Richard V. Jackson

Glucocorticoid receptor polymorphisms and post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is reported in some studies to be associated with increased glucocorticoid (GC) sensitivity. Two common glucocorticoid receptor (GR) polymorphisms (N363S and BclI) appear to contribute to the population variance in GC sensitivity. There is some evidence that there may be a genetic predisposition to PTSD. Hence we studied 118 Vietnam war veterans with PTSD for (i) GR polymorphisms, particularly the N363S and the BclI polymorphisms which are thought to be GC sensitising, and (ii) two measures of GC sensitivity, the low-dose 0.25 mg dexamethasone suppression test (LD-DST) and the dermal vasoconstrictor assay (DVVA). The DST and GR polymorphisms were also performed in 42 combat exposed Vietnam war veterans without PTSD. Basal plasma cortisol levels were not significantly different in PTSD (399.5+/-19.2 nmol/L, N=75) and controls (348.6+/-23.0 nmol/L, N=33) and the LD-DST resulted in similar cortisol suppression in both groups (45.6+/-3.2 vs. 40.8+/-4.1%). The cortisol suppression in PTSD patients does not correlate with Clinician Administered PTSD Scores (CAPS), however there was a significant association between the BclI GG genotype and low basal cortisol levels in PTSD (P=0.048). The response to the DVVA was similar to controls (945+/-122, N=106 vs. 730+/-236, N=28, P=0.42). PTSD patients with the GG genotype, however, tended to be more responsive to DVVA and in this group the DVVA correlated with higher CAPS scores. The only exon 2 GR polymorphisms detected were the R23K and N363S. Heterozygosity for the N363S variant in PTSD, at 5.1% was not more prevalent than in other population studies of the N363S polymorphism in Caucasians (6.0-14.8%). The GG genotype of the BclI polymorphism found to be associated with increased GC sensitivity in many studies showed a tendency towards increased response with DVVA and correlated with higher CAPS scores. In conclusion, the N363S and BclI GR polymorphisms were not more frequent in PTSD patients than controls and reported population frequencies. Our PTSD group did not display GC hypersensitivity, as measured by the LD-DST and DVVA. In a subset of PTSD patients with the BclI GG genotype, CAPS scores and basal cortisol levels were negatively correlated.

New Genetic Insights in Familial Hyperaldosteronism

Abstract: Aldosterone, the major circulating mineralocorticoid, particiates in blood volume and serum potassium homeostasis. Primary aldosteronism is a disorder characterized by hypertension and, in more severe form, hypokalemia, due to autonomous aldosterone secretion from the adrenocortical zona glomerulosa. Improved screening techniques, particularly application of the plasma aldosterone: plasma renin activity ratio, has led to renewed interest in Conns original proposal that primary aldosteronism may be the cause of increased blood pressure in about 10% of adults with hypertension. Glucocorticoid‐remediable aldosteronism (GRA) was the first described familial form of hyperaldosteronism. The disorder is characterized by aldosterone secretory function regulated chronically by ACTH. Hence, aldosterone hypersecretion can be chronically suppressed by exogenous glucocorticoids such as dexamethasone in physiologic‐range doses. This autosomal dominant disorder has been shown to be caused by a hybrid gene mutation formed by a cross‐over of genetic material between the ACTH‐responsive regulatory portion of the 11b‐hydroxylase (CYP11B1) gene and the coding region of the aldosterone synthase (CYP11B2) gene. Familial hyperaldosteronism type II (FH‐II), so named to distinguish the disorder from GRA or familial hyperaldosteronism type I (FH‐I), is characterized by inheritance consistent with an autosomal dominant pattern of autonomous aldosterone hypersecretion which is not suppressible by dexamethasone. Linkage analysis in a single large kindred, and direct mutation screening, has shown that this disorder is unrelated to mutations in the genes for aldosterone synthase or the angiotensin II receptor. A recent genome‐wide search has identified a genetic linkage between FH‐II in this single large kindred and polymorphic gene markers on chromosome 7 in a region that corresponds to cytogenetic band 7p22. This is the first identified locus for FH‐II. Several possible candidate genes have been localized to the 7p22 region. The precise genetic cause of FH‐II remains to be elucidated.

