Processing of somatostatin precursors: evidence for enzymatic cleavage by hypothalamic extract

The action of enzymes extracted from rat hypothalamus on the previously characterized high molecular weight forms of hypothalamic somatostatin-like immunoreactivity (4 K SLI and 25 K SLI) has been investigated in vitro in order to further define the role of these molecules as possible precursors for tetradecapeptide somatostatin (SRIF). Studies of the degradation of endogenous SLI and of synthetic SRIF by hypothalamic enzymes showed that the time course of breakdown of endogenous SLI is markedly slower than that of synthetic SRIF due to the relative stability of 25 K SLI as well as the generation of at least two new immunoreactive molecules. Incubation of purified 25 K SLI with SLI-free hypothalamic extract showed after 10 to 30 min newly formed immunoreactive material of an intermediate size between 25 K SLI and 4 K SLI and after 60 min the emergence of material coeluting with SRIF. These data show that the hypothalamus contains the enzymes necessary for degrading endogenous SLI and for processing the 25 K SLI molecule to SRIF providing further evidence that 25 K SLI might be a biosynthetic precursor for SRIF.     

Familial loading in specific language impairment: patterns of differences across proband characteristics, gender and relative type

There is now little doubt that both environmental factors and genes are likely to make important contributions to the aetiology of specific language impairment (SLI). The most commonly proposed model for understanding these influences is the multifactorial model. In the present study we examine two expectations based on this model: that there will be a systematic relationship between the severity of proband language scores and the rate and severity of SLI in relatives and that relatives will be more strongly affected if they are relatives of a proband of the more rarely affected gender (female) because the latter require a higher genetic liability to become equally impaired. Ninety-three probands and their 300 first-degree relatives participated in this study. Results showed a relationship between proband severity at age 14 and an increased rate of SLI in relatives. This relationship was strong for child siblings and was significant with respect to both rate of SLI and severity over a range of language and literacy measures. In contrast, higher levels of SLI among relatives of female rather than male probands was entirely disproved.     

Frequency of Educational Computer Use as a Longitudinal Predictor of Educational Outcome in Young People with Specific Language Impairment

Computer use draws on linguistic abilities. Using this medium thus presents challenges for young people with Specific Language Impairment (SLI) and raises questions of whether computer-based tasks are appropriate for them. We consider theoretical arguments predicting impaired performance and negative outcomes relative to peers without SLI versus the possibility of positive gains. We examine the relationship between frequency of computer use (for leisure and educational purposes) and educational achievement; in particular examination performance at the end of compulsory education and level of educational progress two years later. Participants were 49 young people with SLI and 56 typically developing (TD) young people. At around age 17, the two groups did not differ in frequency of educational computer use or leisure computer use. There were no associations between computer use and educational outcomes in the TD group. In the SLI group, after PIQ was controlled for, educational computer use at around 17 years of age contributed substantially to the prediction of educational progress at 19 years. The findings suggest that educational uses of computers are conducive to educational progress in young people with SLI.     

Plasma Somatostatin-like immunoreactivity in chemically sympathectomized dogs

The present study was designed to determine the role of the adrenergic nerves upon basal and postprandial gastric and pancreatic SLI release. In 19 chemically sympathectomized dogs peripheral venous plasma SLI levels in the basal and postprandial state were significantly below those of 30 controls for the first 135 min after the ingestion of a fat-protein meal. To determine the origin of this reduction, the SLI release from fundus, antrum and pancreas was studied in anesthetized dogs during the gastric phase of a meal at either pH 7 or pH 2. In response to a liver meal at pH 7 fundic, antral and pancreatic vein SLI levels were below the control and the rise in inferior vena cava SLI was abolished. In response to a liver meat at pH 2, the rise in antral and pancreatic vein SLI as clearly reduced in the sympathectomized dogs, while the decrease in fundic SLI was not influenced. The data demonstrate that adrenergic innervation plays a role in basal and postprandial SLI release from the stomach and pancreas.     

Role of histamine H2-receptors in gastric and pancreatic release of somatostatin-like immunoreactivity during the gastric phase of a meal

The present study was designed to determine the role of H₂-receptors in the postprandial release of somatostatin-like immunoreactivity (SLI) from the gastric fundus and antrum and from the pancreas. In dogs subjected to laparotomy, the pylorus was bisected and a gastric fistula was created, following which 250 ml 20% liver extract (LE) at pH 7 or 2 were instilled intragastrically. In the fundic vein the incremental SLI rise in response to LE at pH 7 was 2423 ± 540 pg/ml during a control infusion of saline and 4780 ± 863 pg/ml during the infusion of cimetidine (1 mg/kg per h) (P < 0.05). In the antral vein the incremental SLI in response to LE at pH 7 was 2182 ± 530 pg/ml during the saline control but did not rise significantly during cimetidine infusion. In the pancreatic vein the incremental SLI level after LE at pH 7 was 1953 ± 358 pg/ml in the control experiments and 4430 ± 1024 pg/ml during cimetidine infusion (P < 0.025). The incremental inferior vena cava SLI level was approximately 925 pg/ml in both groups (not significant).The instillation of LE at pH 2 during the saline control lowered fundic vein SLI by 500 pg/ml; this decline was abolished during cimetidine infusion. In the antral vein the incremental SLI level of 15 750 ± 2514 pg/ml during saline was lowered to only 6728 ± 2257 pg/ml during cimetidine (ifP < 0.025). After LE at pH 2 the incremental pancreatic vein SLI level of if5641 ± to be one regulatory component in the modulation of gastric acid secretion and gastrin release [21,26] during the gastric phase of a meal. The possible involvement of H₂-receptors in this regulatory system is schematized in Fig. 7.Pancreatic SLI release is also influenced by H₂-receptors but this appears to depend on the intragastric pH; stimulation of the receptors appears to lower the pancreatic SLI response to neutral protein and raise the response to acidified protein. If these effects are due to stimulation of gastric and/or pancreatic H₂-receptors can not be determined from the present data.These findings, in conjunction with previous studies [21–25], reveal a highly complex regulatory system for somatostin release during the gastric phase of meal, and indicate that, in addition to the influence of muscarinic-cholinergic [23], adrenergic mechanisms [24] and prostaglandins [25], reveal a histaminergic influence must now be recognized.     

