Biomedical subjects
Publications and source records attributed to G Fink.
Supernatants from mouse spleen hybridoma lines established without previous immunisation were screened immunohistochemically against cryostat sections of human temporal cortex and found to stain a variety of brain structures, including Alzheimer plaques and tangles. The age of the mice had no effect on antibody production.
A young man with acute mania and unilateral cryptorchidism had plasma luteinizing hormone (LH) concentrations that were much higher than the maximum LH concentrations we have found in normal subjects and patients with schizophrenia. Plasma concentrations of testosterone and sex hormone binding globulin were not abnormal, showing that the elevated plasma LH concentrations were probably due to increased secretion of LH-releasing hormone (LHRH). This case supports our previous results which suggest that an abnormally high secretion of LHRH, due presumably to an abnormality in central neurotransmission, may be a feature of acute mania in young men.
The hypothesis that ECT produces selective effects on hypothalamic-pituitary activity was investigated by determining the effect of ECT on pituitary hormone release in nine depressed patients. After ECT there were massive and rapid increases in the plasma concentrations of nicotine- and oestrogen-stimulated neurophysin (NSN and ESN), prolactin (PRL) and adrenocorticotropin (ACTH), smaller increases in plasma luteinizing hormone (LH) and cortisol, a significant decrease in plasma growth hormone (GH) concentration but no change in plasma thyrotropin (TSH). There was significant attenuation of PRL responses with repeated ECT. The hormonal responses to ECT cannot simply be attributed to stress, since a similar pattern of increases in plasma hormone concentrations did not occur in psychologically normal patients in whom plasma hormone concentrations were measured during induction of anaesthesia and abdominal incision for cholecystectomy. Analysis of these hormonal responses in terms of the knowledge available on the neurotransmitter control of pituitary hormone release suggests that some of these hormonal responses to ECT may be mediated by the activation of serotonergic neurones, while others are probably due to direct stimulation of the neuroendocrine neurones themselves.
Twenty patients with bronchial asthma, on long-term oral therapy with theophylline, demonstrated an increased number of suppressor T-cells and impaired graft vs host reaction. Ten asthmatics on other therapy, not including theophylline, as well as ten normal healthy controls, failed to show similar findings. Elimination of suppressor T-cells corrected the above immunological abnormalities in the theophylline-treated patients, while addition of serum from theophylline-treated asthmatic patients to lymphocytes from normal healthy controls, affected the graft vs host reaction of these lymphocytes. We conclude that theophylline induces quantitative as well as qualitative immunological alterations by increasing the number and activity of suppressor T-cells, which most probably secrete a serum factor, responsible for some of the abnormalities observed.
A systematic endocrine investigation in dementia, depression and control subjects showed that plasma growth hormone (GH) was higher in the morning and plasma TSH concentrations were higher throughout the day in Alzheimer-type dementia (ATD) than in age-matched depressed patients (MDD), and plasma TSH concentrations were also higher throughout the day in female ATD compared with age-matched female control subjects. The increased plasma TSH concentrations could not be due to reduced negative feedback because plasma T3, T4 and rT3 were in the normal range. Plasma concentrations of oestrogen-stimulated neurophysin (ESN) were lower throughout the day in ATD compared with MDD and controls and lower in the morning compared with other dementias. The high plasma GH and TSH concentrations in ATD may reflect the reduced hypothalamic content of somatostatin in ATD, and the reduced concentrations of ESN may reflect reduced cholinergic activity in ATD brain. These selective hormonal changes provide a useful diagnostic test for Alzheimer's disease.
Basal plasma luteinising hormone concentrations and the LH responses to LH-releasing hormone injection were higher in 11 young men after recovery from mania than in 15 control subjects. Since plasma concentrations of testosterone and sex hormone binding globulin were similar in the recovered manic compared with the control subjects, the increased LH response to LHRH is likely to have been due to the priming effect of LHRH consequent on an increased release of LHRH into hypophysial portal vessel blood. Abnormal control of LHRH, and thereby LH release, is a state-independent feature in male patients with mania and may be a useful trait marker for this disorder.
The LHRH receptor has been solubilized from male rat anterior pituitary glands, using the zwitterionic detergent 3-((3-cholamidopropyl)-dimethylammonio)-1-propanesulphonate in the presence of a high concentration of sodium chloride. This method gave high yields (up to greater than 70%) of the LHRH-binding site from the membrane preparation. Ligand binding studies using LHRH analogues were carried out to determine dissociation constants for LHRH receptors both in situ in the membrane preparation and for solubilized LHRH receptors. For all the analogues the binding characteristics were similar in both preparations, suggesting that the solubilization procedure left the LHRH receptor undenatured. Gel filtration revealed an apparent molecular weight for the LHRH receptor of 100,000-160,000, with the mean value being approximately twice that found by others using sodium dodecyl sulphate-polyacrylamide gel electrophoretic techniques. The results indicate that the LHRH receptor probably exists in gonadotroph membranes as a large complex of more than one subunit.
