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Biomedical subjects

S L Lightman

Publications and source records attributed to S L Lightman.

At least 217 records · Page 12Linked to original sources
PubMed1992

Neuropeptide Y messenger ribonucleic acid in the magnocellular hypothalamo-neurohypophysial system of the rat is increased during osmotic stimulation.

In the magnocellular hypothalamo-neurohypophysial system of the rat, levels of neuropeptide Y (NPY) mRNA were investigated by in situ hybridization histochemistry both in normal and osmotically stimulated animals. As an osmotic stimulus, animals were given 340 mM NaCl to drink for 12 days. After saline treatment, there was a very marked increase in NPY mRNA in the hypothalamic magnocellular supraoptic (SON) and paraventricular (PVN) nuclei (7600% and 3200%, resp.). These data suggest that magnocellular SON and PVN neurons synthesize NPY in response to the physiological stimulus of increased plasma osmolality.

Animals↗
PubMed1992

5-Hydroxytryptamine stimulates corticosteroid-sensitive CRF release from cultured foetal hypothalamic cells. Role of protein kinases.

5-Hydroxytryptamine (5-HT) has been shown to activate the hypothalamo-pituitary-adrenal axis, possibly by a direct action on hypothalamic CRF synthesis and release. In order to study the mechanisms involved in this effect, foetal hypothalamic cells were cultured and corticotropin-releasing factor-41 (CRF) release was measured by radioimmunoassay. 5-HT induced CRF release in a dose-dependent manner. Further studies were performed with a specific protein kinase C inhibitor, H-7 (1-(5-isoquinolinesulfonyl)-2-methyl-piperazine) and a specific cyclic adenosine monophosphate-dependent protein kinase inhibitor, IP-20. Basal release of CRF-41 from the cultured hypothalamic cells was unaffected by IP-20 and was only diminished at a high (50 microM) concentration of H-7. 5-HT stimulated-CRF release, however, was blocked by both H-7 and IP-20. Dexamethasone and aldosterone both caused a dose-dependent inhibition of 5-HT induced CRF release. These results demonstrate that CRF can be released from hypothalamic neurons in response to 5-HT through a protein kinase C and protein kinase A dependent mechanism and that 5-HT stimulated CRF release can be inhibited by dexamethasone and aldosterone.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1992

Hypothalamic corticotropin-releasing hormone and opioid peptide neurons: functional changes after adrenalectomy and/or castration.

The influences of short- and long-term castration and adrenalectomy (or both) upon corticotropin-releasing hormone (CRH) mRNA levels, CRH peptide levels, and endogenous opioid peptide (EOP) content in the hypothalamus, and basal and CRH-stimulated EOP release in vitro, were examined. Gonadal and adrenal steroids regulated the function of these hypothalamic peptidergic systems in terms of peptide synthesis, storage pools, and secretion. The steroids were also found to alter the sensitivity of EOPergic neurons to CRH. In some cases, evidence was obtained for an interaction between gonadal and adrenal steroids in determining neuronal function (seen as additive or counteractive effects). A finding of major importance was that the response of these peptidergic systems was markedly influenced by the duration of steroid deprivation, the results of chronic treatment often being opposite to those of acute treatment. Lastly, inspection of the data on peptide synthesis, storage and release, revealed that there was no simple relationship between these three parameters even within a single type of peptidergic neuron.

Adrenalectomy↗
PubMed1992

Therapeutic response to somatostatin analogue, BIM 23014, in metastatic prostatic cancer.

Metastatic prostate cancer is well known to respond to hormonal manipulations, but once progression occurs new treatment modalities are required. Specific and systemic antitumour therapy is preferable to local treatments such as radiotherapy in such patients. The finding that somatostatin analogue, BIM 23014, inhibits prostatic tumour growth in animal models is of great interest. We treated 25 poor risk patients with progressive metastatic prostate cancer. Sixteen had also failed to respond to 'total androgen blockade'. Two patients have achieved a partial remission, one of which is maintained at over 30 months, and three had stable disease for over 6 months. Side effects have consisted of mild diarrhoea and abdominal cramp in the first few days of treatment in a minority of the patients. These results are encouraging and further randomized studies are in progress.

Aged↗
PubMed1992

Interleukin-6 and corticotrophin-releasing hormone mRNA are modulated during differentiation of human neuroblastoma cells.