Naloxone-Induced Acth Release in Man Is Inhibited by Clonidine

1. Adrenergic mechanisms play an important role in regulation of ACTH release. We used the α2‐adrenergic agonist, clonidine, as a central nervous system inhibitor of ACTH release to see if it would alter naloxone‐induced ACTH secretion in normal human volunteers.

Effects of simvastatin on blood lipids, vitamin E, coenzyme Q10 levels and left ventricular function in humans

Background  As statin therapy has been reported to reduce antioxidants such as vitamin E and coenzyme Q10 and there are indications that this reduction may cause impairment of left ventricular function (LVF), we studied the influence of simvastatin on LVF and serum vitamin E and coenzyme Q10 levels in humans.

A longitudinal physical profile assessment of skeletal muscle manifestations in myotonic dystrophy

Objectives: To develop an assessment that describes the skeletal muscle manifestations in myotonic dystrophy subjects and then use it to quantify the presentation of skeletal muscle disability and to show change over time. Design: A quantified skeletal muscle assessment was developed and applied three times over a two-year period at intervals around 12 months. Thirty-six subjects with myotonic dystrophy and 20 subjects without neuromuscular disability were evaluated. The assessment comprised manual muscle testing of five pairs of muscles, measuring neck flexor strength with a strain gauge, respiratory function tests, power and lateral pinch grip strength, all tests of impairment. Assessment of the ability to move from sitting to standing and fasten buttons tested disability. Results: Results from subjects with myotonic dystrophy were compared to the normal data. The subjects with myotonic dystrophy were significantly weaker in proximal upper limb muscles, quadriceps, tibialis anterior muscles and neck flexor muscles as well as power and lateral pinch grips. There was also significant reduction in forced expiratory volume at one second (FEV1) and forced vital capacity (FVC). Significant disability was seen in the myotonics in moving from sitting to standing and in fastening buttons. Over the two-year study period proximal upper limb and lower limb muscle strength, FVC and sit-to-stand ability declined significantly. Power grip declined but lateral pinch grip and FEV1 improved significantly. Button fastening ability improved significantly. Conclusion: The test developed was shown to be reliable and sensitive to the change in skeletal muscle manifestations in subjects with myotonic dystrophy who were shown to be significantly weaker than normal subjects.

Increased plasma noradrenaline during low dose adrenaline infusion in resting man and during sympathetic stimulation.

1. Both resting and stimulated (straight‐leg raising and head‐up tilt) levels of arterial and venous plasma noradrenaline were significantly higher during low‐dose adrenaline infusion in five mild hypertensive and four normotensive patients with one adrenal.

Interactions between the stimulated hypothalamic-pituitary-adrenal axis and leptin in humans.

Leptin, produced by adipocytes, has homeostatic effects on body fat mass through inhibition of appetite and stimulation of the sympathetic nervous system. Several studies have reported that high‐dose exogenous glucocorticoids increase circulating leptin concentrations in humans. Conversely, leptin has inhibitory effects on the hypothalamic‐pituitary‐adrenal (HPA) axis, both at the hypothalamic and adrenal levels. We hypothesized that acute hypercortisolism, in the physiological range, may not alter leptin secretion. Four stimuli of the HPA axis were administered to eight healthy male volunteers in a placebo‐controlled study. On separate afternoons, in a randomised order, fasting subjects received i.v. injections of saline, naloxone (125 μg/kg); vasopressin (0.0143 IU/kg); naloxone and vasopressin in combination; or insulin (0.15 U/kg; a dose sufficient to induce hypoglycaemia). Plasma concentrations of adrenocorticotrophic hormone (ACTH), cortisol and leptin were measured before and for 120 min after the injection. The cortisol secretory response was greatest after insulin‐hypoglycaemia, this response was significantly greater than that following naloxone, naloxone/vasopressin, or vasopressin alone. Despite the cortisol release, leptin concentrations were not increased after any stimulus. Insulin‐hypoglycaemia was associated with a decrease in leptin concentration at 60 and 90 min, while naloxone did not alter leptin concentrations. However, basal leptin concentrations were positively correlated with integrated ACTH and cortisol responses to naloxone, but did not correlate with ACTH or cortisol responses to the other stimuli. Thus acute elevations of plasma cortisol, in the physiological range, do not appear to influence plasma leptin concentrations. The fall in plasma leptin concentration after insulin‐induced hypoglycaemia may reflect catecholamine secretion after this stimulus.

