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R J Ross

Publications and source records attributed to R J Ross.

At least 37 records · Page 2Linked to original sources
PubMed2000

Stimulation of endogenous GH and interleukin-6 receptors selectively activates different Jaks and Stats, with a Stat5 specific synergistic effect of dexamethasone.

The interaction of GH, interleukin (IL)-6 and glucocorticoids is likely to be important in regulating the GH-insulin-like growth factor (IGF)-I axis. The signalling cascades activated by GH and IL-6 appear to be very similar, as demonstrated by studies using overexpression of the receptor and other components of the Jak-Stat and mitogen-activated protein (MAP) kinase pathways. Here we show that the human embryonic kidney cell line 293 (HEK293) expresses GH and IL-6 receptors endogenously. To determine which specific pathways might be activated by the two cytokines, at physiological levels of all components, we studied GH and IL-6 mediated signal transduction both under basal conditions and in the presence of overexpressed receptors and Stat proteins. Our results suggest a receptor specificity of Jak2 for GH receptors, and Jak1 for IL-6 receptors. Stat activation in response to GH and IL-6 was determined by reporter gene induction. Both GH and IL-6 were able to induce the reporter gene containing the Stat5 responsive element (LHRE) but the IL-6 response appeared to be mediated mainly through Stat3 activation. In contrast, the reporter gene containing the Stat3 responsive element (SIE) was IL-6 specific. The levels of gene induction by GH and IL-6 were not altered by the co-stimulation with GH and IL-6, suggesting that there is little cross-talk at the Jak-Stat activation level between the two cytokines. Neither GH nor IL-6 activated the MAP-kinase responsive serum response element (SRE), unless GH receptors or gp130 were overexpressed. Transfection of Stat3 or Stat5 expression vectors enhanced the response to GH and IL-6. Stimulation with dexamethasone synergistically enhanced GH activation of the LHRE reporter gene but had no effect on the IL-6 activation of the same reporter or on the SIE reporter gene. Thus, our studies suggest that while each cytokine, GH and IL-6, may activate various members of the Jak-Stat pathway in overexpression studies, specific activation of Stat3 by IL-6 and of Jak2 and Stat5 by GH can be observed in HEK293 cells and that in this system the synergistic effect of dexamethasone appears specific for Stat5.

Cell Line↗
PubMed1999

Rapid eye movement sleep changes during the adaptation night in combat veterans with posttraumatic stress disorder.

BACKGROUND: Hyperarousal in posttraumatic stress disorder (PTSD) is manifested during sleep as well as waking. Elevated rapid eye movement sleep (REMS) phasic activity, likely signifying central nervous system alerting, has been identified in PTSD. The authors reasoned that PTSD compared to control subjects would show particularly increased REMS phasic activity on the first night of polysomnography, with adaptation to a novel environment. METHODS: First-night polysomnograms of 17 veterans with PTSD were compared with those of 11 control subjects. Sleep was also studied in subsets of both groups over two nights. RESULTS: On the first night, the PTSD subjects had a higher density of rapid eye movements in the first REMS period. This measure was increased on the first compared to the second night, but there was no interaction effect between night and group. CONCLUSIONS: REMS changes are again demonstrated in veterans with PTSD. Introduction to a novel environment activated a REMS phasic process, but not differentially in PTSD compared to control subjects.

Adaptation, Physiological↗
PubMed1999

Lack of association between thyroid and adrenal nodules: a histological study.

The prevalence of thyroid nodules is increased in patients with Cushing's disease, but the possibility of an association between thyroid and adrenal nodules in other patient groups has not been formally tested. We have evaluated the co-existence of thyroid and adrenal nodules in retrospective and prospective autopsy studies. Retrospective (83 autopsies) and prospective (29 autopsies) blinded studies of thyroid and adrenal gland histopathology were performed by two experienced histopathologists in unselected autopsies. The presence of nodules, defined as areas of tissue having discrete edges within the gland parenchyma seen as a step difference between the cells or architecture adjacent to the nodule, was determined for each gland. No association was found between the presence of adrenal and thyroid nodules in either the retrospective or prospective studies (p>0.2 for both). In the retrospective study, 23% of specimens had thyroid nodules and 28% adrenal nodules. In the prospective study, 24% of specimens had thyroid nodules and 7% adrenal nodules. The proportion of patients with adrenal nodules in the prospective study was significantly less than that in the retrospective study. In conclusion, thyroid and adrenal nodules are frequent autopsy findings in the general population but we have found no evidence of a relationship between the occurrence of nodules in these glands.

