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Biomedical subjects

R J Ross

Publications and source records attributed to R J Ross.

At least 73 records · Page 4Linked to original sources
PubMed1995

Absence of mutations in the MEN2A region of the ret proto-oncogene in non-MEN 2A phaeochromocytomas.

OBJECTIVE: To determine the presence of abnormalities of the MEN2A region of the ret proto-oncogene in phaeochromocytomas/paragangliomas (PHAEO) of different aetiologies. DESIGN: Total RNA was extracted from tumours and used as templates for reverse transcriptase polymerase chain reactions. A ret primer pair, which encompasses the region which is mutated in the germ-line of patients with MEN 2A, was used. The resulting 262-bp product was sequenced. PATIENTS: Ten PHAEOs were examined. Four tumours were from von Hippel-Lindau disease patients; five were sporadic, isolated tumours; one from a patient with multiple endocrine neoplasia type 2A (MEN 2A). The medullary thyroid cancer from the single MEN 2A patient was also examined. RESULTS: A heterozygous TGC to CGC mutation of codon 634 (cysteine to arginine) was found in the PHAEO and medullary thyroid cancer from the MEN 2A patient. The 262-bp ret fragment was not found in two tumours (one malignant PHAEO and one secretory paraganglioma), although the intra-cellular ret tyrosine kinase domain was detected in these tumours. The cysteine codons were normal in all other non-MEN 2A PHAEOs. CONCLUSION: Mutations of key cysteine codons of the ret proto-oncogene may be specific to MEN 2A.

Adrenal Gland Neoplasms↗
PubMed1995

Primary hyperaldosteronism due to an adrenal adenoma in a 14-year-old boy.

Conn's syndrome due to an adrenal adenoma is very rare in children. This paper reports a 14-year-old boy with primary hyperaldosteronism due to an adrenal adenoma. His biochemistry data were compatible with either bilateral adrenal hyperplasia or an adrenal adenoma. A dexamethasone test did not suppress aldosterone levels. Venous catheter sampling and 75Se-selenomethylcholesterol scanning suggested that the hyperaldosteronism originated at the right adrenal. Computed tomography showed an 8-mm low-density nodule in the right adrenal gland and magnetic resonance imaging confirmed the nodule which had high signal intensity on T2-weighted images consistent with a functioning adenoma. Surgery confirmed the right adrenal adenoma, and the patient was cured by right adrenalectomy. This case illustrates the difficulty of defining the aetiology of primary hyperaldosteronism and we review the biochemical and scanning techniques available to aid in diagnosis. Hypertension is unusual in children and endocrine causes are very rare, but Conn's syndrome should always be considered in the differential diagnosis.

Adenoma↗
PubMed1995

An alternatively spliced human insulin-like growth factor-I transcript with hepatic tissue expression that diverts away from the mitogenic IBE1 peptide.

An alternatively spliced transcript of the human insulin-like growth factor-I (IGF-I) gene is described. The transcript was identified in human liver RNA by reverse transcriptase-polymerase chain reaction, cloning, and sequencing. It contained IGF-I exons 3 and 4, 49 basepairs of exon 5, then exon 6 (exon 4-5-6). The 5'-donor site at the exon 5-6 junction was a cryptic 5'-donor splice site (IGF633). The 3'-acceptor site of the splice was the usual intron-exon 6 junction. A second pair of primers across the exon 5-exon 6 junction was used to confirm the presence of the transcript by reverse transcriptase-polymerase chain reaction. Cloning and sequencing this second fragment confirmed the presence of this splice in human liver. The exon 4-5-6 transcript was quantified at about 10% relative to the exon 4-6 transcript in human livers (n = 7 subjects), but was not detected in other tissues. The exon 4-5-6 transcript was found in cultured human hepatoma HepG2 cells and increased, relative to exon 4-6 transcripts, in response to GH, but not in cultured human lymphoblast IM-9 cells. The exon 4-5-6 splice predicts a prepro-IGF-I of 158 amino acid residues, with an E-peptide sequence of 24 residues (Ec). The deduced Ec peptide sequence is 73% homologous to the rat Eb-peptide sequence. The predicted final residues of the Ec peptide are frameshifted exon 6 codons ending in an in-frame stop codon. The predicted peptide sequences of Ec and Eb differ at the cleavage site of the Eb-peptide fragment (IBE1), which has been shown to have mitogenic activity. These data suggest that 1) the exon 4-5-6 splice has hepatic tissue expression and occurs by the use of a cryptic 5'-donor consensus splice site (IGF633) in exon 5; 2) exon 4-5-6 can be hormonally regulated in cultured human HepG2 cells; 3) exon 4-5-6 is the human counterpart of the rat IGF-IEb, because the complementary DNA and predicted sequences are homologous; and 4) the production of IBE1 is potentially regulated by alternative splicing.

