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Biomedical subjects

R J Ross

Publications and source records attributed to R J Ross.

At least 91 records · Page 5Linked to original sources
PubMed1993

The effects of dexamethasone treatment on immunoreactive and bioactive insulin-like growth factors (IGFs) and IGF-binding proteins in normal male volunteers.

Glucocorticoids inhibit somatic growth in man and laboratory animals, and have long been regarded as suppressors of both stimulated GH secretion and insulin-like growth factor (IGF) activity. Recent evidence suggests, however, that glucocorticoids can be potent GH secretagogues in their own right with concomitant increases in circulating IGF-I levels. IGFs circulate tightly bound to a group of high-affinity binding proteins (IGFBPs) which modulate their actions. In order to investigate the effects of glucocorticoids on serum levels of IGFs and IGFBPs, normal male volunteers were sampled over 24-h periods before and directly after treatment with dexamethasone (2 mg twice daily) for 96 h. Following dexamethasone administration, all volunteers showed a marked increase in mean +/- S.E.M. IGF-I levels over the 24-h sampling period (292.2 +/- 31.8 before dexamethasone, 425.9 +/- 37 micrograms/l after dexamethasone, P < 0.005); there was no change in mean IGF-II levels. Integrated mean insulin levels were raised by dexamethasone treatment (50 +/- 4.6 before dexamethasone, 117 +/- 13.4 mU/l after dexamethasone, P = 0.002) and IGFBP-1 was significantly suppressed (42.9 +/- 8.2 before dexamethasone, 28.0 +/- 7.9 micrograms/l after dexamethasone, P < 0.001). IGFBP-2 levels were similarly suppressed after dexamethasone (319.5 +/- 24.5 before dexamethasone, 214.8 +/- 8.5 micrograms/l after dexamethasone, P = 0.002), and there was a significant increase in IGFBP-3 levels from 3.24 +/- 0.25 to 3.67 +/- 0.32 mg/l (P = 0.0153). Mean IGF bioactivity over the sampling period after dexamethasone was reduced by approximately 60% (0.93 +/- 0.39 before dexamethasone, 0.39 +/- 0.05 U/ml after dexamethasone, P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA.

Family studies of diabetes mellitus (DM) show that patients are more likely to have affected mothers than affected fathers. Since the inheritance of mitochondrial (mtDNA), unlike nuclear DNA, is exclusively maternal, could it be that defect(s) in mtDNA account for some cases of DM? Such defects have been associated with rare neurological syndromes, in some of which DM has been an accompanying feature. We have looked for glucose intolerance and for a previously known point mutation of mtDNA in a family, some of whose members have a multisystem disorder with DM but not neurological involvement. DNA samples were obtained from fourteen family members. The point mutation (affecting position 3243 in the tRNA leucine mitochondrial gene) was found in all three diabetic patients and post mortem tissues in the proband; it was also found in seven offspring of female patients. It was not found in the two children of the male proband. The contribution of this mutation to DM in general is not known but clinicians ought to be aware of the possibility, especially in families with multisystem disease and maternal transmission.

Adult↗
PubMed1992

Varying expressions of alerting mechanisms in wakefulness and across sleep states.

Alerting stimuli, such as intense tones, presented to cats in wakefulness (W) elicit the orienting response (OR) and/or the acoustic startle reflex (ASR) in conjunction with elicited ponto-geniculo-occipital waves (PGOE) from the lateral geniculate body (LGB) and elicited waves from the thalamic central lateral nucleus (CLE). Alerting stimuli presented during rapid eye movement sleep (REM) and non-rapid eye movement sleep (NREM) also elicit PGOE. We presented tones in W, REM and NREM to determine whether CLE could be obtained in sleep and to examine the patterns of responsiveness of PGOE and CLE across behavioral states. Also, we recorded ASR and OR and compared the response patterns of behavioral and central correlates of alerting. The subjects were 7 cats; all exhibited spontaneously occurring waves in LGB and CL. All cats exhibited PGOE and 5 cats exhibited CLE in W, REM and NREM. PGOE and CLE showed less evidence of habituation than did ASR and OR. The pattern of responsiveness of CLE across behavioral states was different from that found for PGOE, and spontaneous CL waves were much rarer than the LGB waves. ASR was elicited in 5 cats during W trials, and in 3 cats during REM trials. OR habituated rapidly in W and did not occur in REM and NREM. The data indicate that central mechanisms of alerting function in sleep states as well as in W and suggest that CLE and PGOE reflect activity in mechanisms underlying cortical desynchronization and visual processes which may act in concert during alerting.