Adrenal Gland Diseases↗
PubMed1999

Electrical stimulation of the amygdala increases the amplitude of elicited ponto-geniculo-occipital waves.

The amygdala projects massively via its central nucleus (CNA) into brain stem regions involved in alerting and ponto-geniculo-occipital (PGO) wave generation. Electrical stimulation of CNA is known to enhance the acoustic startle response (ASR) and influence spontaneous PGO waves. The role of the amygdala in the modulation of ASR and elicited PGO waves (PGOE) was investigated in albino rats. Electrically stimulating CNA within 25 ms prior to an auditory stimulus enhanced ASR and PGOE amplitude in a similar way, with the largest response occurring when the electrical and auditory stimuli were given simultaneously. The data suggest that CNA modulates alerting mechanisms.

Acoustic Stimulation↗
PubMed1999

The GH receptor and GH insensitivity.

Growth hormone (GH) resistance/insensitivity (GHIS) is the finding of elevated GH levels associated with a reduction in the biologic actions of GH. It may be congenital or acquired. In congenital GHIS, over 30 mutations in the GH receptor (GHR) have been described. Dimerization of the GHR activates phosphorylation cascades involving MAP kinases and the Janus kinase, JAK2. This in turn activates the STAT (Signal transducers and activators of transcription) proteins, which translocate to the nucleus. A soluble form of the GHR circulates as a GH binding protein (GHBP), and is derived from the proteolytic cleavage of the extracellular domain of the GHR. The majority of GHR mutations resulting in GHIS are though to affect GH binding, hence the finding of low levels of GHBP in many patients. However, a small group of patients with GHIS have been identified in whom there are normal or high levels of GHBP. Mutations in these patients include, among others, a splice-site mutation that results in the skipping of exon 9. The resultant protein is a truncated GHR that lacks 97% of the intracellular domain of the normal receptor. Patients heterozygous for this mutation have GHIS. In vitro studies have shown the truncated receptor acts as a dominant-negative inhibitor of receptor signalling. The truncated receptor lacks the domains essential for internalization, and is therefore highly expressed on the cell surface. It heterodimerizes with the full-length receptor and blocks signaling. Analysis of GHIS has increased our understanding of the molecular basis for GHIS and helped elucidate the factors that regulate GHR trafficking and signalling.

Alternative Splicing↗
PubMed1999

Effects of growth hormone replacement on physical performance and body composition in GH deficient adults.

OBJECTIVES: Adults with GH deficiency complain frequently of low energy levels resulting in a low perceived quality of life. Body composition is altered, with increased fat mass and decreased lean body mass, and muscle strength is reduced. The aims of this study were to determine the effects of GH replacement on physical performance and body composition in GH deficient (GHD) adults. STUDY DESIGN: The study consisted of a 6-month randomised, double-blind, placebo controlled study of the administration of GH (0.25 IU/Kg/week (0.125 IU/kg/week for the first four weeks)) followed by a 6-month open phase of GH therapy. PATIENTS: Thirty-five GHD adults (17F), mean age 39.8 years (range 21.1-59.9), on conventional replacement therapy as required. METHODS: Maximum aerobic capacity was measured using an incremental walking test to volitional exhaustion on a motorized treadmill. Quadriceps muscle strength was assessed by measuring maximum voluntary contractions and body composition by dual energy X-ray absorptiometry (DEXA). RESULTS: There were no statistically significant changes in quadriceps muscle strength between the GH and placebo groups. In both groups, there was a significant increase in quadriceps muscle strength compared to baseline during the double-blind period (GH group: P = 0.016; placebo group: P = 0.048). Compared to baseline, muscle strength was further improved in the GH treatment group after 12 months of treatment (P = 0.007). No further improvement was noted in the placebo group after 6 months on open GH treatment. In the placebo group, maximum aerobic capacity decreased during the placebo period (P = 0.017). No significant change was observed in the GH group. During open GH treatment the previously placebo treated group had a significant increase of maximum aerobic capacity (P < 0.049) whereas no significant improvement could be seen in the GH group. In the GH group there was a significant increase in lean body mass (P = 0.001) and a significant decrease in fat mass (P < 0.001). No statistically significant changes were noted in the placebo group: the differences in these changes between treatment groups were statistically significant (lean body mass: P = 0.009; fat mass: P < 0.001). The changes in body composition in the GH group during the 6 month placebo-controlled period were maintained during continued open treatment. Similar changes in body composition to those observed in the GH group during the 6 month placebo-controlled period were also seen in the placebo group once the patients received GH treatment. CONCLUSIONS: Our data show that GH replacement in GH deficient adults is associated with favourable changes in body composition, which could be important in the long term health outcome and physical activity of GH deficient patients. Our data support the concept that GH therapy alone, in the absence of some form of exercise programme, may increase the amount of lean tissue but not the quality or functional capacity of this tissue and it may be that training, in addition to GH therapy, may be necessary to significantly increase physical performance in these patients. We suggest that future trials with GH therapy and general approaches to the treatment of GH deficiency should include a planned activity programme as an approach to health improvement in these patients.

