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Biomedical subjects

R Noble

Publications and source records attributed to R Noble.

At least 37 records · Page 2Linked to original sources

The effects of ingestion time of gliclazide in relationship to meals on plasma glucose, insulin and C-peptide levels.

The effect of altering the timing of gliclazide administration in relation to a meal was studied in ten type 2 (non-insulin dependent) chronically treated diabetics. Gliclazide was given 30 min before, at the start of and 30 min after breakfast or omitted altogether. Plasma gliclazide was present at greater than 2 mg/l throughout the study periods. Administration at 30 min after the meal significantly delayed the time to peak for plasma gliclazide. No significant difference was noted in plasma glucose, insulin or c-peptide patterns with any protocol. It is concluded that, in clinical practice, with chronically treated diabetics the timing of gliclazide ingestion in relation to meals is not critical.

Aged↗

Executive performance: the demands of the 1990s.

Top executives will be required to have strong leadership skills, combined with solid communication and team-building skills, to move their organizations through a decade that will promise tight fiscal constraint, increasing involvement in the decision-making process from medical staff, trustees, government officials and facility personnel. The evaluation of the chief executive officer (CEO) will continue along traditional lines with the development of goals and objectives in defined areas of accountability. There will, however, be increased emphasis on the development of measurable standards, and the CEO's ability to lead the organization, motivate the organization's people resources and reallocate resources to meet the organization's mission and the health care needs of the community.

Canada↗

Determinants of the pressor effect of phenylpropanolamine in healthy subjects.

Phenylpropanolamine (PPA) is frequently used in over-the-counter diet aids and cold medicines, In view of concern about the safety of this sympathomimetic agent, we undertook a double-blind, multicenter clinical trial to determine the factors that influence the pressor effect of short-term oral administration of PPA in healthy individuals. Eight hundred eighty-one healthy individuals in four categories of body weight were randomized to receive placebo capsules three times per day (n = 286), a 75-mg sustained-release PPA hydrochloride preparation once per day (n = 296) followed by two doses of placebo capsules, or a 25-mg immediate-release PPA hydrochloride preparation three times per day (n = 299). The median age of the study population was 28 years, 56% were men, 73% were white, and 47% were in excess of 30% above their ideal body weight. Measurements of pulse rate and supine and standing blood pressure were made 11 times during the day of PPA administration. A statistically significant but clinically unimportant pressor effect for the short-term administration of PPA was observed. The effect occurred in the first 6 hours after administration and was greater in the sustained-release group. Significant independent determinants of the pressor effect of PPA were baseline diastolic blood pressure, baseline body weight, and treatment.

Adolescent↗

Descending influences on the cutaneous receptive fields of postsynaptic dorsal column neurones in the cat.

1. The influence of activity in descending systems on the cutaneous receptive field properties of postsynaptic dorsal column (PSDC) neurones has been investigated in chloralose-anaesthetized cats. The main aim of the study was to determine whether the receptive field boundaries of PSDC neurones are under the control of systems descending from the brain. 2. Single-unit recordings were made from the ascending axons of PSDC units in the dorsal columns. Receptive fields were analysed using light tactile and noxious mechanical and thermal stimuli, both before and during a reversible block of spinal conduction produced by cooling the cord rostral of the recording site. 3. The light tactile excitatory fields of PSDC neurones were largely unaffected by the cold-block procedure. 4. In contrast, both the sensitivity of PSDC neurones to noxious stimuli and the area of skin from which they could be effectively excited by such stimuli were found to be profoundly modified by interruption of descending activity. Two-thirds of the units excited by noxious pinch responded more vigorously in the cold-blocked state and one-half from an expanded area of skin. Responses to noxious radiant heat were similarly modified. 5. Inhibition evoked in PSDC neurones, whether by light tactile or noxious stimuli, involved predominantly segmental mechanisms since it remained effective in the cold-blocked state. 6. It is concluded that neurones of the PSDC system are amongst those dorsal horn neurones with receptive field geometries which may be modified by activity in descending systems.

Animals↗

Spatial spread of in-field afferent inhibition in the cat's spinocervical tract.

