Characterizing an ensemble of interacting oscillators: the mean-field variability index.

We introduce a way of characterizing an ensemble of interacting oscillators in terms of their mean-field variability index κ, a dimensionless parameter defined as the variance of the oscillators' mean field r divided by the mean square of r. Based on the assumption that the overall mean field is the sum of a very large number of oscillators, each giving a small contribution to the total signal, we show that κ depends on the mutual interactions between the oscillators, independently of their number or spectral properties. For purely random phasors, or a noninteracting ensemble of oscillators, κ converges on 0.215. Interactions push κ in different directions: lower where there is interoscillator phase coherence, tending to zero for complete phase synchronization, or higher for amplitude synchronization or intermittent synchronization. We calculate κ for several different cases to illustrate its utility, using both numerically simulated data and electroencephalograph signals from the brains of human subjects while awake, while anesthetized, and while undergoing an epileptic fit.

The effects of cigarette smoking and alcohol consumption on blood haemoglobin, erythrocytes and leucocytes: a dose related study on male subjects.

The objective of this study was to quantify the combined dose related effects of cigarette smoking and alcohol consumption on blood haemoglobin concentration, erythrocytes and leucocytes. The subjects consisted of 17,670 males attending for routine health screening, with an average age of 43 years and a range of 16-91 years. The number of cigarettes smoked each day was divided into six categories, and declared alcohol consumption into seven. Of the 42 different combinations of smoking and drinking groups, five were not reported because they contained less than 30 subjects. Haemoglobin concentration was significantly increased in those smoking more than 10 cigarettes per day. Smoking also increased the PCV. Alcohol had no effect on Hb or PCV. The red cell count was reduced by alcohol consumption, with even the lowest consumption producing a significant decrease. Both smoking and drinking raised the MCV in a linear dose relationship. The marked increase in white cell count with smoking was seen even in subjects smoking 10 cigarettes per day or less. It is suggested that social habits such as smoking and drinking should be considered when interpreting blood haematology values. Changes in haematology results could be used to encourage a healthier lifestyle.

Bone density, biochemistry and life-style.

We have assessed the relationship between bone density, biochemistry and life-style factors in a cross-sectional study of 434 pre- and 357 postmenopausal women. Bone-mineral content (BMC) was measured in the non-dominant forearm using single-photon densitometry. Bone mass was corrected for bone size (BMC2) in a sub-set of 263 subjects. Correlation statistics and multiple regression analyses were used to identify physical and biochemical measurements that could be used to best predict BMC or BMC2. These were combined with lifestyle factors, using multiple logistic regression analysis, to identify women at risk of low bone density. Cut-off values were taken as the 5th percentile of the bone density distributions in pre-menopausal women. In postmenopausal women, using BMC2 values to define "risk", and using age, creatinine, alkaline phosphatase, thyroxine treatment, and calcium supplementation as predictors, a sensitivity of 73% and a specificity of 95% were achieved. Such a model may be of use as a "first pass" screening test for osteoporosis.

Peptides related to alpha-melanocyte-stimulating hormone are commonly produced by human pituitary corticotroph adenomas: no relationship with pars intermedia origin.

The presence of immunoreactive (ir)-alpha-MSH has been investigated by immunocytochemistry in 24 pituitary adenomas and one case of corticotroph hyperplasia causing Cushing's disease, in four adenomas causing Nelson's syndrome, and in ten 'silent' corticotroph adenomas. It was found that a high proportion of these adenomas have a population of cells containing ir-alpha-MSH in addition to ir-ACTH. In some instances, these adenomas were clearly not associated with the residual intermediate lobe of the pituitary. Radioimmunoassay of plasma from patients with Cushing's disease or Nelson's syndrome showed elevated levels of ir-alpha-MSH in the majority of cases. Characterization of the ir-alpha-MSH in adenoma cells by immunocytochemistry, using an antiserum selective for acetylated forms of alpha-MSH, suggested that only the desacetyl form was present in each case examined. High-performance liquid chromatography of adenoma tissue extracts revealed material co-eluting with acetylated forms of alpha-MSH in only one of six cases. These results have been compared with corticotroph adenomas in animal pituitary glands, and it is concluded that the presence of alpha-MSH peptides cannot be used as a marker for intermediate lobe tumours, and that desacetyl alpha-MSH is commonly produced by corticotroph adenomas.

A bromocriptine-responsive corticotroph adenoma secreting alpha-MSH in a patient with Cushing's disease.