Two cell clones [BE(2)-C and BE(2)-M17] derived from the human neuroblastoma cell line SK-N-BE(2) express corticotrophin-releasing hormone as well as interleukin-6 mRNA. Both genes are overexpressed, although with a different time course, following exposure to 5 microM retinoic acid, in parallel to the induction of neuroblastic differentiation. On the contrary, we are unable to detect interleukin-1 beta mRNA in these cell lines. Both cytokines are known to increase hypothalamic CRH mRNA. The production of cytokines and neuropeptides by neuroblastoma cells indicate a complex dialogue between tumour cells and anti-tumour immunity.

Blotting, Northern↗
PubMed1992

Effects of cyclosporine A on the hypothalamic-pituitary-adrenal axis and anterior pituitary interleukin-6 mRNA expression during chronic inflammatory stress in the rat.

In the rat, adjuvant arthritis (AA) is an inflammatory joint disease associated with chronic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. We have investigated the effects of the immunosuppressive agent cyclosporine A (CsA) on plasma levels of adrenocorticotropin (ACTH) and corticosterone (B), as well as on anterior pituitary proopiomelanocortin (POMC) and interleukin (IL)-6 mRNA accumulation in control and adjuvant-injected animals. In control animals, CsA reduced basal anterior pituitary POMC and IL-6 mRNA and decreased plasma levels of ACTH and B. Adjuvant-injected animals that were treated with CsA showed no clinical signs of AA. Moreover, CsA inhibited the arthritis-induced increases in pituitary POMC and IL-6 mRNA levels and in circulating ACTH and B. In vitro, CsA reduced the POMC mRNA content of cultured anterior pituitary cells and diminished the stimulatory effects of corticotropin-releasing hormone (CRH) on POMC mRNA expression and ACTH secretion from these cells. These data indicate that CsA has a direct action on the HPA axis and also reduces the activation of the HPA axis seen in chronic inflammatory arthritis.

Adrenocorticotropic Hormone↗
PubMed1992

Response of pituitary and spleen pro-opiomelanocortin mRNA, and spleen and thymus interleukin-1 beta mRNA to adjuvant arthritis in the rat.

During development of adjuvant-induced arthritis (AA) in the rat, pituitary pro-opiomelanocortin (POMC) mRNA expression was increased. Pituitary POMC mRNA was much higher following adrenalectomy and AA. Spleen POMC mRNA also increased with a similar time kinetics, although the levels in the spleen were much lower than those in the pituitary. In control animals, spleen interleukin-1 beta (IL-1 beta mRNA) was undetectable, whereas AA led to the accumulation of IL-1 beta mRNA and the highest levels were seen in the adrenalectomised AA group. Thymic IL-1 beta expression was also increased in AA animals. These results suggest that AA leads to the activation of both the neuroendocrine and the immune systems and the interaction between these systems may play a role in this disease state.

Adrenalectomy↗
PubMed1992

Interleukin-1 beta induces corticotropin-releasing factor-41 release from cultured hypothalamic cells through protein kinase C and cAMP-dependent protein kinase pathways.

Interleukin-1 beta (IL-1 beta) induces a dose-dependent increase in the release of corticotropin-releasing factor-41 (CRF) from dispersed rat fetal hypothalamic cells in culture. This release of CRF could be inhibited by the protein kinase C inhibitor H-7, and by the protein kinase A inhibitor IP-20. This suggests that both protein kinase C and protein kinase A-dependent pathways are involved in the response of CRF to IL-1 beta. Dexamethasone also blocked the CRF response to IL-1 beta, indicating that activated glucocorticoid receptors can inhibit the response of CRF to IL-1 beta.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1992

Chronic stress elevates enkephalin expression in the rat paraventricular and supraoptic nuclei.

Numerous studies have implicated opioids in the regulation of hypothalamic functions. Dynorphin, which is co-expressed with vasopressin in the magnocellular neurons of the paraventricular and supraoptic nuclei, is co-regulated with vasopressin in response to hyperosmolality and appears to inhibit vasopressin and oxytocin release from the posterior pituitary. Enkephalin is present in paraventricular parvocellular neurons and its expression is elevated in response to various stresses. However, enkephalin's presence and roles in paraventricular and supraoptic magnocellular neurons are uncertain. By giving rats daily intraperitoneal injections of hypertonic saline for up to 12 days, we induced a marked increase in enkephalin expression in magnocellular neurons of the paraventricular and supraoptic nuclei, beyond what develops from drinking hypertonic saline. Our results suggest that enkephalin expression in both vasopressin and oxytocin neurons may increase in response to chronic stresses and provide another source of enkephalin in addition to the parvocellular neurons.

