Biomedical subjects
Publications and source records attributed to S J Humphrey.
A novel device for monitoring gait, which can be used in confined spaces, is described. In addition to distance/time assessment of gait, it measures foot separation whilst walking. A field trial illustrates its potential in the investigation of falls.
During July 1989, four cases of Salmonella enteritidis (later identified as PT24) infection were reported by laboratories in Bristol. All those infected had dined at a restaurant in the city. An epidemiological investigation revealed that a number of restaurant staff and 56 customers who had completed a questionnaire had also been ill with gastrointestinal illness. An association was found between illness and eating egg mayonnaise. A 'Combi-oven' egg-cooking technique has been identified as the most likely cause of this outbreak. In view of the widespread commercial use of this cooking method the evidence related to this outbreak is given in detail.
The Lamtec agent monitor is a compact anaesthetic analyser designed to measure halothane, isoflurane and enflurane. It shows good linearity and stability. The faster model can be used for end-tidal measurements up to 25 breaths per minute. Calibration using a standard of the gas to be measured is recommended.
Minoxidil and other potent vasodilators cause coronary arterial injury, right atrial hemorrhagic lesions, and subendocardial necrosis in dogs. This paper discusses the pathogenesis of coronary arterial and right atrial lesions associated with minoxidil in the dog. Acute coronary vascular injury characterized by segmental medial hemorrhage and necrosis and perivascular inflammation occurred only during the first few days of treatment, after which tolerance to further acute injury developed. At 30 d or more of treatment, coronary vascular injury was characterized by perivascular fibrosis rarely attended by medial distortion or hyperplasia and subintimal thickening, changes consistent with responses to previous injury. Right atrial hemorrhagic lesions, unlike coronary vascular injury, often became progressively more extensive with continued treatment. At 3 d, atrial hemorrhage and inflammation were confined to the subepicardium of the right atrium, evidently around affected subepicardial branches of the right coronary artery. At 30 d, fibrovascular proliferative right atrial lesions (granulation tissue with evidence of continual hemorrhage) extended from the epicardium to the myocardium, with eventual replacement of the atrial wall by mature connective tissue at 1 yr of treatment. Minoxidil-induced cardiovascular lesions were not prevented by treatment with a beta-blocker (propranolol), or an alpha-blocker (dibenzylene), or by sympathetic neural activity suppression (surgical sympathectomy or constant carotid sinus nerve stimulation), suggesting that the sympathetic response to the pharmacologic activity of minoxidil was not responsible for the induction of the cardiovascular lesions. Minoxidil-related vascular lesions were confined to the most pharmacologically responsive segment of the arterial system, the coronary arteries, suggesting that medial injury may have been associated with tensile changes in the arterial wall.
To define the role of endogenous prostaglandin (PG) synthesis in the vasodilator response to minoxidil (MNX), whole body and regional hemodynamics were measured in conscious, MNX-pretreated dogs before and after the administration of the cyclooxygenase inhibitor indomethacin (INDO). Twenty minutes after an i.v. dose of 2.0 mg/kg, INDO did not affect the reductions in mean arterial pressure and total peripheral resistance achieved with 1.0 mg/kg of MNX i.v. INDO appeared to selectively reverse MNX's vasodilation in the skin and stomach, as vascular resistance in these two tissues increased to pre-MNX levels. Since INDO also exerts a selective vasoconstriction in the skin and stomach of conscious, nonpretreated dogs (Humphrey and Zins, 1983), the fact that skin and stomach resistances were near baseline with this drug combination implies that MNX continues to exert a net vasodilation in these vascular beds. In contrast to INDO's negligible hemodynamic interactions, MNX's vasodilation was nearly completely reversed by continuous i.v. infusions of the direct vasoconstrictor arginine vasopressin (ADH) administered at a mean dose of 35 mU/kg/min. MNX's reversal by ADH was not matched by maximally effective i.v. infusions of the alpha-adrenergic agonist norepinephrine at a mean dose of 0.4 micrograms/kg/min. These results indicate that the sustained peripheral vasodilation seen with MNX in the conscious dog is not dependent upon the synthesis of endogenous, PG-like dilator substances, as defined by concomitant INDO administration.
GABA antagonists blocked, and diazepam potentiated, inhibition of spontaneous sympathetic activity elicited by electrical stimulation of classic midline medullary depressor sites. Picrotoxin often converted inhibitory effects of raphe stimulation into sympathoexcitatory responses. Serotonin antagonists blocked these sympathoexcitatory responses. The midline medullary raphe complex is heterogeneous in respect to autonomic function with sympathoinhibitory elements mediated at least in part by GABA and sympathoexcitatory pathways mediated by serotonin.
