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Biomedical subjects

S Reichlin

Publications and source records attributed to S Reichlin.

At least 91 records · Page 5Linked to original sources
PubMed1986

Alpha melanocyte stimulating hormone inhibits immunostimulatory and inflammatory actions of interleukin 1.

The ability of interleukin 1 (IL 1) to augment the proliferation of murine thymocytes in vitro was inhibited in a dose-dependent manner by the neuropeptide alpha-melanocyte-stimulating hormone (alpha MSH). The minimal effective concentration of alpha MSH was 10(-11) M. Maximal effect occurred between 10(-8) and 10(-7) M, with diminishing effectiveness at higher concentrations. IL 1-induced production of prostaglandin E (PGE) by fibroblasts was also inhibited by alpha MSH with a biphasic dose response. The minimal effective concentration was 10(-11) M, and maximum effect was achieved at 10(-10) M. alpha MSH appeared to affect the interaction of IL 1 with its target cells in a specific manner, because it did not inhibit basal mitogen-induced thymocyte proliferation or IL 2-induced proliferation of a cytotoxic T lymphocyte line. Furthermore, production of IL 1 by endotoxin-stimulated monocytes was not affected by alpha MSH. An analog of alpha MSH (Nle4, D-Phe7 alpha MSH), which is highly potent in other melanotropin-sensitive systems, did not affect the action of IL 1 on thymocytes, suggesting that the immunomodulatory effects of alpha MSH may not be mediated by the classic melanocyte alpha MSH receptor. The influence of alpha MSH on thymocytes and fibroblasts suggests that alpha MSH is an endogenous antagonist of IL 1, perhaps important for limiting inflammatory damage to host tissues.

Animals↗
PubMed1986

Characterization of forms of immunoreactive somatostatin in sensory neuron and normal and deafferented spinal cord.

In order to determine the contribution made by primary sensory afferents and supraspinal projections to the immunoreactive somatostatin (IRS) content of the spinal cord, measurements were made of the concentration of IRS in the dorsal and ventral halves of the cord in cats subjected to unilateral lumbosacral dorsal rhizotomy (L1-S3) alone or combined with spinal cord transection. The molecular forms of IRS (characterized by gel chromatography) in L7 lumbar spinal cord, L6-S1 dorsal roots, ventral roots and dorsal root ganglia, and sciatic nerve were also determined. S14 was the predominant form in all tissues examined, but two additional molecular forms corresponding to S28 and S11.5 kdalton were present in dorsal root ganglia and spinal cord; S28 but not S11.5 kdalton was detected in both dorsal roots and sciatic nerves. These results indicate that S14 and S28 are transported along the central and peripheral processes of dorsal root ganglia, but that spinal cord S11.5 kdalton originates in the central nervous system. IRS in the dorsal horn was reduced by ca. 40% following dorsal root section. Neither disruption of descending pathways by spinal transection nor surgical isolation of the lumbar segments lowered cord somatostatin content below that produced by dorsal root section, indicating that most of the somatostatin within the cord arises from the dorsal root and from neurons in local spinal segments. Although the total content of IRS in the dorsal horn was reduced by ca. 40% following dorsal rhizotomy, the pattern of molecular forms was not changed accordingly.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗
PubMed1986

Influence of a benzodiazepine, midazolam, and gamma-aminobutyric acid (GABA) on basal somatostatin secretion from cerebral and diencephalic neurons in dispersed cell culture.

To investigate the mechanisms of gamma-aminobutyric acid (GABA) and benzodiazepine-induced growth hormone (GH) release, we studied the effects of GABA and a water-soluble benzodiazepine, midazolam, on basal immunoreactive somatostatin secretion from fetal rat brain in dispersed cell culture. Both GABA and midazolam in concentrations of 10(-5) or 10(-6) M inhibited basal somatostatin secretion from either diencephalic or cerebral neurons in culture. Midazolam (10(-5) M) produced a 33.2 +/- 8.6% suppression (P = 0.004) and 10(-5) M GABA produced a 46.0 +/- 4.3% suppression (P = 0.0003) in the diencephalon cultures. When GABA and midazolam were used in combination over the 10(-5)-10(-9) M range, the drugs were shown to act independently (positive main effect, P less than 0.0001 for either drug by two-way analysis of variance); there was a simple additive effect with no statistically significant interaction between the two drugs over the 36 combinations tested. These results suggest that suppression of the GH inhibitory peptide, somatostatin, may be one of the mechanisms by which GABA and benzodiazepines stimulate GH secretion. Based on previous studies of GABA and benzodiazepine receptors, it appears likely that these drugs produce this inhibitory effect by interacting with unassociated lower affinity receptors which require micromolar concentrations of the drugs, and act through calcium-dependent pathways.