1. Extracellular microelectrode recordings were made from twenty-three spinocervical tract (SCT) cells in the lumbar spinal cord of cats anaesthetized with chloralose and paralysed with gallamine triethiodide. Excitation and inhibition of the cells were elicited by applying small brief (4 mN, 60 ms) localized jets of air to the clipped hair in and around the receptive fields. 2. Receptive field extents ranged from 40 to 180 mm. Excitation occurred in the period 30-130 ms after the start of the stimulus, and in-field afferent inhibition from 130 ms up to 700 ms or more. The inhibition was manifest as a reduction in background discharge and as a reduction in responsiveness to a test stimulus which followed a conditioning stimulus. 3. When the conditioning stimulus was spatially separated from the test stimulus, the degrees of in-field afferent inhibition depended on the spatial separation, even when both were within the excitatory receptive field. The spatial spread of in-field afferent inhibition was limited to 100 mm or less. 4. In two units only, afferent inhibition was produced from a narrow strip just outside the excitatory receptive field. In the other units, it could only be produced from within the excitatory receptive field. 5. The results suggest that the inhibitory input to SCT cells is organized in subdomains no more than 100 mm across, which may correspond to the receptive fields of interneurones between the primary afferent fibres and the SCT cells.

Afferent Pathways↗

Subjective profile of phenylpropanolamine: absence of stimulant or euphorigenic effects at recommended dose levels.

A total of 837 healthy volunteers presenting with various degrees of obesity participated in a large-scale, double-blind, placebo-controlled evaluation of the subjective effects of phenylpropanolamine (PPA), with particular attention to measurement of the euphoriant or stimulant potential of therapeutic doses of the compound. Dosage forms studied were PPA 75 mg sustained release, PPA 25 mg, and placebo. Subjects were recruited from four independent clinical sites. At each site, subjects were stratified according to degree of overweight (normal, mildly overweight, moderately overweight, or severely overweight) and randomly assigned to one of the three drug treatment regimens. Subjective effects were measured 11 times during the 12-hour experimental session using a short-form version of the Addiction Research Center Inventory. Data analysis did not indicate discernible subjective effects that would differentiate PPA from placebo, but did show typical circadian fluctuations. These results provided evidence that therapeutic doses of PPA do not produce the euphoriant or "stimulant" subjective effects that characterize drugs of abuse.

Adolescent↗

Cutaneous excitatory and inhibitory input to neurones of the postsynaptic dorsal column system in the cat.

1. In chloralose-anaesthetized cats single-unit microelectrode recordings were made from axons in the dorsal columns, at the lumbar level, identified as belonging to the postsynaptic dorsal column (PSDC) system. 2. Excitatory and inhibitory receptive field arrangements of a sample of seventy-five PSDC neurones were examined in detail using natural cutaneous stimuli. 3. The sample was characterized by a high degree of convergent input: 80% of units were activated by both light tactile and noxious mechanical stimuli and more than half of those examined were excited by noxious radiant heat. In addition, three-quarters of the units had inhibitory receptive fields on the ipsilateral limb. 4. Twenty-three units (27%) were influenced by input from areas of both hairy and glabrous skin covering the foot and distal limb. Neurones in this group had complex receptive fields, many of which occupied several discontinuous areas of skin. Background and evoked activity of these units could frequently be inhibited by light tactile and/or noxious stimuli. Their inhibitory receptive fields occupied small areas of skin overlapping or adjacent to excitatory fields. 5. Fifty-two units (73%) had receptive fields restricted to areas of hairy skin on the thigh and upper hindlimb. Half the units in this group had coextensive low- and high-threshold excitatory areas but about one-third had a concentric receptive field organization; a high-threshold excitatory component extending beyond, or around, a central low-threshold area. The discharge of these units could be inhibited only by light tactile stimuli. Their inhibitory receptive fields covered extensive areas of skin, sometimes completely surrounding the excitatory field. 6. The complex receptive field arrangements observed for neurones of the postsynaptic dorsal column system are discussed in relation to previous observations on dorsal horn neurones of other ascending tracts.

Action Potentials↗

A controlled clinical trial of the cardiovascular and psychological effects of phenylpropanolamine and caffeine.