The involvement of gamma-aminobutyric acid (GABA) in the vagal-stimulated reflex inhibition of sympathetic nerve discharge (SND) was investigated in the cat. Computer summation was used to assess the sympathoinhibitory response to vagal afferent stimulation and the resultant changes seen with agents known to effect GABAergic neurotransmission. The GABA antagonists picrotoxin and bicuculline at 0.25 to 1.0 mg/kg i.v. attenuated the vagal sympathetic inhibitory response, but increased the 1:1 locking of SND to the arterial pulse. Conversely, the GABA agonist diazepam at 0.3 mg/kg i.v. potentiated the vagal sympathoinhibition, reduced total SND and diminished SND locking to the arterial pulse. Picrotoxin also blocked the vagal sympathoinhibitory response in midcollicular transected cats and when applied topically to the dorsal brain stem. Midcollicular transection forestalled the irregular SND spiking normally seen with picrotoxin in the intact cat, thus resulting in improved 3 cycle/sec SND periodicity. None of these drug-induced changes effected the SND shutoff response to vasopressor tests, however. These results suggest that GABA plays a role in the SND inhibitory response to vagal afferent stimulation in the brain stem, independent of the sinoarterial baroreceptors, and may also be involved in the entrainment of SND to the arterial pulse.
Two trials of an electronic thermometer (Rite Time), designed to record and interpret basal body temperature (BBT) patterns in normal ovulating women, are described. A total of 140 menstrual cycles from 34 women, who used the thermal or symptothermal methods of natural family planning, were studied. Rite Time gave a signal for the start of the infertile period in 117 cycles, of which 114 (97%) appeared to have occurred at appropriate times. Further studies using hormonal and ultrasound reference points for ovulation were carried out in 21 cycles. Rite Time generally produced BBT patterns of quality acceptable for interpretation of the periovulatory BBT shift. About one-half of the volunteers said that they would be willing to replace their conventional charting methods with Rite Time.
The possible role of L-glutamic acid (L-glu) as a neurotransmitter of baroreceptor afferent neurons was investigated in the cat by monitoring the changes in three indices of baroreceptor function seen with the L-glu antagonists L-glutamic acid diethyl ester (GDEE) and 1-hydroxy-3-amino-pyrrolidone-2-(HA-966). Baroreceptor function was determined from a) the computer summed inhibition of sympathetic nerve discharge (SND) evoked by electrical stimulation of vagal baroreceptor afferent pathways, b) the locking of SND to the cardiac cycle, and c) the sympathoinhibitory response to i.v. pressor doses of phenylephrine. Direct bilateral microinjections of GDEE (20 micrograms) and HA-966 (4 micrograms) into the region of the nucleus tractus solitarii (NTS) resulted in immediate, marked reductions in the SND inhibitory response to vagal stimulation, a loss in SND locking to the cardiac cycle, a shift in the arterial pulse/SND phase relation, and a diminished sympathoinhibitory response to phenylephrine. Control microinjections of isotonic saline (1 mu 1/NTS) were devoid of these effects. The vagal induced sympathoinhibitory response was restored after NTS microinjections of GDEE by increasing the intensity of the vagal stimulus, or by directly stimulating the NTS injection site, suggesting that the impairment in baroreceptor function seen with this L-glu antagonist was independent of mechanical or local anesthetic effects. These data strongly suggest that L-glu may act as a neurotransmitter of baroreceptor afferent neurons in the NTS of the cat.
The interactions between baroreceptor and sympathetic pathways were determined in anesthetized cats using computer summation techniques. Electrical stimuli applied to baroreceptor afferent nerves produced an early and late period of inhibition of sympathetic nervous discharge (SND) recorded from the external carotid or inferior cardiac nerves. The late period of baroreceptor-induced inhibition summated algebraically with the cardiac-locked slow wave of SND during all phases of the cardiac cycle. Increases in the intensity of baroreceptor stimulation resulted in an increase in the amplitude and duration of the late inhibition. Alterations in the periodicity of SND failed to effect the late phase of inhibition. Picrotoxin blocked the late period of baroreceptor-induced inhibition but enhanced the cardiac locking of SND. These data indicate that the late period of inhibition reflects the ability of afferent nerves to modulate the amplitude of central sympathetic outflow, regardless of its periodicity. In addition, the central baroreceptor pathways involved in amplitude modulation and temporal locking of SND to the cardiac cycle are distinct and are located at the level of the brain stem. A spinal component of baroreceptor-induced sympathoinhibition is also described.
The effect of alpha-2 adrenergic receptor antagonists on sympathetic nerve discharge (SND) recorded from the external carotid and splanchnic nerves were studied in baroreceptor-denervated cats. Low i.v. doses of piperoxane and rauwolscine dramatically increased SND and produced a concomitant rise in mean arterial pressure and heart rate. High doses of piperoxane also resulted in an increase in SND. High doses of rauwolscine, however, markedly reduced mean arterial pressure, heart rate and SND. The pressor response to i.v. norepinephrine was greatly attenuated by high doses of rauwolscine and slightly reduced by piperoxane. Piperoxane failed to alter SND in catecholamine-depleted animals. In vitro binding experiments indicated that piperoxane and rauwolscine bound selectively to the alpha-2 adrenergic receptor and had little affinity for alpha-1 receptor sites. In addition, rauwolscine displaced [3H]LSD binding. These data indicate that low doses of the alpha-2 receptor antagonist piperoxane and rauwolscine act centrally to increase SND. In addition, the nature of the interactions between central noradrenergic neurons and neurons involved in the genesis of sympathetic nerve activity is discussed.