Animals↗
PubMed1986

Immunocytochemical demonstration of growth hormone-releasing factor in gastrointestinal and pancreatic endocrine tumors.

Growth hormone-releasing factor (GRF), a linear peptide that exists in a number of different molecular forms (GRF-44, -40, -37, and-31) has been shown to be responsible for the acromegaly associated with certain endocrine tumors of the pancreas and other foregut-derived structures. With the use of two anti-sera (#1A850 and G59/901) directed against different segments of the GRF molecule, a series of 24 pancreatic and 35 gastrointestinal endocrine tumors, not associated with acromegaly, were surveyed systematically for immunocytochemical localization of GRF in the tumor cells. Strong immunoreactivity for GRF was encountered in 10 tumors (6 pancreatic and 4 gastrointestinal). While all ten tumors were immunoreactive against G59/901, which recognizes GRF-44, -40, and -37, two jejunal carcinoids showed additional immunostaining with 1A850 that is specific for GRF-44. Seven of these ten tumors were also immunoreactive for a variety of other regulatory peptides and neurotransmitters, including gastrin, insulin, glucagon, serotonin, substance P, somatostatin, pancreatic polypeptide, vasoactive intestinal peptide (VIP), and adrenocorticotropic hormone (ACTH). No consistent pattern of association between GRF and the other regulatory substances was evident. These findings indicate that, even in the absence of associated acromegaly, up to 17% of endocrine tumors of the gastro-entero-pancreatic (GEP) axis show immunoreactivity for GRF and that such reactivity is associated more frequently with pancreatic (25%) than with gastrointestinal (11%) endocrine tumors.

Amino Acid Sequence↗
PubMed1986

Nursing behaviour, prolactin and postpartum amenorrhoea during prolonged lactation in American and !Kung mothers.

In order to determine the effects of protracted nursing in American women, blood was collected hourly for 24 h and nursing periods recorded in 20 mothers, 10 amenorrhoeic, 3 3/4 to 17 1/4 months postpartum (PP), and 10 menstruating, 5 1/4 to 46 months PP. These data were compared to the daytime nursing behaviour and 1000-1100 h PRL of women among !Kung hunter-gatherers of Botswana, a non-contraceptive using population with a birth space interval of greater than 3 years. Intense nursing behaviour maintained amenorrhoea and hyperprolactinaemia for 1 to nearly 2 years PP in both American and !Kung mothers. Among Americans, 80 min of nursing per day, in conjunction with a minimum of six nursing episodes, was highly predictive of remaining amenorrhoeic up to 18 months PP. Amenorrhoea was always accompanied by hyperprolactinaemia, but delay in the onset of menses was related more to nursing behaviour than to a particular 24 h PRL level. The 1000-1100 h sample is equivalent to and about half of the 24 h mean in high and low intensity nursers, respectively. The !Kung women were similar to the high intensity nursing American women in 1000-1100 h PRL, percent amenorrhoeic, and the number of minutes of daytime nursing.

Adult↗
PubMed1986

Phase I evaluation of recombinant interleukin-2 in patients with advanced malignant disease.

Seventeen patients with refractory malignant tumors were treated with recombinant human interleukin-2 (IL-2) administered by weekly bolus intravenous (IV) injection in a phase I dose escalation trial. Patients received 10,000 to 1,000,000 U/m2 per injection over a course of 3 to 33 weeks. Toxicity was dose related and consisted primarily of fever, chills, nausea, and vomiting. Hypotension was observed at doses of 500,000 U/m2 or higher and in one instance was sufficiently severe to require pressors. No tumor regression was seen and all patients eventually developed progressive disease. Blood levels of cortisol, ACTH, prolactin, and growth hormone as well as the acute phase reactant C-reactive protein (CRP) increased after the administration of IL-2 in most patients. Serum IL-2 levels in excess of 250 U/mL were detected five minutes after an IV injection of 1,000,000 U/m2, after which the levels declined with a half-life of approximately 25 minutes. No alteration in lymphocyte surface phenotype or enhancement in natural cell-mediated cytotoxicity against natural killer (NK)-sensitive and resistant tumor cell lines was observed when these parameters were measured weekly just before the IL-2 injections. However, a dramatic but transient decline in circulating lymphocytes and NK activity was noted within hours of receiving IL-2. This effect was independent of fever and was not abrogated by pretreatment with ibuprofen or metyrapone. The majority of patients developed serum IgG antibodies of IL-2 detectable with a sensitive enzyme-linked immunosorbent assay (ELISA) and a nitrocellulose dot blot assay. The development of anti-IL-2 antibodies was not associated with symptoms suggestive of serum sickness, reductions in serum complement levels, or deterioration in lymphocyte tumoricidal activity. This investigation provides insight into the in vivo actions of this potent biological response modifier and will assist in the design of future studies with IL-2 administered alone or in conjunction with other treatment modalities.

