor control can remain dopamine responsive.
To test the hypothesis that substrate utilization during mild-intensity exercise differs in non-insulin-dependent diabetes mellitus (NIDDM) compared with nondiabetic subjects, seven lean healthy subjects (L), seven obese healthy subjects (O), and seven individuals with NIDDM were studied during 40 min of mild-intensity cycling (40% of peak O2 uptake). Systemic utilization of plasma glucose (Glc Rd) was determined by using isotope dilution methods. Gas exchange was measured to determine rates of carbohydrate (CHO) and lipid oxidation. During exercise, when CHO oxidation was greater than Glc Rd, the net oxidation of glycogen was calculated as the difference: CHO oxidation - Glc Rd. During mild-intensity cycling, the respiratory exchange ratio was similar across groups (0.87 +/- 0.02, 0.85 +/- 0.02, and 0.86 +/- 0.01 in L, O, and NIDDM subjects, respectively), and CHO oxidation accounted for one-half of total energy expenditure during exercise. Glc Rd increased during exercise and was greatest in subjects with NIDDM (3.0 +/- 0.2, 2.9 +/- 0.2, and 4.5 +/- 0.4 ml.kg-1.min-1 in L, O, and NIDDM subjects, respectively, P < 0.05), yet Glc Rd was less than CHO oxidation during exercise, indicating net oxidation of glycogen. Glycogen oxidation was greater in L and O than in NIDDM subjects (3.4 +/- 1.0, 2.5 +/- 0.9, and 1.7 +/- 0.8 ml.kg-1.min-1; P < 0.05). In summary, during mild-intensity exercise, NIDDM subjects have an increased Glc Rd and a decreased oxidation of muscle glycogen.
Hereditary hypocalcemic vitamin D-resistant rickets is attributable to defects in the nuclear receptor for 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. Two novel point mutations (I314S and R391C) identified in the hormone-binding domain of the human vitamin D receptor (VDR) from patients with hereditary hypocalcemic vitamin D-resistant rickets confer the receptor with sharply reduced 1,25-(OH)2D3-dependent transactivation. These natural mutations, especially R391C, also lead to a second specific consequence, namely impaired heterodimeric interaction with retinoid X receptor (RXR). While the transactivation ability of the I314S mutant can be largely restored by providing excess 1,25-(OH)2D3, R391C activity is more effectively restored with exogenous RXR. These observations are reflected also in the clinical course of each patient: the patient bearing the I314S mutation showed a nearly complete cure with pharmacological doses of a vitamin D derivative, whereas the patient bearing R391C responded only partially to such therapy. Further tests with patient fibroblasts and transfected cells show that the activity of the I314S VDR mutant is augmented somewhat by added RXR, while transactivation by the R391C mutant is best corrected by RXR in the presence of excess hormone. Thus, the effects of hormone vs. RXR in bolstering these mutant VDRs, such that they mediate efficient transactivation, are not entirely separable. The unique properties of these genetically altered receptors establish a new subclass of natural human VDR mutants that illustrate, in vivo, the importance of both 1,25-(OH)2D3 binding and heterodimerization with RXR in VDR action.
Primary orthostatic tremor (OT), a clinical syndrome in which a rapid (14 to 16 Hz), regular lower limb tremor causes unsteadiness on standing, may be associated with a postural upper limb tremor of similar frequency. We used H2 15O PET to analyze the abnormal pattern of cerebral activation associated with the postural upper limb tremor in four patients with primary OT. Patients had regional cerebral bloodflow (rCBF) measured during involuntary tremor while maintaining a posture with their outstretched right upper limb and again at rest. Tremor was associated with abnormal bilateral cerebellar and contralateral lentiform and thalamic activation. These findings were evident on group analysis of pooled PET data after transformation into standard stereotactic space and in single subjects when PET images were coregistered with structural MRI of the brain. At rest, cerebellar blood flow was significantly increased bilaterally in OT when compared with age- and sex-matched controls. We have previously demonstrated similar abnormal bilateral cerebellar activation in essential and writing tremors and conclude that abnormal bilateral overactivity of cerebellar connections is a common feature of tremulous disorders.
Many recreational and elite runners participate in distance races each year. When these events are conducted in hot or cold conditions, the risk of environmental illness increases. However, exertional hyperthermia, hypothermia, dehydration, and other related problems may be minimized with pre-event education and preparation. This position stand provides recommendations for the medical director and other race officials in the following areas: scheduling; organizing personnel, facilities, supplies, equipment, and communication; providing competitor education; measuring environmental stress; providing fluids; and avoiding potential legal liabilities. This document also describes the predisposing conditions, recognition, and treatment of the four most common environmental illnesses: heat exhaustion, heatstroke, hypothermia, and frostbite. The objectives of this position stand are: 1) To educate distance running event officials and participants about the most common forms of environmental illness including predisposing conditions, warning signs, susceptibility, and incidence reduction. 2) To advise race officials of their legal responsibilities and potential liability with regard to event safety and injury prevention. 3) To recommend that race officials consult local weather archives and plan events at times likely to be of low environmental stress to minimize detrimental effects on participants. 4) To encourage race officials to warn participants about environmental stress on race day and its implications for heat and cold illness. 5) To inform race officials of preventive actions that may reduce debilitation and environmental illness. 6) To describe the personnel, equipment, and supplies necessary to reduce and treat cases of collapse and environmental illness.