Alternative Splicing↗
PubMed1995

Diagnosis and selective cure of Cushing's disease during pregnancy by transsphenoidal surgery.

The diagnosis of Cushing's Disease during pregnancy is complex because the biochemical features are obscured by changes in the normal hypothalamo-pituitary-adrenal axis that occur during gestation. To date, treatment has not been successful and there is a high incidence of maternal and fetal complications. We report the case of a 24-year-old woman with Cushing's disease who presented during her 16th week of pregnancy. Diagnosis was confirmed by the finding of elevated serum and urinary free cortisol levels with loss of the normal circadian rhythm of serum cortisol. Cortisol levels failed to suppress after a low-dose dexamethasone test but suppressed after a high-dose test. There was an exaggerated serum cortisol and plasma adrenocorticotrophin (ACTH) response to corticotrophin-releasing hormone (CRH). Magnetic resonance (MR) scanning demonstrated a pituitary tumour and cure was effected by transsphenoidal surgery where tumour immunostaining for ACTH was removed. Postoperatively the patient made an uncomplicated recovery; serum cortisol and plasma ACTH levels were undetectable at 9 days following surgery and recovery of the hypothalamo-pituitary axis occurred at 99 days after surgery. Caesarean section was performed at 38 weeks of pregnancy and a healthy but small female infant was delivered. This case illustrates the biochemical features of Cushing's disease during pregnancy and is the first report of the use of CRH testing and MR scanning in this clinical situation. The cure by surgery and successful outcome for mother and infant, with preservation of normal anterior pituitary function, suggest that transsphenoidal surgery may be the treatment of choice.

Adrenocorticotropic Hormone↗
PubMed1995

Regulation of hepatic mRNA levels for the growth hormone receptor in rats with altered thyroid status.

Changes in thyroid status have a major effect on the GH/IGF-I axis. In the rat, there is a single gene for the growth hormone receptor (GHR), that is transcribed into two different sized mRNA transcripts following alternative splicing, one transcript codes for the GHR (4.0-4.5 kb) and the other growth hormone binding protein (GHBP) (1.2-1.3 kb). We have studied the regulation of hepatic GHR gene expression by thyroid hormones in male Wistar rats rendered hypothyroid (n = 6) and hyperthyroid (n = 6) compared to controls (n = 6). By northern blot analysis, two transcripts with an estimated size of 4.2 and 1.2 kb, respectively, were detected in all groups. Hyperthyroidism was associated with a significant increase in the 4.2 kb transcript compared to hypothyroidism (P < 0.05), but no changes were observed in the 1.2 kb transcript. Thus, our results suggest that in the rat hyperthyroidism is associated with either increased hepatic gene transcription or decreased clearance of the 4.2 kb transcript for the GHR compared with hypothyroidism.

Alternative Splicing↗
PubMed1995

Amygdaloid control of alerting and behavioral arousal in rats: involvement of serotonergic mechanisms.