Acoustic Stimulation↗
PubMed1992

Peripheral and central components of alerting: habituation of acoustic startle, orienting responses, and elicited waveforms.

Behavioral orienting (OR), the acoustic startle reflex (ASR), pontogeniculooccipital (PGO) waves in the lateral geniculate body, and midlatency auditory evoked responses (MLR) represent components of alerting. The habituation rate for each was examined to test the hypothesis that OR, ASR, and PGO waves have related underlying neural mechanisms and determine the similarity in responsiveness between elicited PGO waves (PGOE) and elicited waves in the thalamic central lateral nucleus (CLE), a site that yields MLR. PGOE and CLE waves did not habituate in amplitude after 120 tones; however, the pattern of responses for each waveform was different. OR and ASR significantly decreased amplitude across trials with OR exhibiting a faster, more pronounced decrement. Some separation exists between the peripheral (OR and ASR) and central (PGOE and CLE) components of alerting. PGO and CL waves may have common underlying neural mechanisms.

Animals↗
PubMed1992

Administration of human recombinant insulin-like growth factor-I to patients following major gastrointestinal surgery.

OBJECTIVE: The aim was to study the pharmacokinetic parameters and biological activity of a single dose of human recombinant IGF-I (rhIGF-I) administered to patients following major gastrointestinal surgery. DESIGN: A double blind placebo controlled externally randomized study of 30 patients; the study commencing 24 hours after major colonic or gastric surgery. MEASUREMENTS: After a baseline blood sampling day, IGF-I (40 micrograms/kg by single subcutaneous dose, n = 20) or placebo (n = 10) was administered and serum and urine samples collected over the ensuing 72 hours. Serum IGF-I, IGF-II, IGF binding proteins (IGFBP-1, IGFBP-3), GH and insulin were measured by radioimmunoassay. Serum IGF bioactivity was assessed using a validated porcine cartilage bioassay. Serum and urinary electrolytes were measured by standard methodology. RESULTS: Serum immunoreactive IGF-I levels peaked at 4 hours following injection of IGF-I (1.09 +/- 0.12 U/ml mean +/- SEM), remained elevated for 15 hours and returned to basal levels by 24 hours after injection. IGF bioactivity was increased by 57% 6 hours after IGF-I injection. Mean levels of IGFBP-1 and IGFBP-3, IGF-II and GH were unaffected by IGF-I administration. Insulin levels were suppressed at 30 minutes following injection of IGF-I compared with the placebo group (16.9 +/- 3.0 mU/I vs 32.3 +/- 7.1, P = 0.02); thereafter, there were no differences in insulin levels. The mean change in serum creatinine following IGF-I (-6.3 +/- 3.0 mmol/l) was significantly different from that in the control group (+7.2 +/- 6.2, P = 0.03). Creatinine clearance rose from a mean of 71.6 +/- 7.5 ml/min to 83.2 +/- 7.6 ml/min after IGF-I treatment (P = 0.02). In the IGF treated patients, cholesterol levels consistently fell (-0.20 +/- 0.05 mmol/l); this was not observed in the placebo group (+0.20 +/- 0.14, P = 0.006). Basal serum potassium levels in the IGF treatment group (4.1 +/- 0.1 mmol/l) fell to 3.8 +/- 0.1 at 4 hours (P = 0.002) and 3.6 +/- 0.1 at 10 hours (P = 0.001) returning to a level of 4.0 +/- 0.1 (P = 0.293) at 24 hours after injection. There were no other observed differences in serum or urinary electrolytes or serum free fatty acids and triglycerides. Pharmacokinetic parameters derived from baseline adjusted IGF-I measurements revealed a slow absorption of the administered dose with a Tmax of 5.0 +/- 0.43 hours and an elimination half-life of 10.8 +/- 1.2 hours. The computed volume of distribution was 0.33 +/- 0.05 I/kg and the clearance on average 25 ml/min. CONCLUSION: A single subcutaneous dose of IGF-I normalized circulating IGF-I levels in post-operative patients, was well tolerated and without side-effects. IGF bioactivity was increased and associated with a fall in serum cholesterol, potassium and creatinine levels and a rise in creatinine clearance. Further long-term studies are now required to assess the anabolic effects of rhIGF-I in this type of patient group.