Clinical and in-vitro investigations have been performed on a corticotroph adenoma removed from a patient suffering from Cushing's disease. Prior to surgery, the patient's Cushing's disease had been successfully controlled, clinically and biochemically, by long term administration of bromocriptine. After selective adenomectomy, tumour tissue was investigated by a perfused isolated cell column technique. It was shown that the tumour cells secreted immunoreactive- (IR)- ACTH and IR-alpha-MSH and that the release of both peptides was promptly suppressed by dopamine. Chromatographic analysis of the secreted IR-alpha-MSH revealed a high proportion of acetylated alpha-MSH; smaller amounts of desacetyl alpha-MSH and diacetyl alpha-MSH were present. The relevance of these findings to the proposal that certain corticotroph adenomas are derived from the intermediate lobe of the pituitary is discussed. It is concluded that there is little direct evidence for involvement of the residual zona intermedia of the adult human pituitary in the development of Cushing's disease.

Ectopic ACTH production by a thymic carcinoid tumour.

An ACTH-producing thymic carcinoid tumour was diagnosed in a 10-year-old girl, 8 years after bilateral adrenalectomy for Cushing's syndrome. The peptides produced by the tumour were characterised thoroughly. High circulating levels of beta-endorphin and other peptides may have contributed to mood and behaviour disturbances.

The distribution of immunoreactive alpha-melanocyte-stimulating hormone cells in the adult human pituitary gland.

It has been suggested that a proportion of the adenomas and the nodular hyperplasia of cells in the pituitary gland in cases of Cushing's disease are derived from cells of the pars intermedia rather than the pars anterior. The evidence can be summarized as follows: the posterior site of adenoma or nodular hyperplasia in the pituitary, the innervation of cells and the suppressive response to the dopamine agonist bromocriptine in vivo or to dopamine in vitro. All these observations infer analogy with cells of the pars intermedia of other species, which are controlled by direct neural tonic dopaminergic inhibition. The adult human pituitary gland, however, does not possess a morphologically distinct pars intermedia, due to regression of the rudimentary fetal pars intermedia after birth, with mixing of cells into the pars anterior and pars nervosa. Since cells of the pars intermedia characteristically synthesize alpha-MSH, we have studied this peptide in order to assess the occurrence and distribution of intermedia-derived cells in the adult human pituitary. Sections from 100 pituitaries, removed at autopsy, were stained by an indirect immunoperoxidase technique using non-cross-reacting antisera specific for alpha-MSH and ACTH. Immunoreactive alpha-MSH (IR-alpha-MSH) cells were found in a total of 97 specimens. Of these, only ten cases showed a marked concentration of IR-alpha-MSH cells in the zona intermedia. In the majority of pituitaries, IR-alpha-MSH cells were more commonly seen in the pars anterior than in the zona intermedia; in 41 cases, IR-alpha-MSH cells were completely absent from the zona intermedia.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of pro-opiomelanocortin-derived peptides in pituitary and ectopic adrenocorticotrophin-secreting tumours.

The molecular forms of pro-opiomelanocortin in plasma of normal subjects and plasma and tissue extracts from patients with disorders of the hypothalamic-pituitary-adrenal axis have been characterized using gel filtration chromatography under acid dissociating conditions, and the molecular forms further investigated by high pressure liquid chromatography and affinity chromatography. A large molecular weight MSH/ACTH fragment was observed in all plasma samples chromatographed, although the proportions of this fragment were significantly greater in patients with the ectopic ACTH syndrome. A similar profile was observed in tumour extracts: a greater proportion of large molecular weight precursors was observed. Immunoreactive-gamma-MSH in extracts of ectopic tumours displayed marked and variable heterogeneity, and affinity chromatography with Concanavalin A-Sepharose indicated that this was due to differential glycosylation. High pressure liquid chromatography of a peak of amino terminal pro-opiomelanocortin (N-POC(1-76)) and 22 000 mol. wt MSH/ACTH indicated two peaks in each peptide, again possibly due to differential glycosylation. A possible neurointermediate lobe origin of atypical invasive pituitary tumours is discussed.

A case of pituitary dependent Cushing's disease with clinical and biochemical features of the ectopic ACTH syndrome.