The role of 5-HT mechanisms in the amygdala in the modulation of sleep and arousal states and PGO waves was examined. Studies of the amygdala suggest that it provides a neural mechanism by which emotionally-relevant or significant stimuli may influence behavioral state and alerting mechanisms. The amygdala projects massively (via the central nucleus) into brainstem regions involved in alerting and in the generation of REM and PGO waves. Serotonergic innervation of the amygdala comes from DRN and to a lesser degree MRN. Microinjections of 5-HT into the amygdala produced short-latency changes of state from NREM and REM with the effect being relatively greater in REM. Microinjections of the 5-HT antagonist, methysergide, increased sleep efficiency and increased PGO wave frequency in waking and NREM. These results demonstrate an important role for the amygdala in the control of behavioral state and alerting mechanisms and suggest that 5-HT exerts some of its regulatory effects via an influence on forebrain regions.

Amygdala↗
PubMed1994

Rapid eye movement sleep disturbance in posttraumatic stress disorder.

The subjective sleep disturbance in posttraumatic stress disorder (PTSD), including the repetitive, stereotypical anxiety dream, suggests dysfunctional rapid eye movement (REM) sleep mechanisms. The polysomnograms of a group of physically healthy combat veterans with current PTSD were compared with those of an age-appropriate normal control group. Tonic and phasic REM sleep measures in the PTSD subjects were elevated on the second night of recorded sleep. Increased phasic REM sleep activity persisted in the PTSD group on the subsequent night. During the study, an anxiety dream occurred in a PTSD subject in REM sleep. The results are consistent with the view that a dysregulation of the REM sleep control system, particularly phasic event generation, may be involved in the pathogenesis of PTSD. The finding of a specific disturbance of sleep unique to PTSD may have significant implications for the design of effective treatments for PTSD.

Adult↗
PubMed1994

Central administration of two 5-HT receptor agonists: effect on REM sleep initiation and PGO waves.

Cholinergic neurons in the pedunculopontine tegmental (PPT) and the laterodorsal tegmental (LDT) nuclei are implicated in the generation of rapid eye movement sleep (REM) and ponto-geniculo-occipital (PGO) waves. Serotonin (5-HT) has a role in sleep-wake regulation and appears to inhibit PGO wave generation. We studied the effects of the central infusion of the relatively specific 5-HT1A receptor agonist 8-hydroxy-2-(n-dipropylamino)tetralin (DPAT) and the less specific 5-HT1 receptor agonist 1(3-chlorophenyl)piperazine (mCPP) on the regulation of REM and on PGO wave generation. DPAT (0.0, 0.002, 0.01, 0.08, and 0.8 microgram/0.5 microliter normal saline) and mCPP (0.0, 0.02, 0.2, 2.0, and 20.0 micrograms/0.5 microliter normal saline) were infused unilaterally into the peribrachial region of PPT (PB) in cats. Additionally, DPAT (0.01 microgram/0.5 microliter) was infused bilaterally into PB in a separate experiment. Low dosages of DPAT (unilateral or bilateral) decreased successful entrances into REM (0.01 microgram) and time spent asleep (0.002 microgram and 0.01 microgram) without affecting outward behavior. No dosage of mCPP significantly decreased the number of REM episodes, and neither drug decreased REM episode duration once REM had been entered. Neither drug affected the rate of PGO waves independently of modulating behavioral state. We propose that 5-HT1A receptor mechanisms have an inhibitory role in actual REM initiation, possibly by facilitating endogenously generated excitation of brainstem startle mechanisms at the onset of REM.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Motor dysfunction during sleep in posttraumatic stress disorder.

A subjective disturbance of sleep, including the occurrence of repetitive, stereotypical anxiety dreams, is characteristic of posttraumatic stress disorder (PTSD). The phenomenology of the PTSD anxiety dream has seemed most consistent with an underlying rapid eye movement (REM) sleep dysfunction. However, motor behavior reportedly can accompany PTSD dreams, and normal REM sleep typically involves a nearly total paralysis of the body musculature. As a means of understanding this discrepancy, anterior tibialis muscle activity during sleep was studied in a group of Vietnam combat veterans with current PTSD and in an age-matched normal control group. The PTSD subjects had a higher percentage of REM sleep epochs with at least one prolonged twitch burst; they also were more likely to have periodic limb movements in sleep, during nonrapid eye movement sleep. Both these forms of muscle activation also have been observed in REM behavior disorder (RBD), a parasomnia characterized by the actual enactment of dream sequences during REM sleep. The identification of RBD-like signs in PTSD adds to the evidence for a fundamental disturbance of REM sleep phasic mechanisms in PTSD.