Aged↗
PubMed1992

Operation Haven.

Explore the source record for details and available documents.

Humans↗
PubMed1991

Effects of stimulus intensity on elicited ponto-geniculo-occipital waves.

Waves similar to spontaneous ponto-geniculo-occipital (PGO) waves of paradoxical sleep (PS) in cats are elicited by tones and can be considered a form of evoked potential termed PGOE. The aims of the present experiment were to determine: (1) the effects of tone intensity on the probability of producing PGOE; (2) the effects of intensity on the amplitude and latency of PGOE across slow-wave sleep (SWS) and PS; (3) whether the effects of intensity on PGOE are similar to those on a particular form of auditory evoked potential known as the mid-latency response (MLR). Increasing the intensity of the stimulus from 60 to 100 in 10 dB increments resulted in increased probability, increased amplitude, and decreased latency of PGOE in both SWS and PS. This pattern was similar to published findings with MLR, and latencies of PGOE (roughly 60-100 msec) fell within the range of 'C wave' type of MLR recorded in intralaminar nuclei of the thalamus of cats. The possibility that PGOE and MLR share underlying mechanisms and represent the same phenomenon is discussed with particular attention to the function of the mechanisms during alerting and orienting.

Acoustic Stimulation↗
PubMed1991

The effects of changing state on elicited ponto-geniculo-occipital (PGO) waves.

Waves similar to ponto-geniculo-occipital (PGO) waves occurring spontaneously in the lateral geniculate body (LGB), pons, and occipital cortex during rapid eye movement (REM) sleep can be elicited in the LGB and the cortex by tones in waking (W), non-rapid eye movement sleep (NREM), and REM. In W, the elicited waves (PGOE) sometimes accompany orienting responses (OR). We have hypothesized that REM is a state resembling exaggerated "orienting" in part because spontaneous PGO waves similar to PGOE accompanying OR are constantly observed in REM. The present experiment tested whether: (1) PGOE and OR were strongly correlated in W across a large number of tone presentations as might be predicted if PGOE were central wave form markers for a state of orienting; and (2) recovery of responsiveness of PGOE to tones would then be greater in REM than NREM, as might be expected if REM but not NREM were a state in which central mechanisms of orienting were highly active. Tones were presented in W and then in REM and NREM to six cats in order to measure the degree of habituation of OR and PGOE simultaneously. PGOE and OR exhibited a degree of independence: the former were readily produced in W despite the rapid decline in OR across trials. Recovery in the amplitude of PGOE occurred in both NREM and REM. The recovery tended to be greater in REM than NREM, although this was not statistically significant. Refinements of the theory that REM represents a state of exaggerated internal orienting are discussed.

Acoustic Stimulation↗
PubMed1991

Pyridostigmine fails to increase either spontaneous or GHRH-stimulated GH secretion during day or night in growth hormone-insufficient children.