Two hundred eighty-eight healthy normotensive volunteers with various degrees of obesity participated in a double-blind, placebo-controlled evaluation of the acute effects of phenylpropanolamine hydrochloride (PPA) and caffeine on blood pressure, pulse, and subjective effects. Dosage forms studied were PPA 75 mg sustained-release (SR), PPA SR 75 mg with caffeine 200 mg, caffeine 200 mg, and placebo. Data analysis indicated no significant cardiovascular or subjective effects due to PPA. Caffeine, however, was associated with statistically reliable though clinically insignificant changes from baseline diastolic blood pressure in both supine and standing positions. The rank order of the change indicated larger increases for the subjects who received caffeine, either alone or in combination with PPA, as compared with those who received PPA alone or placebo. No statistically significant differences between PPA and placebo were observed. Subjects in the heavier weight categories had higher blood pressure levels throughout the session as compared with those of normal weight. There was no difference among the study groups in subjective effects. These results provide evidence supporting the safety of currently recommended doses of sustained-release PPA, either alone or in combination with small doses of caffeine in healthy individuals.

Adult↗

Relationships between hair-follicle afferent terminations and glutamic acid decarboxylase-containing boutons in the cat's spinal cord.

Axoaxonic synapses are common features of hair-follicle afferent boutons. We have attempted to discover the identity of the neurotransmitter in the associated axon terminals by combining intra-axonal labelling of hair-follicle afferent axons with immunocytochemistry in a correlated light and electron microscopical study. Boutons containing glutamic acid decarboxylase, an enzyme responsible for the synthesis of the inhibitory transmitter gamma-aminobutyric acid, formed synaptic-like associations with hair-follicle afferent boutons. This suggests that hair-follicle afferent axons can be inhibited presynaptically.

Animals↗

Comparative efficacy and safety of ceftizoxime, cefotaxime and latamoxef in the treatment of bacterial pneumonia in high risk patients.

One hundred and thirty-five patients with bacterial pneumonia who had risk factors (alcoholism, chronic obstructive pulmonary disease, corticosteroid therapy diabetes mellitus, advanced age, solid tumours) were randomly allocated in a double-blind fashion to receive either ceftizoxime (2-4 g every 8 h), cefotaxime (1-2 g every 4 h), or latamoxef (2-4 g every 8 h). Of the 84 patients evaluable for efficacy, clinical cure was achieved in 91%, 85%, and 89% of ceftizoxime- (20/22), cefotaxime-(23/27), and latamoxef-treated (31/35) patients, respectively. Adverse reactions occurred in one of 45 ceftizoxime-treated patients, one of 43 cefotaxime-treated patients, and seven of 47 latamoxef-treated patients. Abnormal laboratory values during therapy were seen in 50% of latamoxef-treated and 43% of cefotaxime-treated patients and in 29% of ceftizoxime-treated patients. Hypoprothrombinaemia occurred in five latamoxef-treated patients and one of these patients experienced an episode of haematemesis. In this study, ceftizoxime, cefotaxime, and latamoxef were similarly effective; however, the incidence of side effects was most frequent with latamoxef.

Aged↗

Excitatory actions of single impulses in single hair follicle afferent fibres on spinocervical tract neurones in the cat.

1. In cats under chloralose anaesthesia single dorsal root ganglion cells with axons innervating hair follicles were stimulated intracellularly to produce single impulses. At the same time single spinocervical tract (s.c.t.) neurones were recorded extracellularly, from their axons in the upper lumbar cord. 2. When the receptive field of the afferent fibre was contained within the impulse firing zone of the s.c.t. cell, a single afferent impulse increased the probability of firing of the neurone. In thirty-nine pairs of units, where the afferent fibre had a group II conduction velocity, coupling was very efficient and for seventeen pairs the single afferent impulse produced one or more impulses in the s.c.t. cell in at least 90% of trials. The mean number of impulses evoked in s.c.t. cells by a single group II afferent impulse was 1.47. The latencies of the impulses ranged from 1.5 to 14.0 ms, with times to peak and total durations of 2.5-17.5 ms and 4.5-28.0 ms respectively. For two pairs of units where the afferent fibre had a group III conduction velocity the effectiveness of single afferent impulses was much less and the latencies, but not the durations, of the impulses were longer (12 and 17 ms). 3. When the receptive field of the hair follicle afferent fibre was outside, but close to, the firing zone of the s.c.t. neurone there was no indication that single afferent impulses affected the probability of neuronal discharge for thirteen of fifteen pairs of units. Weak excitation was observed in two pairs and this was clear only when two or more afferent impulses were employed. 4. There was a tendency for hair follicle afferent fibres with their receptive fields at or near the centre of the s.c.t. cell's firing zone to be most effective, producing shorter latency responses with more impulses at higher frequencies. When the afferent's field was peripherally located in the s.c.t. neurone's firing zone there was a wide range of responses but these included those with the longest latencies and very few impulses. 5. The results are discussed with reference to previous work on the spinocervical tract and to the known actions of single impulses on other neuronal types. Suggestions are made for the possible excitatory neuronal circuits linking hair follicle afferent fibres to the s.c.t. neurones.