Absorptiometry, Photon↗
PubMed1999

Truncated growth hormone receptor isoforms.

Truncated forms of the growth hormone receptor (GHR) that lack the majority of the cytoplasmic domain have been identified in a number of human tissues. In vitro, these truncated receptors act as dominant-negative inhibitors of the growth hormone (GH) signal and also generate large amounts of growth hormone binding protein (GHBP). Mutations that lead to high levels of expression of the truncated GHR are associated with short stature and GH insensitivity. Thus, truncated GHRs may be important as a physiological regulator of GH signalling in addition to providing a mechanism for the production of GHBP.

Animals↗
PubMed1999

New growth hormone receptor exon 9 mutation causes genetic short stature.

A novel form of congenital growth hormone insensitivity syndrome (GHIS), which lacks the classic phenotype associated with this condition, is described. Dominant inheritance is shown to result from a heterozygous 876-1 G to C transversion of the 3' splice acceptor site preceding exon 9 in the growth hormone receptor (GHR) gene. The result of this mutation is a severely truncated cytoplasmic domain of the GHR, which is incapable of transmitting a signal. The mutant receptor is shown to form a heterodimer with the wild-type GHR, the activity of which is inhibited in a dominant-negative manner.

Base Sequence↗
PubMed1999

The effects of dose, nutrition, and age on hexarelin-induced anterior pituitary hormone secretion in adult patients on maintenance hemodialysis.

Malnutrition is common in chronic renal failure (CRF) and adversely affects prognosis. In view of the anabolic action of GH in CRF, we have studied the effects of hexarelin, a GH secretagogue, on CRF. An iv dose-response study in six 20- to 40-yr-old well nourished hemodialysis (HD) patients was followed by administration of the maximally effective dose to six 20- to 40-yr-old healthy controls, six 20- to 40-yr-old poorly nourished HD patients, and six 50- to 70-yr-old poorly nourished HD patients. GH secretion (area under the curve over 180 min, mean +/- SE) after 2 and 1 microg/kg doses (10.7 +/- 4.2 and 8.2 +/- 5.2 min/U x L, respectively) was greater than after placebo (0.60 +/- 0.11 min/U x L; P < 0.001 and P < 0.05, respectively). The most effective dose (2 microg/kg) produced similar GH secretion (11.4 +/- 3.3 min/U x L) in controls. GH secretion in the younger poorly nourished HD group (19.0 +/- 4.4 min/U x L) was not significantly different from that in the well nourished 20- to 40-yr-old HD patients (P = 0.06). GH secretion in the older, poorly nourished HD patients (9.4 +/- 2.2 min/U x L) was similar to that in the young, poorly nourished group (P = 0.18). ACTH and cortisol concentrations increased in all groups, whereas PRL concentrations were not affected in CRF. The profound action of hexarelin on GH secretion has been shown to extend to CRF. Trends were evident toward increasing efficacy in malnourished subjects and decreasing efficacy with age. Further studies are required to determine whether the acute actions of hexarelin can be translated into long term anabolic changes.

Adrenocorticotropic Hormone↗
PubMed1999

Leptin binding activity changes with age: the link between leptin and puberty.

The timing of the physical transition from child to adult is determined by a biological clock that switches off the pituitary gonadal axis during infancy until puberty. Body composition (and in particular, fat mass), through leptin, are critical signals to this clock. However, no direct relationship between leptin and puberty has been demonstrated. Leptin is bound in the circulation by a high-affinity binding protein, which has been identified as a soluble leptin receptor. We found circulating levels of leptin binding activity (LBA) to be low at birth, to be high in the prepubertal years, to fall through puberty, and then to remain stable during adult life. LBA correlated with pubertal status in both boys and girls. We postulate that the fall in LBA, associated with increasing age and puberty, reflects a reduction in expression of truncated leptin receptors, and leptin is then available to the full-length receptor, which transmits the biological signal for leptin. The high levels of LBA occur during the years when the pituitary gonadal axis is quiescent. Thus, the change in LBA could explain how leptin regulates puberty.