OBJECTIVE The aim of the study was to investigate whether pyridostigmine, a cholinesterase inhibitor which is thought to act at the hypothalamus to inhibit somatostatin secretion, would augment spontaneous or GHRH-stimulated serum GH levels in patients with GH-insufficiency. DESIGN Oral pyridostigmine 60 mg or placebo was administered at the start of a 9-h subcutaneous infusion of either GHRH (1-29)NH2 10 micrograms/kg/h or saline control. Studies were performed during the daytime (0900-1800 h) in five patients, and the night-time (2100-0600 h) in a further five. PATIENTS Ten short, pre-pubertal children (aged 6-11 years; eight boys) with growth hormone insufficiency were studied. MEASURES Blood for serum GH was sampled every 20 min, and analysed using the PULSAR program. RESULTS The subcutaneous infusion of GHRH 10 micrograms/kg/h increased mean serum GH levels (+/- SEM): by day 17.7(+/- 6.8) vs placebo 2.2(+/- 0.4) mU/l (P less than 0.01), and by night 26.9(+/- 3.3) vs 5.5(+/- 1.3) mU/l (P less than 0.05). There was a significant rise in mean 'baseline' GH concentration: by day 5.5(+/- 1.7) vs 1.0(+/- 0.0) mU/l (P less than 0.05); and night 8.2(+/- 2.7) vs 1.3(+/- 0.3) mU/l (P less than 0.05). Pyridostigmine failed to produce a significant overall increase in either spontaneous or GHRH-stimulated GH secretion by day or night, although there was a significant rise in mean GH levels during the 3 h following pyridostigmine administration in the morning: 4.4(+/- 1.1) vs 2.4(+/- 0.5) mU/l (P less than 0.001). GHRH or pyridostigmine given singly or in combination had no significant effect on the number of pulses. Side-effects attributable to pyridostigmine occurred in seven children. CONCLUSIONS Pyridostigmine, either on its own or as an adjuvant therapy in combination with GHRH, acts for only a brief time and does not offer any potential benefit in the management of children with short stature.

Abdominal Pain↗
PubMed1991

Levels of GH binding activity, IGFBP-1, insulin, blood glucose and cortisol in intensive care patients.

OBJECTIVE: To investigate levels of serum GH binding activity, insulin-like growth factor binding protein-1 (IGFBP-1), blood glucose, serum insulin, and cortisol in patients on the Intensive Therapy Unit. DESIGN: Case-control study of severely ill patients admitted to the Intensive Therapy Unit. PATIENTS: Six critically ill patients (51-78 years) who required ventilatory and nutritional support and six healthy age, sex, height and weight matched controls. MEASUREMENTS: Patients and controls were studied for two 24-hour periods; the patients before and after commencing parenteral nutrition, the controls whilst fasted and on a second occasion when fed a diet equal in protein and calories to that of the patients' parenteral nutrition. Samples were taken hourly for measurement of IGFBP-1, blood glucose, serum insulin and cortisol. Growth hormone binding activity was measured at 0 hours. RESULTS: Blood glucose levels were higher in the patients than controls in both the fasted (mean +/- SEM 5.1 +/- 0.5 vs 3.8 +/- 0.2 mmol/l, P = 0.04) and fed states (10.1 +/- 1.6 vs 5.0 +/- 0.1 mmol/l, P = 0.02) and patients' insulin levels were also higher when fed (81.5 +/- 31.6 vs 24.2 +/- 4.8 mU/l, P = 0.046) although there were no significant differences between patients and controls when fasted. IGFBP-1 levels were inversely related to insulin levels in both the patients and controls; mean IGFBP-1 concentrations were higher in fasted patients than in controls (123 +/- 38 vs 52 +/- 9, P = 0.046) but when fed, both groups had similar mean levels. Serum GH binding activity was low in the patients and did not change with feeding. Mean 24-hour cortisol levels were higher in the patients than in controls, whether fasted or fed, and showed no nyctohemeral rhythm. CONCLUSIONS: We have previously reported that critically ill patients have low levels of IGF-I with augmented basal levels of GH. The present results demonstrate that these changes in the GH-IGF-I axis are associated with insulin resistance with respect to blood glucose and high levels of IGFBP-1 when patients are fasted. However, when fed, the inverse relationship of IGFBP-1 to insulin is preserved. Patients have low levels of GH binding activity and increased mean cortisol levels. Interventional studies in this patient group with GH and IGF-I must take account of these changes in binding protein and cortisol levels.