Action Potentials↗

Actions of trains and pairs of impulses from single primary afferent fibres on single spinocervical tract cells in cat.

1. In cats under chloralose anaesthesia single lumbosacral dorsal root ganglion cells of hair follicle afferent fibres were stimulated intracellularly to produce trains or pairs of impulses. At the same time, single spinocervical tract (s.c.t.) neurones were recorded extracellularly, from their axons in the upper lumbar spinal cord. Afferent fibre-neurone pairs were chosen in which the receptive field of the fibre was contained within the excitatory receptive field (firing zone) of the neurone. 2. Trains of impulses of 2.0 Hz were less effective in increasing the probability of s.c.t. cell firing than trains at 0.67 Hz, and this latter rate was usually less effective than trains at 0.33 Hz. 3. Successive responses to individual members of a train of hair follicle afferent impulses were variable. In some pairs of units succeeding responses declined until a fairly consistent plateau was reached. In others there was no decline and the responses remained irregular. 4. Pairs or short trains of impulses revealed two phenomena: over the first 5 ms or so following an impulse in a group II hair follicle afferent fibre, a second or small group of impulses produced a greater response from the s.c.t. neurone but at intervals of 25-200 ms there was a profound depression of the responses evoked by the second member of a pair of impulses. For A delta afferent fibres the early facilitation lasted for at least 25 ms. 5. It is concluded that a single impulse in a single hair follicle afferent fibre from within the excitatory receptive field of a s.c.t. neurone has complex actions on transmission through that neurone. An initial excitatory influence is followed by a long-lasting depression that influences transmission through the system for at least 1500 ms. Possible mechanisms underlying this depression are discussed.

Action Potentials↗

An intracellular study of spinocervical tract cell responses to natural stimuli and single hair afferent fibres in cats.

1. Intracellular recordings were made from spinocervical tract (s.c.t.) neurones in cats anaesthetized with chloralose and paralysed with gallamine triethiodide. 2. In one series of experiments the cells' receptive fields were examined with the use of natural stimuli. Hair movement within the impulse firing zone of the cell evoked excitatory post-synaptic potentials (e.p.s.p.s) from which impulses were generated; in addition, in the majority of s.c.t. cells tested, areas were found within the impulse firing zone where hair movement elicited both e.p.s.p.s and inhibitory post-synaptic potentials (i.p.s.p.s). Outside the firing zones, both regions evoking e.p.s.p.s and regions evoking i.p.s.p.s were observed in all neurones examined in detail (ten cells). The responses of these neurones to a variety of natural stimuli showed the receptive fields of s.c.t. cells to be more complex than previously thought. 3. In a second series of experiments, intracellular recordings from s.c.t. cells were combined with intracellular recording and stimulation of single dorsal root ganglion cells belonging to group II hair follicle afferent fibres. When the afferent fibres innervated skin within the impulse firing zone of the s.c.t. cell, single afferent impulses evoked e.p.s.p. complexes consisting of both mono- and polysynaptic components; no i.p.s.p.s were observed in response to single hair follicle afferent impulses or to trains. Although the monosynaptic e.p.s.p. component was often large and had a fast rise time, s.c.t. cell impulses usually arose from the later components. Afferent fibres innervating the central region of the s.c.t. cell firing zones tended to evoke relatively large e.p.s.p.s with fast rise times. The rise times and amplitudes of the e.p.s.p.s evoked by afferent fibres from the periphery, however, varied between afferent fibres but included the slowest and smallest in the total sample of synaptically coupled pairs. Afferent fibres from outside the s.c.t. cell's firing zone were usually ineffective in setting up post-synaptic potentials, but one group III hair follicle afferent fibre, from an inhibitory receptive field component, gave rise to i.p.s.p.s. 4. The effects of pairs and trains of afferent impulses at intervals of 10, 25, 50, 100 and 200 ms were examined. At 25 ms the response to the second afferent impulse was profoundly less than that evoked by the first and was still substantially reduced at 200 ms interval. In all synaptically coupled pairs studied, the e.p.s.p. complex evoked by the second afferent impulse was smaller in amplitude than that evoked by the first.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