Adolescent↗
PubMed1999

Serum leptin levels during the menstrual cycle of healthy fertile women.

Leptin is a protein, produced by adipose tissue, which has cytokine and hormonal properties. Serum leptin levels can be considered as a measure of body fat mass, and are involved in regulation of body weight. Previous studies suggest that leptin may have an additional role in reproduction, and there is also evidence for involvement in the hypothalamic-pituitary-gonadal axis. In this study, we investigate the possible changes in serum leptin concentration throughout the menstrual cycle. Samples were collected from apparently healthy, fertile women at different stages in their menstrual cycle, timed precisely according to the luteinising hormone (LH) surge. Mean serum leptin levels were significantly higher in the luteal phase (median 11.4 ng/mL) than in the follicular phase (median 10.0 ng/mL) (P < 0.001). In addition, mean serum leptin levels correlated with body mass index (r = 0.54, P < 0.05), but showed no correlation with luteal-phase progesterone levels. Results showed that levels of serum leptin vary during the menstrual cycle, and add to the mounting evidence that leptin has a role in reproduction. These fluctuations should be taken into account whenever studies are performed using female subjects.

Adult↗
PubMed1998

Effects of electrical stimulation in the amygdala on ponto-geniculo-occipital waves in rats.

We examined the role of the amygdala in the modulation of sleep and ponto-geniculo-occipital (PGO) waves in the rat. The amygdala projects massively, via its central nucleus, into brainstem regions involved in alerting and in the generation of rapid-eye movement (REM) sleep and PGO waves. Electrical stimulation of the central nucleus of the amygdala during REM sleep increased PGO wave amplitude. Stimulation during non-REM sleep decreased PGO wave frequency. The results indicate that the amygdala has a role in modulating brainstem neural mechanisms underlying alerting during sleep.

Amygdala↗
PubMed1998

Acquired growth hormone resistance in adults.

Acquired growth hormone resistance (AGHR) may be defined as the combination of a raised serum growth hormone (GH) concentration, low serum insulin-like growth factor-1 (IGF-1) concentration and a reduced anabolic response to exogenous GH. A wide range of conditions exhibit the syndrome to a variable degree, including sepsis, trauma, burns, AIDS, cancer, and renal or liver failure. The primary defect seems to be a reduction in IGF-1 concentration which then leads to increased GH concentration by a loss of negative feedback. It is not clear whether IGF-1 concentration falls because of decreased production or increased clearance from the circulation, or both. Treatment to reverse the biochemical defect by restoring IGF-1 levels, either by the administration of GH or IGF-1, has resulted in improvements in a wide range of metabolic parameters and, more recently, to definite clinical benefit in well-defined groups, such as patients with AIDS. These results cannot be extrapolated to other groups with AGHR as a recent unpublished report suggested increased mortality in critically ill patients treated with GH. Research needs to focus on the molecular basis of AGHR if we are to develop therapies for catabolism.

Adult↗
PubMed1998

Serum collagen crosslinks as markers of bone turn-over during GH replacement therapy in growth hormone deficient adults.

OBJECTIVES: Bone metabolism is an important target for GH replacement therapy. However, in adults, treatment periods exceeding 12 months are required for a positive effect of GH on bone mineral density. Thus, to detect an early effect of GH on bone, markers of bone turn-over are important. Pyridinoline (PYR) and deoxypyridinoline (DPYR) are well-defined sensitive markers of bone resorption, but to date only urinary assays have been available. We report the use of a novel assay to measure changes in serum PYR and DPYR in GH deficient (GHD) adults during GH replacement therapy. STUDY DESIGN: The study consisted of a 6-month randomized, double-blind, placebo-controlled study of the administration of GH (Genotropin) (0.25 IU/Kg/week (0.125 IU/kg/week for the first four weeks)) followed by a 6-month open phase of GH therapy. PATIENTS: Thirty-five GHD adults (17 women; mean age 39.8 years; range 21.1-59.9) on conventional hormone replacement therapy as required, were studied. MEASUREMENTS: Bone formation was analysed using serum bone alkaline phosphatase (BAP) and serum osteocalcin (OC). Bone resorption was analysed using serum pyridinoline (PYR) and serum deoxypyridinoline (DPYR). Bone mineral density (BMD) was determined by dual energy X-ray absorptiometry (DEXA). RESULTS: After 6 months placebo treatment there were no significant changes in any of the bone markers analysed, nor in BMD. In the active arm of the study there was a significant increase in serum OC, BAP, PYR and DPYR (P = 0.03, P = 0.004, P = 0.003 and P = 0.01, respectively), remaining significantly elevated over their baseline levels for the subsequent 6 months of treatment (P = 0.04, P = 0.009, P = 0.003 and P = 0.04, respectively). No changes were observed in BMD in any of the groups after 6 months GH treatment. In the active arm of the study, after 12 months GH treatment there was a significant increase in BMD at both the lumbar spine and femoral neck (P = 0.01 for both sites). CONCLUSIONS: In summary, the present study confirms that administration of GH treatment to GHD adult patients significantly activates bone remodelling, with the effect of GH both in bone formation and bone resorption markers being maximal after 6 months of treatment. The serum assay for PYR and DPYR has a number of practical and theoretical advantages over the urine assay and gave similar results to those previously reported for the urine assay.