Abdomen↗
PubMed1991

The induction of a specific protease for insulin-like growth factor binding protein-3 in the circulation during severe illness.

The insulin-like growth factors (IGF-I and IGF-II) are almost completely bound in the circulation to specific binding proteins (IGFBPs). These IGFBPs appear to play a pivotal role in maintaining circulating levels and modulating the delivery of the IGFs to the tissues. A large proportion of the circulating IGFs are bound with high affinity to one of the binding proteins. IGFBP-3. The mechanism by which these IGFs are transferred from the circulatory pool to the tissue receptors is at present unclear. Recent studies in late pregnancy have demonstrated the presence of specific proteases which may modify the IGFBPs such that their affinities for the IGFs are reduced. In this paper, we have demonstrated the presence of a heat-sensitive cation-dependent proteolytic enzyme specific for IGFBP-3 in the serum of five severely ill patients. The activity of this protease was found to vary in these patients, becoming more apparent during fasting than when studied after commencement of parenteral nutrition, indicating that one of the influencing factors in the activity of this protease is the nutritional intake of the patient. Age- and sex-matched healthy adults were also studied in a similar protocol, but no proteolytic modification of any of the IGFBPs was found in any of the samples examined. As the levels of both IGF-I and IGF-II were found to be low in the patients, the presence of a circulatory protease suggests that this may be an adaptive response to increase the bioavailability of the IGFs and possibly to improve the nitrogen retention and counter the catabolic state in severe illness.

Aged↗
PubMed1990

REM sleep suppression by monoamine reuptake blockade: development of tolerance with repeated drug administration.

Drugs that block monoamine reuptake initially suppress rapid eye movement (REM) sleep in the cat and other species. Less is known about the effects of repeated drugs administration. Desipramine (DMI) and sertraline [1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1 -naphthylamine] (SER), which are relatively specific in blocking norepinephrine and serotonin reuptake, respectively, were each given to cats for approximately two and a half weeks. Six-hour sleep polygraphic records were obtained under the placebo condition, after acute drug administration, and again during chronic drug administration. DMI and SER both reduced REM sleep percentage acutely and in each case. Significant tolerance then developed. These actions of DMI and SER reflected changes in mean REM sleep episode duration as well as REM sleep episode number. Such differential effects of acute and chronic monoamine reuptake blockade on REM sleep behavior in the cat may ultimately be correlated with pharmacological changes at the receptor level.

1-Naphthylamine↗
PubMed1990

Effects of monoamine reuptake blockade on ponto-geniculo-occipital wave activity.

Norepinephrine (NE) and serotonin (5HT) likely inhibit the generation of ponto-geniculo-occipital (PGO) waves. Either desipramine (DMI) or sertraline (SER:1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthyl amine) was administered in the cat for 2.5 weeks to probe noradrenergic and serotonergic mechanisms, respectively. Placebo days were compared with the first day of drug and with days that followed 2.5 weeks of drug (chronic). PGO rates during REM sleep and the preceding transition period were significantly decreased by either chronic DMI or SER. Cat PGO waves resemble waves that accompany alerting to intense or novel stimuli in wakefulness. Depressive disorders in humans have features of hyperarousal; PGO wave suppression by antidepressant drugs may relate to clinical antidepressant actions.

1-Naphthylamine↗
PubMed1990

Subcutaneous growth hormone-releasing hormone augments pulsatile nocturnal GH release in GH-insufficient children, but may also raise basal GH secretion.