Receptive field profiles and integrative properties of spinocervical tract cells in the cat.

The receptive fields of sixteen spinocervical tract (s.c.t.) cells whose responses were recorded extracellularly were mapped using discrete and uniform jets of air given at equally spaced locations on the clipped fur of cats anaesthetized with chloralose. All the cells whose receptive fields were on the thigh or upper hind limb showed approximately unimodal gradients of sensitivity to stimulation within their excitatory receptive fields. The response magnitudes declined steadily as the stimuli were moved sequentially from the centres to the peripheries of the fields and abrupt edges were not found. Spatial summation from within the excitatory receptive field was studied in twelve s.c.t. cells. These cells showed a poor ability to summate the responses to two spatially separated air jets when these stimuli were applied simultaneously within their receptive fields. No significant summation was found in twenty-five out of thirty-one trials and in six of these trials (four cells) the responses were significantly reduced. Summation was found in six trials (four cells). Lack of summation or response reduction was more prevalent when the individual response levels were low (less than impulses stimulus-1). These results are discussed in relation to similar findings for cells of somatosensory relay nuclei and cortex.

Action Potentials↗

Relations between spinocervical and post-synaptic dorsal column neurones in the cat.

1. In chloralose-anaesthetized cats single-unit micro-electrode recordings were made at the lumbosacral level either from axons in the dorsolateral funiculus and dorsal columns, identified as belonging to the spinocervical tract (s.c.t.) or post-synaptic dorsal column (p.s.d.c.) pathway respectively, or from neurones in the dorsal horn similarly identified. 2. Attempts were made to show that s.c.t. and p.s.d.c. neurones had axons that bifurcated, so that they sent branches into both the ipsilateral dorsolateral funiculus and the dorsal columns. That is, that some, or all, of the presumed s.c.t. or p.s.d.c. axons were common to both populations. In addition, the effects of stimuli applied to the ipsilateral dorsolateral funiculus at C3 and C1 on the resting discharges of p.s.d.c. neurones were examined in order to determine the effectiveness of the link between the s.c.t. and the p.s.d.c. pathway. 3. Thirty-three s.c.t. units (twenty-six axonal recordings and seven soma-dendritic recordings) and thirty p.s.d.c. units (twenty-four axonal and six soma-dendritic recordings) were examined for bifurcating axons by electrically stimulating the dorsolateral funiculus at C3 and the dorsal columns at C4. None of the p.s.d.c. units could be antidromically activated from the ipsilateral dorsolateral funiculus with stimulus strengths up to 40 V or seventy times threshold for antidromic activation from the dorsal columns. Similarly, twenty s.c.t. units could not be activated antidromically from the dorsal columns at stimulus strengths up to 30 V or thirty times threshold for their antidromic excitation from the dorsolateral funiculus. Thirteen s.c.t. units were antidromically activated from the cervical dorsal columns, eight at seventeen or more times threshold for their activation from the dorsolateral funiculus and five at between two and nine times threshold. All s.c.t. units that were activated antidromically from both the cervical dorsal columns and the dorsolateral funiculus showed similar latencies for the two responses. 4. Twenty-five p.s.d.c. units were examined for the effects of ipsilateral dorsolateral funiculus stimulation on their resting activity. In thirteen, clear evidence of facilitatory effects from C3 were observed, whereas similar results were seen in only six of these units when C1 was stimulated and the effects were less. The facilitation had a latency of 3-16 ms and lasted for 6-22 ms. In all but one of the twenty-five units, stimulation at both C1 and C3 produced profound inhibition of the resting discharge that began at between 8 and 26 ms and lasted for up to 300 ms.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

Effects of hind limb nerve section on lumbosacral dorsal horn neurones in the cat.