Electrooculography↗
PubMed1994

Changes in hepatic insulin-like growth factor-binding proteins -1, -2 and -3 mRNA levels in rats with altered thyroid status.

Changes in thyroid status have a major effect on the GH/insulin-like growth factor (IGF) axis. The majority of IGF in the circulation is bound to specific IGF-binding proteins (IGFBPs) of which six have been cloned and sequenced. We have studied changes in hepatic gene expression of IGFBP-1, -2 and -3, in male Wistar rats rendered hyperthyroid (thyroxine, 200 micrograms/kg per day) or hypothyroid (propylthiouracil, 0.1% daily). Littermates of the same age were used as controls (n = 6 in each group). Thyroxine was measured by radioimmunoassay, and hepatic IGFBP-1, -2 and -3 mRNA levels by Northern blot analysis using specific rat cDNA probes with a 28S ribosomal probe as a loading control. Mean +/- S.E.M. thyroxine levels were 247.0 +/- 44.5 (hyperthyroid group), < 9.0 (hypothyroid group) and 76.0 +/- 4.5 nmol/l (control group). IGFBP-1 and -2 mRNA levels in the hypothyroid animals compared with the controls were significantly increased, but similar levels of expression were found in thyrotoxic and control rats. IGFBP-3 mRNA levels in hypothyroid animals were decreased, and increased in thyrotoxic animals. Thus, in the adult rat, hypothyroidism is associated with increased hepatic IGFBP-1 and -2 gene expression, but decreased IGFBP-3 gene expression, while in thyrotoxicosis there are normal IGFBP-1 and -2 mRNA levels but increased IGFBP-3 gene expression. These results suggest that there is specific and different transcriptional regulation for IGFBP-1, -2 and -3 in hypo- and hyperthyroid rats.

Animals↗
PubMed1994

Expression of IGFBP-1 in normal and cirrhotic human livers.

Cirrhosis of the liver, a condition characterised by hepatocyte regeneration, is also associated with elevated insulin levels and insulin resistance. In animal models hepatic regeneration is associated with increased IGFBP-1 gene expression. Insulin is known to be an inhibitor of IGFBP-1 gene expression and circulating insulin levels in man demonstrate a negative correlation with IGFBP-1 levels. To further our understanding of the regulation of IGFBP-1 in cirrhosis we have studied steady state levels of IGFBP-1 mRNA in human liver from three groups of patients: Group 1, tissue obtained at the time of harvesting donor liver for orthotopic liver transplantation (n = 4); group 2, patients undergoing major liver resection with no histological evidence of chronic liver disease (n = 4); and group 3, patients undergoing orthotopic transplantation for chronic liver failure (n = 9). Simultaneous samples of serum were taken at the time of surgery in some patients and in these patients IGFBP-1 mRNA levels were related to circulating levels of IGFBP-1 and insulin. IGFBP-1 mRNA was detectable in all the human liver samples with the greatest levels seen from the normal livers of group 2 patients. Insulin levels were elevated in the cirrhotic group 3 patients compared to a normal range as were IGFBP-1 levels. There was no relationship between circulating levels of IGFBP-1 and IGFBP-1 gene expression. In conclusion, IGFBP-1 mRNA is present in human adult liver at the time of surgery and also in cirrhotic liver despite high levels of insulin suggesting that there are factors other than insulin regulating IGFBP-1 gene expression.

Adult↗
PubMed1993

The amplitude of elicited PGO waves: a correlate of orienting.