Growth hormone-releasing hormone (GHRH) when given s.c. to GH-insufficient children either as pulses, or once or twice daily, promotes linear growth. These treatment regimens, however, are not ideal as they require frequent drug administration and a significant proportion of patients do not show improved growth. We have now investigated the GH response to a nocturnal s.c. infusion of GHRH (1-29)NH2, at two dosages, 5 and 10 micrograms/kg/h, in a group of five GH-insufficient children. The s.c. infusion of GHRH between 2100 h and 0600 h augmented nocturnal pulsatile GH release in all five children. There was a dose-dependent response for the GH area under the curve (AUC), and mean total GH concentration. The AUC for GH was significantly greater after the 10 than 5 micrograms/kg/h GHRH which in turn was greater than that after placebo; mean (SD) AUC: 14816 (3978), 8125 (1931), 3032 (1582) mU min/l respectively (P less than 0.01 and P less than 0.05). There was no significant change in the number of GH pulses during the 9-h infusions when the subjects were infused with GHRH 10 or 5 micrograms/kg/h compared to placebo, and they occurred at similar times although the number of pulses tended to be greater after GHRH; the mean (SD) numbers of GH pulses were 5.0 (0.7), 3.8 (0.8), 3.2 (0.8), respectively. There was however a significant rise in the mean baseline GH concentration in all patients during the infusion of GHRH 10 micrograms/kg/h compared to placebo, but not with 5 micrograms/kg/h. Thus, GHRH(1-29)NH2 given s.c. augmented nocturnal pulsatile GH release in GH-insufficient children but it also increased baseline GH secretion. These results suggest that a sustained release preparation of GHRH could be a potential treatment for GH-insufficient children, and that a dose of 5 micrograms/kg/h would promote pulsatile GH release, but that at higher dosage it may also raise basal GH secretion.

Child↗
PubMed1989

The effects of tones on PGO waves in slow wave sleep and paradoxical sleep.

Ponto-geniculo-occipital (PGO) waves are macropotential waveforms occurring spontaneously during paradoxical sleep (PS) in the pons, the lateral geniculate body (LGB), and the occipital cortex of the cat. In our earlier work (6, 20) tones elicited waves in the LGB and the occipital cortex during both slow wave sleep (SWS) and PS that resembled PGO waves in form and amplitude. Using a limited and variable number of trials, we observed that these elicited waveforms, which we term elicited PGO waves (PGOE), seemed to decline rapidly in amplitude and probability during SWS but not during PS. The present two experiments served as a more rigorous test of the hypothesis that the rate of habituation of PGOE would be more rapid in SWS. In a first experiment seven cats were studied in up to four sessions in PS and four in SWS; each session consisted of 32 1000-Hz, 90-dB SPL tones lasting 90 ms. We found that (i) the number of PGOE was significantly greater in PS; (ii) the mean amplitude of the waves was greater in PS; (iii) the probability of eliciting a wave tended to decline faster in SWS, but some decline also occurred in PS; and (iv) on the first trial, PGOE were more easily produced in SWS. Results of a second experiment with five cats suggested that the decline in the probability of PGOE in PS was not accounted for by differences in the ease of eliciting them at different times into a PS episode. The role of the dorsal raphe nucleus (DRN) in modulating state-dependent differences in PGOE is discussed.

Animals↗
PubMed1989

Response to growth hormone-releasing hormone as evidence of hypothalamic defect in optic nerve hypoplasia.

Hypothalamic-pituitary function was studied in four children with Optic Nerve Hypoplasia (ONH). All were found to be growth hormone deficient when provoked with glucagon or insulin induced hypoglycaemia (ITT), but did respond to bolus injection of GHRH. This indicates a primary hypothalamic defect. Virtual absence of pituitary tissue on high resolution CT scan explained the poor response of one child. One child has shown an excellent response to treatment with subcutaneous GHRH, which is physiologically the most appropriate treatment for this condition.

Child↗