The sciatic and saphenous nerves of one hind limb were sectioned in young adult cats anaesthetized with halothane. Between 19 and 55 days later, under chloralose anaesthesia, dorsal horn neurones in the L6 and L7 segments were recorded and their receptive field properties examined. In seven animals recordings were made from identified spinocervical tract, post-synaptic dorsal column and dorsolateral funicular neurones as well as from neurones that did not project through these pathways. Thirty-one neurones were intracellularly stained with horseradish peroxidase, and fifty-three were recorded extracellularly and located by reference to stained cells. In two animals (both 31 days after nerve section) no attempt was made to identify axonal projections of the dorsal horn neurones in order to avoid any effects of cervical cord search stimuli on the cells' properties, but all isolated extracellularly recorded units were examined. On the side ipsilateral to the nerve sections 143 units were recorded. In all experiments, neurones in the medial three-quarters of the dorsal horn had no discernible cutaneous, mechanosensitive receptive fields between 19 and 55 days after nerve section. There were only two exceptions to this generalization, one neurone being one of the most rostral cells in the sample (in caudal L5) and the other being one of the most caudal cells (in caudal L7). We present evidence to show that neither of these two neurones had inappropriate receptive fields in terms of the somatotopic organization of the dorsal horn. All other neurones with receptive fields on the skin were appropriately located in the somatotopic map laid out in the dorsal horn. There was no evidence for gross anatomical changes in the dendritic trees of dorsal horn neurones following sciatic and saphenous nerve sections. We have been unable to confirm that, following loss of cutaneous receptive fields by peripheral nerve section, dorsal horn neurones in adult cats acquire 'inappropriate' receptive fields. Possible reasons for this are discussed.

Animals↗

Extrinsic control of phasic supraoptic neurones in vitro: burst initiation and termination following brief changes in excitatory drive.

Experiments were performed to investigate the responses of phasic supraoptic cells in hypothalamic slices to brief (2-3 sec) changes in excitatory drive, induced by varying the level of local glutamate stimulation. A brief increase in excitation during a silent period immediately triggered a prolonged burst of firing, similar in duration to the ongoing phasic bursts. A transient decrease in excitation during a phasic burst evoked a protracted quiescence, reminiscent of a typical silent period. These results support the idea that in phasic cells the effects of brief synaptic inputs may be amplified in time to produce a prolonged change in electrical activity and associated hormone release.

Afferent Pathways↗

Effects of morphine and D-Ala, D-Leu enkephalin on the electrical activity of supraoptic neurosecretory cells in vitro.

Experiments were performed to investigate the effects of morphine and [D-Ala2, D-Leu5]enkephalin on supraoptic cells in hypothalamic slices in vitro. To ensure the presence of a steady background activity, the cells were recorded with glutamate-filled glass microelectrodes and the level of activity was controlled by selecting a suitable retaining current (0.1-9.8 nA). Under these conditions, supraoptic cells showed either the non-phasic (65%) or phasic (35%) firing pattern previously associated with oxytocin or vasopressin cells, respectively. During perifusion of the slice with morphine (10 microM), 10 out of 17 non-phasic supraoptic cells were profoundly inhibited, five cells showed no response and the remaining 2 cells were excited. Similarly with [D-Ala2, D-Leu5]enkephalin (10 microM), 11 out of 15 non-phasic cells were inhibited, 3 cells showed no response and 1 cell was excited. The inhibition produced by morphine or [D-Ala2, D-Leu5]enkephalin could be reversed by concomitant application of naloxone (10 microM). In contrast to the profound effects seen in the non-phasic cells, only 1 out of 13 phasic cells tested with either morphine or [D-Ala2, D-Leu5]enkephalin was inhibited. The remaining 12 phasic cells showed no change in either their overall firing rate or pattern of activity during opiate perifusion. These results provide further evidence that, in addition to their inhibitory effects within the posterior pituitary, opiates can directly suppress the electrical activity of magnocellular neurosecretory cells at the level of the hypothalamus. However, the absence of an opiate effect on the phasic cells might suggest that the action of opioid peptides within the hypothalamus would be exerted predominantly on the oxytocin, rather than the vasopressin cells.

Animals↗