Adult↗
PubMed1998

Comparison of the diagnostic utility of the simplified and standard i.m. glucagon stimulation test (IMGST).

OBJECTIVE: To compare the peak GH and cortisol responses to the simplified and standard i.m. glucagon stimulation test (IMGST) in order to determine whether the use of a simplified form of this test results in a loss of diagnostic utility. PATIENT AND DESIGN: A retrospective study of 35 consecutive patients with pituitary disease who underwent a standard IMGST to measure GH (n = 34) or cortisol (n = 21) reserve at the programmed investigation unit of the Northern General Hospital, Sheffield. MEASUREMENTS: Cortisol, glucose and GH levels were measured at baseline and 30, 60, 90, 120, 150, 180, 210 and 240 min during the standard IMGST. We used the hormone levels at baseline, 150 and 180 min for the simplified IMGST and compared the cortisol and GH responses achieved. RESULTS: The median (range) peak GH and cortisol responses to simplified and standard IMGST were comparable 4.2 (0.5-47.5) vs 5.4 (0.5-47.5) mU/l (P = 0.75) and 635 (306-1669) vs 647 (306-1669) nmol/l (P = 0.801), respectively. Using the standard 'cut-off' points to assess GH (9 mU/l) or cortisol deficiency (580 nmol/l) there was no significant loss of diagnostic utility (P = 0.98 and P = 1.00, respectively). CONCLUSIONS: The simplified and standard IMGST have a similar diagnostic utility. The simplified IMGST could replace the standard IMGST as a screening test for GH and cortisol reserve in pituitary disease. The insulin-induced hypoglycaemia stress test can be reserved for cases in which a second assessment of pituitary reserve is clinically indicated or because of an indeterminate biochemical result.

Adolescent↗
PubMed1998

Elicited pontogeniculooccipital waves and phasic suppression of diaphragm activity in sleep and wakefulness.

Fractionations are 20- to 100-ms pauses in diaphragm activity that occur spontaneously during rapid-eye-movement (REM) sleep, sometimes in association with pontogeniculooccipital (PGO) waves. Auditory stimuli can elicit fractionations or PGO waves during REM sleep, non-REM (NREM) sleep, and waking; however, their interrelationship has not been investigated. To determine whether the two phenomena are produced by a common phasic-event generator in REM sleep, we examined PGO waves and fractionations that were elicited by auditory stimuli (tones) presented to freely behaving cats across states. Tones elicited PGO waves and two types of fractionations: short-latency fractionation responses (SFRs; 10- to 60-ms latencies) and long-latency fractionation responses (LFRs; 60- to 120-ms latencies). Both a PGO wave and a SFR were elicited in 60-70% of trials across states, but each could be elicited alone. The latencies and durations of elicited SFRs were similar across states, but the latencies of elicited PGO waves in REM sleep (mean 62.5 ms) were significantly longer than in waking or NREM sleep. Elicited SFRs consistently occur with shorter latencies than do PGO waves, in contrast to spontaneous fractionations, which have a variable relationship to PGO waves and usually occur 10-40 ms after the onset of the PGO wave. The LFR then, elicited most frequently during REM sleep, resembles a spontaneous fractionation in its temporal relationship to the PGO wave and may reflect the bias toward motoneuronal inhibition characterizing REM sleep but not NREM sleep or waking. We conclude that, although PGO waves and SFRs share some features, like LFRs they probably are generated by different neuronal populations. In three cats there was no correlation between PGO waves and fractionations, whereas in one cat they were associated in REM sleep (LFRs and SFRs) and waking (SFRs only). Thus the majority of evidence argues against the existence of a common phasic-event generator in REM sleep.

Acoustic Stimulation↗