The SPEAK study rationale and design: A linguistic corpus-based approach to understanding thought disorder.

AIM: Psychotic symptoms are typically measured using clinical ratings, but more objective and sensitive metrics are needed. Hence, we will assess thought disorder using the Research Domain Criteria (RDoC) heuristic for language production, and its recommended paradigm of "linguistic corpus-based analyses of language output". Positive thought disorder (e.g., tangentiality and derailment) can be assessed using word-embedding approaches that assess semantic coherence, whereas negative thought disorder (e.g., concreteness, poverty of speech) can be assessed using part-of-speech (POS) tagging to assess syntactic complexity. We aim to establish convergent validity of automated linguistic metrics with clinical ratings, assess normative demographic variance, determine cognitive and functional correlates, and replicate their predictive power for psychosis transition among at-risk youths. METHODS: This study will assess language production in 450 English-speaking individuals in Australia and Canada, who have recent onset psychosis, are at clinical high risk (CHR) for psychosis, or who are healthy volunteers, all well-characterized for cognition, function and symptoms. Speech will be elicited using open-ended interviews. Audio files will be transcribed and preprocessed for automated natural language processing (NLP) analyses of coherence and complexity. Data analyses include canonical correlation, multivariate linear regression with regularization, and machine-learning classification of group status and psychosis outcome. CONCLUSIONS: This prospective study aims to characterize language disturbance across stages of psychosis using computational approaches, including psychometric properties, normative variance and clinical correlates, important for biomarker development. SPEAK will create a large archive of language data available to other investigators, a rich resource for the field.

Renin and aldosterone secretion in pheochromocytoma. Effect of chronic alpha-adrenergic receptor blockade.

Patients suffering from pheochromocytoma characterized by an exclusive or almost exclusive excess of norepinephrine showed no (one patient) or only a moderate increase (two patients) in renin and aldosterone secretion. In those three patients with concomitant distinct hypersecretion of epinephrine, renin release (and aldosterone secretion except in one patient) was markedly enhanced. Similar results were obtained in a patient with excess norepinephrine and dopamine secretion. Renin release was markedly reduced in all patients during preoperative long-term alpha-adrenergic receptor blockade. With the exception of one patient, increased renin and aldosterone secretion was abolished. The results indicate that augmentation in renin release depends on the ratio of the different catecholamines secreted by the pheochromocytoma and their different effe-tiveness in stimulating beta-adrenergic receptors. Even in the presence of excess catecholamine secretion, there is evidence that renin secretion is predominantly mediated by beta receptors rather than by renal vascular alpha-adrenergic receptors. Normalization of catecholamine-induced enhanced renin release in patients with pheochromocytoma during chronic alpha-adrenergic receptor blockade supports the assumption that (alpha-) adrenergic blocking agents inhibit renin secretion distal to their blockade of specific adrenergic receptors. However, contrary to beta-adrenergic blockade, circadian rhythm of renin release seems to remain intact during alpha-adrenergic blockade.

Studies on the metabolism of steroid hormones in a virilizing adrenal cortex adenoma.

Slices of an adreno-cortical adenoma which had been obtained at operation from an 11-year-old girl with clinical signs of virilism were incubated with each of the following steroids: [1,2-3H]progesterone, [4-14C]pregnenolone, [1,2-3H]testosterone, [4-14C]androstenedione and [7-3H]dehydroepiandrosterone, respectively. Isolation and identification of the free radioactive metabolites were achieved by gel column chromatography on Sephadex LH-20, thin-layer chromatography, radio gas chromatography and isotope dilution. After incubation of progesterone, the following metabolites were identified: 11beta-hydroxyprogesterone, 16alpha-hydroxyprogesterone, 17alpha-hydroxyprogesterone, 21-deoxycortisol, corticosterone and cortisol. Pregnenolone was metabolized to 17alpha-hydroxypregnenolone, progesterone, dehydroepiandrosterone, androstenedione and 11beta-hydroxyandrostenedione. When testosterone was used as substrate, 11beta-hydroxytestosterone, androstenedione and 11beta-hydroxyandrostenedione were found as metabolites, whereas androstenedione was metabolized to testosterone and 11beta-hydroxyandrostenedione. After incubation of dehydroepiandrosterone, only androstenedione and 11beta-hydroxyandrostenedione were isolated and identified. From these results, it appears that cortisol was formed in the adenoma tissue via 21-deoxycortisol and corticosterone. Delta4-3oxo steroids of the C19-series arose exclusively from pregnenolone via 17alpha-hydroxypregnenolone and dehydroepiandrosterone, and not from progesterone and 17alpha-hydroxyprogesterone. Calculated on the amounts of metabolites formed, the highest enzyme activities were those of the 11beta-hydroxylase and the 17alpha-hydroxylase. It is interesting to note that only traces of testosterone were detected after incubation of androstenedione, whereas testosterone yielded large amounts of androstenedione.