Systemic hemodynamics and blood flow were measured in conscious beagle dogs treated with the nonsteroidal antiinflammatory agent indomethacin. Twenty minutes after 2 mg/kg of indomethacin i.v., mean arterial blood pressure increased 5%, but cardiac output fell 24%, due to a decline in heart rate (-10%) and stroke volume (-18%). Small nonsignificant reductions in total bone, coronary, spleen, renal, and brain blood flow paralleled this fall in cardiac output. Larger, statistically significant reductions in arterial perfusion were seen in the skin (-30%), stomach (-47%), and small intestine (-27%). The corresponding 83, 101, and 38% increases in vascular resistance in these tissue beds largely accounted for the 41% increase in total peripheral resistance with indomethacin. Vascular resistance increased slightly in the vehicle control group due to reduced skeletal muscle blood flow seen in both treatment groups. Ovarian and thyroid blood flow also decreased with indomethacin. Indomethacin thus exerts a relatively specific vasoconstriction in the skin and upper gastrointestinal tract of the conscious dog.
A series of 1-[1-(3,4-dimethoxy-1H-2-benzopyran-1-yl)alkyl]-4-arylpiperazines that shows hypotensive activity in the conscious rat has been investigated. Structure-activity relationships are described. A typical example that was investigated in greater detail is 1-[2-(3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)ethyl]-4-(4-fluorophenyl)piperazine. This compound decreases sympathetic nerve activity recorded from the external carotid and splanchnic nerves of baroreceptor-denervated cats and, therefore, has a central component to its mechanism of action. It also blocks pressor effects of norepinephrine and phenylephrine and is thus an alpha-adrenergic antagonist. Binding data characterize this as alpha 1-adrenergic receptor blockade.
The effects of serotonin (5-HT) receptor agonists and antagonists on sympathetic nervous discharge (SND) recorded from the external carotid and splanchnic nerves were studied in baroreceptor-denervated cats. Intravenous administration of the 5-HT antagonists methysergide (0.025-1.6 mg/kg), metergoline (0.01-0.32 mg/kg), cyproheptadine (0.05-1.6 mg/kg) and cinanserin (0.2-6.4 mg/Kg) was associated with a prolonged dose-related inhibition of SND. Maximum reductions in SND produced by methysergide, metergoline, cyproheptadine and cinanserin were 90, 72, 71 and 50%, respectively. In contrast, a progressive increase in SND was observed in vehicle control animals. Methysergide, metergoline and cyproheptadine failed to reduce SND in cats pretreated with the 5-HT synthesis inhibitor p-chlorophenylalanine. Clonidine (20 micrograms/kg i.v.) significantly inhibited SND (-73%) in p-chlorophenylalanine-treated cats. The selective 5-HT agonists 5-methoxydimethyltryptamine and lisuride also reduced SND in a dose-dependent manner. The time course of the depressor effects of 5-methoxydimethyltryptamine and lisuride correlate well to their ability to inhibit 5-HT cell firing. These data indicate that 5-HT agonists which act presynaptically to inhibit 5-HT cell firing and antagonists which act postsynaptically to block the effect of synaptically released 5-HT both mediate a central reduction in SND. It is concluded that central 5-HT neurons facilitate transmission in central sympathetic pathways.
The effects of alpha-adrenergic receptor antagonists on sympathetic nervous discharge (SND) recorded from the external carotid and splanchnic nerves were studied in baroreceptor intact and denervated cats. Prazosin (50 microgram/kg, i.v.) produced a rapid fall in mean arterial pressure (MAP) and no significant change in heart rate (HR) in baroreceptor denervated cats. Prazosin administration was also associated with a prolonged inhibition of SND. Nerve activity was significantly reduced within 5 min of prazosin administration remained depressed throughout the 2 h observation period. Like prazosin, WB-4101 (0.5 mg/kg, i.v.) also produced significant reductions in MAP and SND. In addition, WB-4104 produced a transient bradycardia. The decreases in MAP and SND were reversed by piperoxane (0.5 mg/kg, i.v.). Both prazosin and WB-4101 inhibited the pressor response to i.v. norepinephrine. In baroreceptor intact cats, prazosin decreased MAP and SND, but did not affect HR. In contrast, phentolamine (1 mg/kg, i.v.) decreased MAP but increased SND and HR. These data indicate that the sympatholytic action of WB-4101 and prazosin results from a centrally mediated reduction in SND as well as a peripheral blockade of alpha-adrenergic receptors. These data further suggest that noradrenergic neurons normally facilitate the outflow of sympathetic nerve activity from the central nervous system.
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