Ponto-geniculo-occipital (PGO) waves spontaneously occur in the pons, lateral geniculate body (LGB), and occipital cortex during rapid eye movement sleep (REM), and PGO-like waves (PGOE) may be elicited in LGB during sleep and waking. Because REM has been hypothesized to be a state of continual "orienting" or "hyper-alertness," we tested whether the amplitudes of PGOE in "alerting" situations (the abrupt onset of a loud sound or presentation of a novel stimulus within a series of stimuli) that evoke orienting responses (OR) would be greater than those following stimuli without OR. We also compared PGOE accompanying OR to PGOE during REM and NREM when OR are absent. The amplitudes of PGOE in W were greatest when OR were observed, and the amplitudes of PGOE accompanying OR were not significantly different from PGOE amplitudes in REM. Likewise, the amplitudes of PGOE during REM were not significantly different from those of the highest amplitude spontaneous PGO waves. We propose that the presence of PGOE signals registration of stimuli and that stimuli of sufficient significance to induce behavioral OR in waking also elicit PGOE of significantly greater amplitudes in all behavioral states. These findings support the hypothesis that the presence of high-amplitude PGO waves in REM indicates that the brain is in a state of more-or-less continual orienting.

Acoustic Stimulation↗
PubMed1993

Acquired growth hormone resistance in patients with hypercatabolism.

Sepsis, surgery and critical illness are associated with an increased catabolic rate, which if prolonged delays recovery and increases morbidity and mortality. There is evidence that changes in the GH/IGF-I axis are permissive to protein catabolism. Critically ill, septic patients have high basal levels of GH, low levels of IGF-I and its carrier binding protein IGFBP-3, high levels of an inhibitory binding protein, IGFBP-I, and increased serum protease activity which reduces the affinity of IGFBP-3 for IGF-I. Overall there is a reduction in the indirect IGF-I-mediated anabolic actions of GH and an increase in the direct catabolic actions of GH. These physiological changes may be adaptive when a sick patient is fasting; however, the availability of modern intensive care means that these changes are no longer an advantage. GH and IGF-I, in pharmacological doses, promote positive nitrogen balance, in both animal models and man. Preliminary studies with IGF-I in postsurgical patients suggest that it may provide a practical therapy. Future studies need to focus on outcome measures in relation to the use of GH and IGF-I as anabolic therapies.

Carrier Proteins↗
PubMed1993

Effects of hypothyroidism and hyperthyroidism on insulin-like growth factors (IGFs) and growth hormone- and IGF-binding proteins.

Normal thyroid status is a prerequisite for the normal growth and development of many tissues. The interrelationships between the thyroid and pituitary-GH-insulin-like growth factor (IGF) axes are complex and not yet fully understood. We have studied the effects of hypothyroidism (n = 22) and hyperthyroidism (n = 17) on levels of serum immunoreactive IGF-I and II, IGF-binding proteins (IGFBP-1 and -3), and IGF bioactivity before and during treatment. We have also assessed changes in GH-binding activity (GHBP). Mean immunoreactive (IR) IGF-I levels in the hypothyroid group rose from 106.6 +/- 10.6 micrograms/L at diagnosis to 139.9 +/- 12.7 micrograms/L (P = 0.009) on normalization of thyroid function. In hyperthyroidism, mean IGF-I levels (258.9 +/- 33.9 micrograms/L) were high initially and fell to 188.7 +/- 14.8 micrograms/L (P = 0.04) after treatment. IR IGF-I levels correlated positively with free T3 and free T4 and negatively with TSH levels. Mean serum IGF-II levels were low in hypothyroid patients (375.2 +/- 37.3) and rose during treatment (516.9 +/- 59.4 micrograms/L; P = 0.04). In the hyperthyroid subjects, however, there was no significant change during therapy (625.0 +/- 66.9 vs. 621.9 +/- 120.8 micrograms/L; P = 0.98). IGF bioactivity potency ratios were low in the hypothyroid group (0.26 +/- 0.03 U/mL) and rose to 0.71 +/- 0.10 U/mL (P = 0.01) during treatment. IGF bioactivity in the hyperthyroid group was also low (0.38 +/- 0.05 U/mL) and rose significantly during treatment (0.81 +/- 0.06 U/mL; P = 0.003). Mean IGFBP-1 levels (29.8 +/- 5.7 micrograms/L) were unaltered by treatment of hypothyroid subjects (28.4 +/- 4.8 micrograms/L). In contrast, IGFBP-1 levels in the hyperthyroid subjects were high at diagnosis (134.6 +/- 26.6 micrograms/L) and fell significantly (71.3 +/- 14.3 micrograms/L; P = 0.04) during treatment. In the hypothyroid group, IGFBP-3 levels rose from an initial mean of 1.98 +/- 0.17 to 2.67 +/- 0.27 mg/L (P = 0.04) during treatment. The higher mean pretreatment levels in the thyrotoxic group (3.46 +/- 0.32 mg/L) were unaltered by treatment (3.20 +/- 0.51 mg/L; P = 0.71). GHBP was low in the hypothyroid group at diagnosis (28.5 +/- 2.5%) and rose during treatment to 40.6 +/- 3.9% (P = 0.02). We have confirmed that IR IGF-I levels are low in hypothyroidism and have demonstrated a reduction in IGF bioactivity and IGF-II and IGFBP-3 levels, and low GH-binding activity, which may reflect a reduction in the processing of GH receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1993