Adult↗
PubMed1986

Regulation of growth hormone and somatomedin-C secretion in postmenopausal women: effect of physiological estrogen replacement.

To determine the effects of estrogen deficiency and replacement on GH secretion, we measured the 22-h GH secretory pattern and response to 1 h of light exercise in 16 normal postmenopausal women before and after treatment replacement with ethinyl estradiol (20 micrograms/day for 15 days). To determine whether the changes found were due to pituitary sensitization by estrogen, the response to synthetic GH-releasing hormone (GHRH; 1.0 microgram/kg, iv) was measured. To assess the biological effectiveness of GH in estrogen-treated women, somatomedin-C (Sm-C) responses to GHRH were measured. Pre- and postestrogen GH secretion rates, expressed as mean areas circumscribed by plasma GH values, were as follows: 22-h study, 1.4 +/- 0.1 (+/- SEM) vs. 2.0 +/- 0.3 ng/ml X h (P = 0.04; n = 5); during 1 h of exercise, 2.3 +/- 0.4 vs. 3.2 +/- 0.4 ng/ml X h (P = 0.03; n = 16); after GHRH-(1-40), 6.7 +/- 1.7 vs. 8.5 +/- 1.5 ng/ml X h (P = 0.12; n = 16). There also was a modest but significant increase in resting plasma GH (1.5 +/- 0.2 vs. 2.3 +/- 0.5 ng/ml (P = 0.039). Pre- and postestrogen plasma Sm-C concentrations were 0.56 +/- 0.08 and 0.32 +/- 0.03 U/ml, respectively (P = 0.006; n = 16). Thus, estrogen therapy increased spontaneous and exercise-induced GH secretion in postmenopausal women and reduced Sm-C levels. The mechanisms of GH elevation by estrogen may include both central effects and a negative feedback linkage to reduced plasma Sm activity.

Aged↗
PubMed1986

Sustained rises in serum thyrotropin, thyroxine, and triiodothyronine during long term, continuous thyrotropin-releasing hormone treatment in patients with amyotrophic lateral sclerosis.

In a pilot therapeutic trial, four patients with amyotrophic lateral sclerosis (ALS) were treated with long term, continuous infusions of TRH, three intrathecally and one epidurally. They had prompt increases in serum TSH and thyroid hormone concentrations, averaging 120% for TSH, 49% for serum T4, 68% for the serum free T4 index, 49% for serum T3, and 67% for the serum free T3 index. These elevations were statistically significant for all but serum T3 and persisted for the duration of treatment (4-7 months). Mean values during treatment were near the upper limit of normal for each of these hormone measurements. After TRH withdrawal, serum TSH fell transiently below the normal range. A comparison group of four patients with ALS treated by twice weekly intrathecal bolus doses of TRH had no significant changes in serum TSH, T4, or T3. During continuous TRH treatment, the responsiveness of both TSH and PRL to a standard iv TRH stimulation test was blunted, but not abolished. Basal serum PRL was occasionally elevated in the two women during continuous TRH treatment, but was normal in the men, and serum GH was normal in all patients. In the patients receiving continuous TRH treatment, indexes of end-organ effects of thyroid hormone were inconclusive; none had a rise in serum ferritin, one of four had a rise in serum sex hormone-binding globulin, and three had increased creatinuria. These results provide direct evidence in man that chronic TRH administration can cause modest sustained increases in serum TSH and thyroid hormones, though the metabolic consequences of these changes are uncertain, and appears to raise the set-point of the pituitary-thyroid axis, i.e. the serum T4 and T3 concentrations needed for a given degree of suppression of basal TSH secretion.

Amyotrophic Lateral Sclerosis↗
PubMed1986

Somatostatin: historical aspects.

Somatostatin, in essence an almost universal chalone, initially described as a 14 amino-acid-long peptide that inhibits growth hormone (GH) release, has been shown to be one of a family of related peptides, ubiquitous in distribution and versatile as a paracrine factor with a potentially important role in the regulation of gut, pancreatic, and nervous system function, in addition to its well-recognized influence on the pituitary secretion of GH and thyroid-stimulating hormone. With the development of new super agonists, it has become possible to manipulate the endocrine milieu, to modify gut, pancreatic, and pituitary function, and, in the case of several diseases such as acromegaly and intractable diarrhoea, to make a significant advance in therapy.