Hypercalcitoninaemia in patients with pheochromocytoma.

As pheochromocytoma sometimes is accompanied by medullary thyroid carcinoma (in the sense of multiple endocrine adonomatosis type II = Sipple-Syndrome), serum calcitonin (CT) was measured by radioimmunoassay in 4 patients with pheochromocytoma. Before extirpation of the adreno-medullary tumor, serum CT was distinctly increased to 3 and 30 ng/ml in 2 of 4 patients, respectively. After removal of the tumor, serum CT was normal in the patients and pentagastrin stimulation produced no exaggerated CT response. In hydrochloric acid extracts from the two corresponding pheochromocytoma tissues, immunoreactive-Calcitonin (IR-CT) was detected, the concentrations amounting 1 and 4 ng/mg wet tissue. These findings suggest that hypercalcitonism in patients with pheochromocytoma cannot always be ascribed to the thyroid, i.e. increased calcitonin levels do not necessarily indicate a medullary carcinoma of this organ.

[Biosynthesis of C19- and C21-steroids in tissue slices of paraganglioma and pheochromocytoma (author's transl)]. / Biosynthese von C19- und C21-Steroiden im Paragangliom und Phäochromozytom des Menschen.

The biogenesis of C19- and C21-steroids has been studied in tissue slices of a paraganglioma, of a pheochromocytoma and of human adrenal cortex using radioactive steroids. Slices of paraganglioma as well as of pheochromocytoma metabolise 17-hydroxyprogesterone to cortisone, cortisol, 11-deoxycortisol and testosterone. The rate of formation of these steroids, however, by the two tumours is 8--15 times less than that in normal adrenal cortex tissue. After incubation of dehydroepiandrosterone with tissue slices of paraganglioma and pheochromocytoma, 7alpha-hydroxydehydroepiandrosterone, 11beta-hydroxy-4-androstene-3,17-dione and 4-androstene-3,17-dione were found as metabolites; testosterone was converted by both tissues to 4-androstene-3,17-dione. 17-Hydroxypregnenolone was converted to a small extent (1.7%) to dehydroepiandrosterone by slices of paranganglioma. These results show that enzymes of steroid biosynthesis (hydroxylases, oxidoreductases, delta4(-5)-isomerases, C17(-20)-desmolases) are present in both paraganglioma and pheochromocytoma.

Short-term fluctuations in plasma cortisol in Cushing's syndrome.

Short-term fluctuations in plasma cortisol were determined overnight in twelve patients with Cushing's syndrome: eight patients with bilateral adrenal hyperplasia of hypothalamic-pituitary orgin, three patients with a cortisol producing adenoma and one patient with a carcinoma of the adrenal cortex. While either secretory episodes in plasma cortisol or a fixed pattern of cortisol secretion were observed both in patients with pituitary dependent and in those with pituitary independent hypercorticism, a typical night-day variation in plasma cortisol was only found in one of the eight patients with Cushing's syndrome of hypothalamic-pituitary origin. The patient with a cortisol producing carcinoma showed only minor fluctuations in plasma cortisol throughout the test period. The results indicate that no discrimination can be made between patients with pituitary dependent or independent Cushing's syndrome by demonstrating an episodic or a fixed secretion of cortisol. It seems, however, that the finding of a typical night-day variation in hormone secretion points to hypercorticism of hypothalamic-pituitary orgin.