Adrenalectomy↗
PubMed1992

Action of interleukin-2 and interleukin-4 on CRF mRNA in the hypothalamus and POMC mRNA in the anterior pituitary.

We have used the technique of in situ hybridization histochemistry to determine corticotropin-releasing factor (CRF) mRNA in the hypothalamic paraventricular nucleus (PVN) and proopiomelanocortin (POMC) mRNA in the anterior pituitary of rats given a single ip injection of either interleukin (IL)-2 or IL-4. IL-2 increased POMC mRNA in the anterior pituitary in a dose-dependent manner. The effect was apparent both at 4 and 24 h after injection. No effect of IL-2 on CRF mRNA in the PVN was detected in these animals, suggesting that the increase in POMC mRNA was not driven by an increase in CRF. IL-4 was without effect at the hypothalamic level although this cytokine did result in a decrease in POMC mRNA in the anterior pituitary.

Animals↗
PubMed1992

Low-dose cyclosporin therapy of ocular inflammation: preliminary report of a long-term follow-up study.

Cyclosporin A (CsA) is an effective therapy for severe intraocular inflammation but nephrotoxicity and hypertension are major side effects even in low dose in combination with oral corticosteroids and clinical studies on the long-term effects of low-dose CsA therapy outside the field of organ transplantation are lacking. This multicentre, open, longitudinal study has been established to evaluate the long-term efficacy and side effects of low-dose CsA therapy (initial dose less than or equal to 5 mg/kg/day, with a maximum dose of 7 mg/kg/day, and total treatment duration greater than 3 months) in severe ocular inflammation where conventional therapy had failed to control the disease or caused intolerable side effects. Visual response to treatment, clinical signs and symptoms of side effects, biochemical and haematological parameters have been recorded at 3-monthly intervals since January 1987 and will continue until December 1993. Data for 74 patients (age 35.5 +/- 16.6 years) and 293 follow up visits are presented in this preliminary report. [table: see text] Other side effects include (% of all visits): hypertrichosis (4.2), headache (2.8), cramps (1.8), arthropathy (1.8), paraesthesiae (1.8), abdominal pain (1.5), weakness (1.5), dyspepsia (1.4), nausea (1.4), others (4).

Blood Pressure↗
PubMed1992

Proliferative vitreoretinopathy. Lymphocytes in epiretinal membranes.

BACKGROUND: To investigate the potential contribution of inflammatory and immune-mediated processes contributing to the pathogenesis of proliferative vitreoretinopathy (PVR), an immunohistochemical study was undertaken to characterize the infiltrating inflammatory cells in epiretinal membranes surgically removed from the eyes of patients with PVR. METHODS: Twenty-one epiretinal membranes obtained surgically from eyes with PVR complicating rhegmatogenous retinal detachment were studied immunohistochemically using the ABC technique and a panel of monoclonal and polyclonal antibodies. RESULTS: T lymphocytes were found in 18 of the 21 specimens and generally constituted a small percentage of the total cell number. CD4+ T cells were found in 14 of the 18 membranes containing T cells. Three of six frozen membranes contained T cells that were positive for the interleukin-2 receptor. In 5 of 16 membranes studied, cells positive for the macrophage/monocyte marker were found. No B lymphocytes or neutrophils were identified, and there were no deposits of complement or immunoglobulins. Positive staining for the class II MHC antigen HLA-DR was found in 7 of the 21 membranes, a result that was more consistent in frozen than in fixed tissues. CONCLUSION: The study suggests that T lymphocytes are present in PVR epiretinal membranes and may be activated. These cells have the potential to play a role in the pathobiology of PVR.

Cell Membrane↗
PubMed1992

Sympathetic ophthalmia: visual results with modern immunosuppressive therapy.

Sympathetic ophthalmia is a rare bilateral panuveitis that follows penetrating injury to one eye. The use of systemic corticosteroids has transformed the prognosis, and good acuity in the sympathizing eye can now be achieved. The use of immunosuppressive drugs, such as cyclosporin and azathioprine, in combination with the steroids, allows control of the intraocular inflammation at a much lower steroid dose, with concomitant reduction in the systemic side effects that accompany the use of systemic steroids.

Adolescent↗
PubMed1992

Haemodynamic and neurohumoral response in heart failure produced by rapid ventricular pacing.