Animals↗
PubMed1986

Systemic toxicity of diphtheria toxin-related fragments (CRM26, CRM45), a hormone-toxin hybrid protein (TRH-CRM45), and ricin A.

As a preliminary step in evaluating the use of thyrotropin releasing hormone (TRH) linked to toxin fragments for systemic treatment of pituitary disease, we have examined the metabolic degradation, tissue distribution, renal excretion, and toxicity in rats of TRH-CRM45 which consists of TRH coupled to CRM45, a diphtheria toxin-related polypeptide. For comparison, we have similarly studied CRM45, CRM26 (a smaller diphtheria toxin-related fragment), and ricin A. All four proteins were found to concentrate in the kidney and liver relative to blood (in comparison to bovine serum albumin), tissue:plasma ratios for the kidney being much higher than those observed for the liver. Radioiodinated CRM45 and ricin A were rapidly cleared from the circulation with similar patterns. Systemic toxicity studies showed that at doses greater than 2 micrograms/100 g body wt (bw), CRM45 caused a decrease in growth rate and caused renal damage. CRM45 modified with 2-pyridyldithio(propionate) groups as well as TRH-CRM45 was significantly less toxic than CRM45, as was TRH-CRM45. CRM26 had no discernible effect on the growth rate of the animals. Ricin A, at a dose of 50 micrograms/100 g bw slowed the growth rate of rats, but specific liver or kidney damage could not be detected. These findings define an upper range of doses for possible therapeutic use.

Animals↗
PubMed1986

Cyclic AMP regulates somatostatin mRNA accumulation in primary diencephalic cultures and in transfected fibroblast cells.

Although the factors controlling the secretion of the neuropeptide somatostatin have been extensively studied, little is known about the mechanisms that control somatostatin biosynthesis. Somatostatin secretion is regulated by numerous agents that increase intracellular levels of cAMP. We sought to determine whether cAMP also regulates somatostatin mRNA accumulation. We found that forskolin elicited an increase in somatostatin secretion and mRNA levels in primary cultures of rat diencephalic cells. Another secretagogue, KCl, was as effective as forskolin in causing somatostatin secretion but had no effect on mRNA accumulation. Somatostatin expression in fibroblast cells transfected with the somatostatin gene was also regulated by forskolin. These results demonstrate that somatostatin mRNA accumulation can be regulated through a cAMP-dependent pathway, that this pathway is operative in heterologous cells transfected with the somatostatin gene, and that stimulation of somatostatin secretion and mRNA accumulation can be uncoupled from one another.

Animals↗
PubMed1986

Effect of acrylonitrile on the rat pituitary: enlargement of Golgi region in prolactin cells, crinophagy in prolactin cells and growth hormone cells.

Since it has been shown that acrylonitrile prevents the appearance of spontaneous pituitary adenomas, we have investigated its effect in acute experiments on rat pituitaries by histology, immunocytochemistry, electron microscopy and morphometry; in addition, serum prolactin and growth hormone levels were measured by radioimmunoassay. Electron microscopy of prolactin cells revealed hypertrophy of the Golgi region without significant change in volume densities and diameters of forming and storage granules. In the 24 h group, crinophagy was observed in prolactin cells and growth hormone cells. Corticotrophs, thyrotrophs and gonadotrophs were unaltered. Dilation, congestion and rupture of capillaries, as well as pericapillary and intercellular oedema were evident in the 24 h group. One hour after intravenous acrylonitrile injection, serum prolactin levels were within the normal range, whereas at 24 h, hyperprolactinemia was noted. Serum growth hormone concentrations were unchanged. It can be concluded that acrylonitrile has a complex effect on prolactin cells. Hypertrophy of Golgi complex and hyperprolactinemia may reflect increased prolactin synthesis and release. Since volume densities and diameters of secretory granules in prolactin cells remained unchanged, it appears that newly synthesized prolactin was preferentially released and not the prolactin stored in secretory granules. Crinophagy may be the morphological manifestation of a discrepancy between hormone synthesis and release suggesting increased degradation of unused hormone by lysosomes.

Acrylonitrile↗
PubMed1985

Vasoactive intestinal peptide and PHI stimulate somatostatin release from rat cerebral cortical and diencephalic cells in dispersed cell culture.