The nucleotide sequence of cDNA encoding the human substance P precursor, beta-preprotachykinin (beta-PPT), has been determined. The source of mRNA was a human laryngeal carcinoid tumour that contained a high concentration of immunoreactive substance P. The human beta-PPT polypeptide is 129 amino acids long and contains regions encoding substance P and neurokinin A, each flanked by basic amino acid residues. Residues 72-107 of the human beta-PPT polypeptide encode the sequence of neuropeptide K, an N-terminally extended form of neurokinin A recently isolated from porcine brain.
Subcellular fractions were prepared from the hypothalamus-preoptic area and the 'remainder of the brain' of intact male and female rats at 0, 8, 25 and 72 days of age. Proteins associated with each fraction were subjected to SDS-PAGE chromatography and stained with Coomassie Brilliant Blue. Developmental changes were found to occur in proteins associated with the soluble (14,600, 15,000, 29,900, 38,900 and 49,000 mol. wt), nuclear (40,000-50,000 and 13,800-16,000 mol. wt.), mitochondrial-lysosomal (49,000-52,000 mol. wt.) and microsomal (14,400, 20,000, 50,100, 56,900 and 130,000 mol. wt.) fractions. In addition, soluble proteins were greater in males than in females at days 0 (53,000-56,000 mol. wt.; probably tubulin) and 25 (14,600 and 15,000 mol. wt.). These changes in brain proteins probably reflect important structural and functional changes that occur during maturation and sexual differentiation of the brain.
Sex differences in brain protein synthesis were investigated by analyzing the in vitro translation products of poly (A)+ mRNA isolated from the hypothalamus-preoptic area of male, female and androgenized female (injected with testosterone propionate at day 4) rats at different stages of development. Poly (A)+-enriched mRNA, prepared by oligo (dT)-chromatography of total RNA extracted by guanidine thiocyanate, was translated in either a rabbit reticulocyte lysate or cell-free wheat germ system supplemented with either [35S]methionine or a [3H]amino acid mix. The translation products were analyzed by one- and two-dimensional SDS-PAGE. Several developmental and androgen-induced changes were found in the translation products of specific mRNA species, the most important of which was a sex difference (higher in the male) in the apparent amount of mRNA coding for proteins with the electrophoretic characteristics of actin and tubulin. These developmental and sex differences in the apparent amounts of specific mRNA species in brain may be the cause or result of functional and structural changes such as neurite growth and synapse formation.
The number of glucocorticoid receptor sites in lymphocytes was estimated and plasma cortisol concentrations measured in 17 depressed patients, 12 patients with chronic schizophrenia, and 31 healthy control subjects. The number of receptor sites was significantly lower in the depressed patients than in either the controls or the patients with chronic schizophrenia, but there were no differences between the groups in the dissociation constants of the glucocorticoid receptors or the plasma cortisol concentrations. When two control subjects were studied intensively over 28 hours a slight diurnal variation in the number of glucocorticoid receptors was detected. The lower numbers of glucocorticoid receptors in the lymphocytes of depressed patients may explain why such patients, who often have hypercortisolaemia, do not show the clinical features of excess production of cortisol.
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We have developed a fluorescence cell sorting (FACS) method for the separation of neurofibrillary tangles from post-mortem brain from cases of Alzheimer's disease and Down's syndrome. Neurofibrillary tangles in brain homogenate were selectively labelled with the fluorescent dye congo red. Using FACS the tangles were separated from other tissue components on the basis of fluorescence and forward-angle light scatter to give a fraction highly enriched in tangles, which were identified by light and crossed polarisation microscopy. Tangles were not observed in a comparison fraction, collected at the same time, of weakly fluorescent particles of similar size to the tangles. Thus FACS provides a non-denaturing method for obtaining preparations of neurofibrillary tangles for purposes of further analysis.
B-Lymphocytes from two patients with Alzheimer's disease and one healthy subject were transformed into lymphoblastoid cells by exposure to Epstein-Barr virus. In culture, more than 50% of these cells secreted sufficient IgM or IgG antibody (mainly IgM) to allow immunohistochemical screening against cryostat sections of normal and Alzheimer temporal cortex. More than 30% of the IgM antibodies from each subject recognised brain components, namely: neurons, astrocytes, nuclei, nucleoli, and Alzheimer plaques and neurofibrillary tangles. This methodology represents a major addition to the procedures currently available for the generation of antibodies towards normal and pathological structures in human brain.