OBJECTIVE: The aim was to determine the exact sequence of hormone changes during the progression of fluid retention in a canine model of "congestive cardiac failure" induced by rapid right ventricular pacing, and during recovery when pacing is stopped. METHODS: Rapid ventricular pacing at a rate of 250 pulses.min-1 was used in six mongrel dogs with implanted right ventricular pacemakers. Right heart haemodynamics were measured by means of Swan Ganz catheterisation, allowing flow measurement by thermodilution and pressure measurement by external manometry. Plasma renin activity, arginine vasopressin, and atrial natriuretic factor were assayed on venous blood samples by radioimmunoassay. Noradrenaline was assayed by high pressure liquid chromatography. RESULTS: The onset of rapid pacing was accompanied by a fall in cardiac output and a rise in pulmonary arterial, pulmonary capillary wedge, and right atrial pressures. Noradrenaline and atrial natriuretic factor rose. Plasma renin activity showed an initial fall followed by a rise, and arginine vasopressin was unchanged in the first 8 h. When rapid pacing was continued for a further 35 d, clinical signs of fluid retention appeared by day 28, by which time cardiac output had fallen, and central pressures risen further. Atrial natriuretic factor peaked at around 14 d whereas plasma renin activity, arginine vasopressin, and noradrenaline tended to reach a plateau at about d 20 and then to show further increases as clinical signs of fluid retention appeared; this was most marked with plasma renin activity. Cessation of pacing at d 35 caused a rapid reversal (increase) of cardiac output but a more gradual reversal (decrease) of right heart pressures over 5 d; only wedge pressure returned to base line. Arginine vasopressin and plasma renin activity fell rapidly to around 40% of the final pacing levels and reached basal values after 8 h and 48 h respectively. Noradrenaline fell after 8 h and reached basal levels in 5 d. Atrial natriuretic factor fell quickly by 60% after 8 h but remained above basal levels for 5 d. At the end of pacing, body weight fell rapidly in conjunction with a large diuresis. CONCLUSIONS: These findings are compatible with a major role of one or more of renin, vasopressin, and noradrenaline in the pathophysiology of the fluid retention of heart failure; the manifestations are not counteracted by the rise in atrial natriuretic factor.

Animals↗
PubMed1992

Experimental autoimmune uveoretinitis (EAU) versus experimental allergic encephalomyelitis (EAE): a comparison of T cell-mediated mechanisms.

EAU is a model of ocular inflammatory disease. EAU resembles another T cell-mediated autoimmune disease--experimental allergic encephalomyelitis--since both have increased expression of MHC class II molecules in the target tissue, can be adoptively transferred by activated CD4+ T cells and are inhibited by cyclosporin A. The immunological findings will be compared to find out if the same cellular mechanisms are involved in both diseases.

Animals↗
PubMed1992

Plasma and cerebrospinal fluid arginine vasopressin in patients with and without fever.

Hyponatraemia has been described in association with a number of acute infectious diseases, mainly bacterial and tuberculous meningitis and pneumonia, and has been attributed to inappropriate secretion of arginine vasopressin (AVP). The mechanism of inappropriate AVP production is uncertain, but there is experimental evidence to suggest that fever may stimulate secretion of AVP into plasma and cerebrospinal fluid. In this study, AVP concentrations in plasma and cerebrospinal fluid from 37 febrile children with infections have been compared with those from 27 afebrile control subjects. Ten of the febrile children had meningitis (eight bacterial, two viral) and the remainder a variety of other infectious diseases. Seventy four per cent of febrile infected children were hyponatraemic (serum sodium less than 135 mmol/l) compared with only 8% of the afebrile controls. Plasma AVP concentrations were significantly higher in the febrile patients (median 2.92 pmol/l, range 1.0-23.25, n = 28) than in controls (median 1.67 pmol/l, range 0.57-6.0, n = 14) but there was no significant difference in cerebrospinal fluid AVP concentrations. There was no difference in plasma AVP concentrations between patients with meningitis and those with infections not involving the central nervous system. Careful attention should be paid to fluid and electrolyte balance in all children with acute infections.

Adolescent↗
PubMed1992

Behçet's disease: activated T lymphocytes in retinal perivasculitis.

A 38-year-old man who died from systemic Behçet's disease had previously suffered from severe, recurrent bilateral retinal vasculitis, and anterior uveitis for 10 years. Immunopathological examination of the eyes postmortem revealed marked hyaline thickening of the retinal and optic nerve vessels. The vessels had an intramural and perivascular infiltrate of T lymphocytes which stained positively for CD4 and IL2 receptor surface markers. Small numbers of cells in the optic nerve head, retinal vascular endothelium, and retinal pigment epithelium were HLA DR positive.

Adult↗