Endocrine and cardiac paracrine actions of insulin-like growth factor-I (IGF-I) during thyroid dysfunction in the rat: is IGF-I implicated in the mechanism of heart weight/body weight change during abnormal thyroid function?

Thyroid hormones are essential for the normal growth and development of many tissues. In the rat, hypothyroidism is associated with growth impairment, and hyperthyroidism with the development of a hypercatabolic state and skeletal muscle wasting but, paradoxically, cardiac hypertrophy. The mechanism by which thyroid hormone produces cardiac hypertrophy and myosin isoenzyme changes remains unclear. The role of IGF-I, an anabolic hormone with both paracrine and endocrine actions, in producing cardiac hypertrophy was investigated during this study in hyperthyroid, hypothyroid and control rats. A treated hypothyroid group was also included in order to assess the effect of acute normalization of thyroid function. Body weight was significantly lower in the hyperthyroid (mean +/- S.E.M.; 535.5 +/- 24.9 g, P < 0.05), hypothyroid (245.3 +/- 9.8 g, P < 0.001) and treated hypothyroid (265.3 +/- 9.8 g, P < 0.001) animals when compared with controls (618.5 +/- 28.6 g). Heart weight/body weight ratios were, however, significantly increased in the hyperthyroid (2.74 +/- 0.11 x 10(-3), P < 0.01) and treated hypothyroid (2.87 +/- 0.07 x 10(-3), P < 0.001) animals when compared with controls (2.26 +/- 0.03 x 10(-3). Serum IGF-I concentrations were similar in the control and hyperthyroid rats (0.91 +/- 0.07 vs 0.78 +/- 0.04 U/ml, P = 0.26), but bioactivity was reduced by 70% in hyperthyroid serum, suggesting a circulating inhibitor of IGF. Serum IGF-I levels (0.12 +/- 0.03 U/ml, P < 0.001) and bioactivity (0.12 +/- 0.04 U/ml, P < 0.001) were significantly lower in the hypothyroid group. Liver IGF-I mRNA levels were not statistically different in the control and hyperthyroid animals, but were significantly reduced in the hypothyroid animals (P < 0.05 vs control). Heart IGF-I mRNA levels were similar in the control and hypothyroid rats, but were significantly increased in the hyperthyroid and treated hypothyroid animals (increased by 32% in hyperthyroidism, P < 0.05; increased by 57% in treated hypothyroidism, P < 0.01). Cardiac IGF-I was significantly elevated in hyperthyroidism (0.16 +/- 0.01 U/mg heart tissue, P < 0.01), was low in hypothyroidism (0.08 +/- 0.01 U/mg, P < 0.01) and was normalized in the treated hypothyroid group (0.11 +/- 0.01 U/mg vs control, 0.13 +/- 0.01 U/mg). Low body mass during both hypothyroidism and hyperthyroidism is therefore associated with reduced systemic IGF bioactivity. In hypothyroidism there is a primary defect in the endocrine function of IGF-I, while in hyperthyroidism serum IGF bioactivity is reduced in the presence of normal endocrine production of this anabolic hormone.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