To determine the effect of vasoactive intestinal peptide (VIP) on the secretion of somatostatin by neurons, dispersed fetal cerebral cortical and diencephalic cells grown in culture were exposed on day 10 or 11 of culture to various concentrations of VIP, and for comparison to the structurally related peptides PHI (Peptide Histidine Isoleucine-27), growth hormone (GRH1-44-NH2) and secretin and to cholecystokinin. VIP elicited a dose-dependent release of somatostatin from both cortical and diencephalic cells, the lowest effective concentration being 6 X 10(-9) M. PHI also brought about release of somatostatin, but was between 0.06 and 0.1 times as potent as VIP. Placed together in a concentration of 10(-7) M, the two peptides did not have an additive effect. In this system GRH1-44-NH2, secretin and CCK octapeptide were without effect.

Animals↗
PubMed1985

Effects of carbamazepine on cerebrospinal fluid somatostatin.

This paper reports the reduction of the concentration of the neuropeptide somatostatin in the CSF of patients with affective illness during treatment with the anticonvulsant carbamazepine. None of the other psychotropic agents used in this study similarly affected CSF somatostatin, although zimelidine appeared to increase CSF somatostatin in a small number of patients. The potential mechanism and significance of the effects of carbamazepine on CSF somatostatin are discussed in relation to the psychotropic, anticonvulsant, and analgesic properties of carbamazepine.

Adrenocorticotropic Hormone↗
PubMed1985

Reduced axoplasmic somatostatin transport in hypothyroid rats.

The effect of hypothyroidism on neuronal function was studied by measuring axoplasmic transport of immunoreactive somatostatin in rat sciatic nerve by the ligation technique. Accumulation of immunoreactive somatostatin proximal to a ligature was linear up to 8 h in normal, in thyroidectomized, and in parathyroidectomized rats. The transport rate was decreased by 38% in thyroidectomized rats as compared to normal rats and was unchanged in parathyroidectomized rats. Sciatic nerve content of somatostatin in hypothyroid rats did not differ from control. Reduced accumulation of immunoreactive somatostatin in hypothyroid rats may be due to a decrease in somatostatin synthesis or in axoplasmic transport, or to an increase in the degradation rate of the peptide.

Animals↗
PubMed1985

Vasoactive intestinal peptide is a physiological mediator of prolactin release in the rat.

To determine whether VIP functions as a physiological PRL-releasing factor, the effects of immunoneutralization of endogenous vasoactive intestinal peptide (VIP) on the PRL secretory response to suckling and ether stress were assessed. Using a porcine VIP-thyroglobulin conjugate as antigen, a peptide-specific antiserum was generated in a rabbit which bound porcine VIP with a Kd of 5.1 X 10(-11) M and a maximum binding capacity of 1830 ng/ml. In a RIA, this antiserum demonstrated immunoreactive VIP in tissue extracts of various regions of the brain and gastrointestinal tract. IR VIP in extracts of cerebral cortex and hypothalamus coeluted with synthetic porcine VIP on Bio-Gel P-30 column chromatography. Using chronically implanted right atrial catheters for blood sampling to avoid effects of stress and anesthesia, PRL blood levels in normal controls began to rise almost immediately after initiation of suckling from basal values of 3.0 +/- 0.9 ng/ml to reach a plateau of 158.1 +/- 33.5 ng/ml after 40 min. When the VIP antiserum was administered immediately before initiation of suckling, the onset of the PRL response was delayed by 40 min, but PRL levels then rose at a slower rate to reach the plateau level of normal animals approximately 80 min later. When VIP antiserum was administered to rats who had been suckling for at least 1 h, PRL levels fell from a mean basal elevated level of 152.7 +/- 16.0 ng/ml to a nadir of 50.4 +/- 9.1 ng/ml 80 min after injection and then gradually returned to basal levels. The effect of VIP antiserum was studied in rats in whom PRL secretion was increased by exposure to ether, a stimulus that acts on the release phase of PRL secretion. In rats in whom the depletion-transformation of PRL was induced by a prior brief period of suckling, subsequent exposure to ether caused a rise in serum PRL levels. The response was completely blocked in rats given VIP antiserum, whereas animals given nonimmune serum showed a significant increase in serum PRL to 38.6 +/- 17.3 ng/ml. We conclude from these studies that VIP mediates the acute PRL response to suckling and is required for maintenance of PRL levels in continuously suckling animals but is not the only factor causing PRL elevation. Complete abolition by the VIP antiserum of the PRL response to ether indicates that the effect of the anesthetic is mediated entirely by the release of VIP. These findings are consistent with the view that VIP is a physiological PRL-releasing factor in the rat.

Animals↗