Monoclonal antibodies were raised to membranes of hypoglossal nuclei from normal human post-mortem brain. Two of these clones were recloned to yield antibodies ES.18 and ES.19. Antibody ES.18 stained some, but not all, neuronal perikarya in the medulla oblongata and other brain areas. Neurons stained by this antibody did not have a common neurotransmitter or physiological function, although they tended to be large. Perikarya in the basal forebrain nucleus from a case of Alzheimer-type dementia were stained much more intensely by ES.18 than were these perikarya in a control brain. Antibody ES.19 did not stain neuronal perikarya but stained glial fibrillary acidic protein-positive processes below the pia, in the subependymal layer and in the molecular layer of the cerebellum of control and Alzheimer brains. This antibody also stained the numerous glial fibrillary acidic protein-positive astrocytes in Alzheimer cerebral cortex, but did not stain glial fibrillary acidic protein-positive astrocytes in the white matter of brains from controls or cases of Alzheimer-type dementia. The staining pattern of ES.19 suggests that fibrous astrocytes in Alzheimer cerebral cortex are antigenically different from fibrous astrocytes in white matter.
Asthmatic patients have a deficiency of concanavalin A-(Con A) induced suppressor cell function. We tested whether oral colchicine 0.5 mg twice daily for 7 days could correct this immunoregulatory abnormality. Peripheral blood mononuclear cells were incubated with Con A and then suppression of proliferation was measured by coculture of these cells with healthy volunteers' mononuclear cells and phytohaemagglutinin. Sixteen asthmatic patients had significantly (P less than 0.002) decreased Con A-induced suppressor cell function (17.0 +/- 17.2%, mean +/- s.d.) as compared to 13 healthy volunteers (37.9 +/- 14.9%). Oral colchicine significantly (P less than 0.05) increased, though only partially corrected, these 16 asthmatic patients' Con A-induced suppressor cell function (28.1 +/- 14.3%). Asthmatic patients had an increased number of monocytes (691 +/- 289 vs 388 +/- 271/mm3 for normals, P less than 0.01) and a normal number of lymphocytes, Leu 4+ total T cells, Leu 3+ helper/inducer T cells, and Leu 2+ suppressor/cytotoxic T cells as well as a normal Leu 3/Leu 2 ratio. Oral colchicine significantly (P less than 0.005) decreased the number of monocytes (451 +/- 255/mm3) without significantly affecting the number of lymphocytes, Leu 4+, Leu 3+, or Leu 2+ T cells, or the Leu 3/Leu 2 ratio. These results are consistent with the hypothesis that the deficiency of Con A-induced suppressor cell function in asthmatic patients may be due, in part, to an increased number and/or abnormal activity of monocytes. If so, then oral colchicine may have partially corrected the deficiency of Con A-induced suppressor cell function by decreasing the number and/or modulating the activity of monocytes.
We have investigated the effects of hyperprolactinemia, produced by pituitary isografts under the kidney capsule (16-20 days), on the LH releasing action and priming effect of LH-releasing hormone (LHRH) in normal and hypogonadal (hpg) female mice. The pituitary grafts increased the plasma prolactin concentrations about 3-fold in normal intact mice and 4-fold in hpg mice. The extent of the graft-induced hyperprolactinemia was reduced by ovariectomy in normal mice, but was the same in grafted hpg compared with intact normal mice despite the absence in the hpg mice of functioning ovaries. The priming effect of LHRH could be elicited in both types of mice by giving two injections of LHRH separated by an interval of 60 min. Hyperprolactinemia did not reduce the amount of LH released in response to a first injection of LHRH, but did reduce significantly the amount of LH released (primed) in response to a second injection of LHRH. Ovariectomy significantly increased the magnitude of the releasing action of LHRH in normal mice and prevented the graft-induced reduction of LHRH priming. These results show that hyperprolactinemia in normal and hpg mice suppresses the magnitude of the priming effect of LHRH. This may be an important mechanism by which prolactin reduces gonadotropin secretion.
To determine whether high plasma cortisol concentrations are a distinctive feature of depression or whether plasma cortisol is also elevated in other forms of psychosis, cortisol concentrations were measured in 59 patients with acute functional psychoses, six non-psychotic depressed patients and 37 control subjects, all free of antidepressant and neuroleptic drugs for at least three months. Patients with schizo-affective disorder, manic type, had the highest concentrations throughout the day and those with major depressive disorder, psychotic sub-type had higher concentrations than controls in the afternoon and evening. Manic and schizophrenic patients had cortisol concentrations above controls in the afternoon only. Elevated concentrations were not related to the presence of depressed mood or to duration of stay in hospital, and a return to normal occurred irrespective of the type of treatment used. Thus raised plasma cortisol concentrations are a feature of psychotic illness, but in drug-free patients are not specific for severe depression.