A case of atypical pituitary dependent Cushing's disease is reported. The patient presented with clinical symptoms similar to those of the ectopic ACTH syndrome; notably a marked hypokalaemic alkalosis, widely fluctuating plasma cortisol levels, greatly elevated plasma ACTH levels, and failure to suppress both plasma cortisol and ACTH levels following high dose oral dexamethasone. However, a large aggressive pituitary tumour was detected by skull X-ray and computed tomography. Removal of the pituitary tumour led to full remission of the patient's Cushing's syndrome. Pro-opiomelanocortin (POMC) related peptides in the plasma and tumour tissue extract of this patient have been characterized by gel-filtration and Concanavalin-A Sepharose affinity chromatography, indicating processing of POMC in a manner more usually associated with ectopic tumours.

Pituitary ACTH dependent Cushing's syndrome due to ectopic production of a bombesin-like peptide by a medullary carcinoma of the thyroid.

A 41-year-old man presented with Cushing's syndrome and the biochemical features of ectopic ACTH production. Investigation revealed mediastinal metastases from a medullary carcinoma of the thyroid. The peripheral plasma contained grossly elevated levels of bombesin-like immunoreactivity (irBombesin) as well as calcitonin; blood sampling via a venous catheter confirmed a gradient of irBombesin, but not of ACTH, in the mediastinal vein draining the tumour. On extraction the tumour contained a bombesin-like peptide, but not vasopressin or corticotrophin releasing factor and only very low levels of ACTH; immunohistochemical studies showed positive immunostaining for bombesin and calcitonin but none for ACTH or CRF. No ACTH was released from dispersed tumour cells in vitro. However an extract of the tumour stimulated ACTH release in vitro from perifused dispersed rat anterior pituitary cells. This is the first reported case of Cushing's syndrome due to ectopic production of a bombesin-like peptide, causing excessive pituitary ACTH secretion.

Measurement of immunoreactive gamma-MSH in human plasma.

A radioimmunoassay for immunoreactive gamma-MSH (IR-gamma-MSH) in human plasma has been developed. The assay is capable of detecting normal basal circulating levels which range from less than 20-100 ng/1 at 0900 h. Plasma levels are raised concomitantly with ACTH during insulin induced hypoglycaemia and CRF stimulation and suppressed with dexamethasone. Chromatographic characterisation of IR-gamma-MSH in plasma demonstrates a major peak of IR-gamma-MSH, corresponding to purified glycosylated N-terminal pro-opiomelanocortin 1-76, when IR-gamma-MSH is secreted from the pituitary. In contrast IR-gamma-MSH produced ectopically appears to be heterogeneous.

Corticotrophin-releasing factor--mediated adrenocorticotrophin release from rat anterior pituitary cells is potentiated by C-terminal gastrin-releasing peptide.

The remission of Cushing's syndrome following surgical removal of a tumour containing bombesin-like immunoreactivity (BLI), but insignificant levels of ACTH, is described. However, an acid extract of the tumour tissue caused the release of ACTH from isolated rat anterior pituitary cells in vitro. These observations led to an investigation of the effects of synthetic C-terminal gastrin-releasing peptide (GRP(14-27] on ACTH release from isolated rat anterior pituitary cells. GRP(14-27) (10-1000 ng/ml) directly stimulated the release of ACTH in vitro, whereas lower doses (10-1000 pg/ml), ineffective themselves in eliciting ACTH release, potentiated the CRF-mediated in-vitro release of ACTH.

Pro-opiocortin related peptides in human pituitary and ectopic ACTH secreting tumours.

Basal and stimulated secretion of N-terminal pro-opiocortin (Pro-gamma-MSH), ACTH and LPH from seven pituitary and three ectopic ACTH secreting tumours have been studied in vitro using a perfused isolated cell system. The peptides were shown to be released concomitantly and in equimolar amounts. The pituitary tumours responded to stimulation with rat stalk median eminence extracts (SME) and synthetic AVP. However, peptide release from the ectopic tumours, although pulsatile, remained autonomous. Prior to surgery, gel-chromatographic profiles of plasma immunoreactive ACTH showed only one peak, which eluted in the position of 1-39 ACTH, in patients with the pituitary tumours, but there was a second peak of large molecular weight ACTH present in the plasma from those with the ectopic ACTH syndrome. This second form of ACTH could not be detected in any of the tumour cell column effluents. An eighth pituitary tumour was atypical, in its unusually large size, clinically aggressive nature and spectrum of peptide release. Although peptide release in response to stimulation with SME was similar to that observed with the other pituitary tumours, the chromatography of the plasma ACTH resembled the ectopic plasma pattern, showing two peaks of immunoreactivity.