Adrenocorticotropin hyperresponsiveness in myotonic dystrophy following oral fenfluramine administration.

The plasma immunoreactive adrenocorticotropin and cortisol responses to oral fenfluramine hydrochloride (1.5mg/kg body wt) or placebo were examined in 11 patients with myotonic dystrophy, 4 controls with facioscapulohumeral dystrophy, a similarly debilitating muscle wasting disease, and 14 normal controls in single‐blind studies performed in mid‐afternoon.

Naloxone-induced ACTH release: mechanism of action in humans.

Our understanding of the neuroendocrine control of ACTH secretion has undergone rapid advances since the discovery of corticotrophin-releasing hormone (CRH) in 198 1 (Orth, 1992). This 41-amino acid peptide is stored together with vasopressin in some or all of the parvicellular neurones of the paraventricular nucleus of the hypothalamus and different stimuli cause varying amounts of these two peptides to be released into the hypophyseal portal circulation (Inder et al., 1995). In humans and other species, CRH and vasopressin act synergistically to cause ACTH release from anterior pituitary corticotropes @e Bold et al., 1984). Other putative ACTH secretagogues such as angiotensin 11, adrenaline and noradrenaline have no effect on ovine CRH-induced ACTH release in humans (Orth, 1992). Thus, the principal ACTH secretagogues in humans are CRK and arginine vasopressin (AVP). The opioid antagonist naloxone was first reported to increase plasma ACTH and cortisol in humans in 1979 (Volavka et al., 1979). It was finally realized that doses of naloxone in the 10-20mg range, an order of magnitude higher than standard clinical doses, were required to cause cortisol release in man (Morley et al., 1980; Grossman & Besser, 1982). Significant increases in both ACTH and cortisol after naloxone administration to humans have been reported in randomized, double-blind, placebo-controlled studies (Al-Damluji et al., 1990; Torpy et al., 1993). In both of these studies, and in all other studies where ACTH and cortisol were both measured, ACTH rose first and peaked about 15 minutes prior to the cortisol peak, suggesting that naloxone causes cortisol secretion by releasing ACTH. Naloxone induced ACTH release in humans is blocked by pretreatment with the a ] -adrenergic antagonist, thymoxamine (Grossman & Besser, 1982), and the al-adrenergic agonist,

Hypersensitivity of the hypothalamic-pituitary-adrenal axis to naloxone in post-traumatic stress disorder

Naloxone, which increases endogenous corticotropin-releasing hormone (CRH) release by blocking an inhibitory opioidergic tone on the hypothalamic-pituitary-adrenal (HPA) axis, was administered in a dose-response protocol to seven healthy volunteers and 13 patients with treated posttraumatic stress disorder (PTSD). Six of the PTSD patients showed an increased hormonal response to the lowest naloxone dose (6 micrograms/kg) compared to both the control subjects and the other PTSD patients. This difference persisted on detailed subgroup analysis, although it was less marked at the highest naloxone dose (125 micrograms/kg). The responses of the other seven PTSD patients were indistinguishable from those of the control group. The greater responses of the six PTSD patients could not be explained on the basis of associated psychiatric illnesses or psychotropic drug therapy, and did not correlate with standard psychological testing or severity of PTSD. The results of this preliminary study therefore suggest that a hypersensitivity of the HPA axis to endogenous CRH stimulation may occur in PTSD.