Association of D16S515 microsatellite with specific language impairment on Robinson Crusoe Island, an isolated Chilean population: a possible key to understanding language development

Specific language impairment (SLI) is a developmental language disorder that occurs for no known reason. The disorder affects 2-8% of children. Some scientific evidence suggests that genetic factors are implicated in the etiology of SLI. The disorder is genetically complex. Two novel loci, SLI1 on chromosome 16q24 (MIM 606711) and SLI2 on chromosome 19q13 (MIM 606712), have been found to be highly correlated with SLI. Four genes have been identified as susceptibility genes. SLI occurs at an unusually elevated incidence (35%) among the population of Robinson Crusoe Island (Chile), which also has a high consanguinity rate. This finding supports the influence of genetic mechanisms in the transmission of SLI based on a founder effect. To investigate further the genetic involvement in this population, we collected blood samples from 115 islanders from 13 families with a language-impaired proband and from 18 families with a normal-language proband. The analysis of micro satellite marker D16S515, located in locus SLI1, demonstrated that the 230-bp allele was correlated with SLI and that the 232-bp allele was correlated with normal language development. The domain containing the D16S515 marker, therefore, may play a role in language development.     

Physiological circulating levels of secretin-like immunoreactivity in the human do not stimulate free fatty acid production

An in vivo study was carried out to establish whether infused secretin, which achieves physiological levels of secretin-like immunoreactivity (SLI), promotes lipolysis. Six healthy volunteers received two infusions after separate 8 h overnight fasts. The paired infusions of either 500 ml of normal saline or 150 C.U. of porcine secretin in 500 ml of normal saline were infused at a constant rate of 1.38 ml/min. Venous blood was sampled at 0, 1, 2, 3, 4, 5 and 6 h after the infusion started. Mean plasma concentrations of SLI were significantly higher after infusion of saline with secretin in comparison to infusion of saline alone but remained within the physiological range. Mean serum free fatty acid (FFA) and 3-hydroxybutyrate concentrations rose significantly with time during both infusions but the mean FFA and 3-hydroxybutyrate concentrations did not differ significantly between infusions at each time of assessment. We conclude that a lipolytic role for secretin has not been shown to be of importance in relation to the in vivo rise in FFA concentrations observed in the fasting normal subject.     

Gastric inhibitory polypeptide stimulated secretion of somatostatinlike immunoreactivity from the stomach: inhibition by acetylcholine or vagal stimulation

The possible involvement of gastric somatostatinlike immunoreactivity (SLI) in the acid inhibitory action of gastric inhibitory polypeptide (GIP) was studied in an isolated perfused rat stomach. GIP, in a dose of 5 or 50 ng/mL, caused a 4- and 12-fold increase in SLI secretion, respectively. At the higher dose level the stimulated secretory rate declined throughout the perfusion suggesting that secretion exceeded the capacity to synthesize SLI under excessive GIP stimulation. Acetylcholine (10 microM) or vagal stimulation (7 V, 10 Hz, 5 ms) completely inhibited GIP-stimulated SLI secretion. It is therefore proposed that the acid inhibitory activity of GIP is probably mediated via release of gastric SLI and this action is under cholinergic control.     

Dose-dependent inhibitory and non-inhibitory action of somatostatin on insulin release in rats

The dose-dependent effect of intravenously infused synthetic somatostatin-14 on basal and postprandial insulin and gastrin release was assessed in anesthetized rats.Infusion of 1 ng · kg^?1 · min^?1 elicited a significant reduction of basal and postprandial insulin levels compared to the saline control group. At 15 ng · kg^?1 · min^?1 basal insulin was not affected but postprandial insulin levels were still significantly reduced. At 30 ng · kg^?1 · min^?1 neither basal nor stimulated insulin levels were affected. At the highest concentration of 120 ng · kg^?1 · min^?1 basal and postprandial insulin levels were suppressed similar to the lowest infusion rate of 1 ng · kg^?1 · min^?1. Basal gastrin levels were significantly reduced only at the highest rate of 120 ng · kg^?1 · min^?1. A significant reduction of postprandial gastrin levels was observed at 15 ng · kg^?1 · min^?1 and all higher infusion rates employed. Measurements of plasma somatostatin-like immunoreactivity (SLI) demonstrated that plasma SLI levels during the lowest infusion rate of 1 ng · kg^?1 · min^?1 were not different from the controls. No significant rise of plasma SLI levels was observed in response to the test meal. The higher infusion rates elicited a dose-dependent increase in plasma SLI levels. These data demonstrate that in rats somatostatin exerts a biological effect on insulin release at very low doses while certain greater infusion rates have no suppressive effect. Gastrin secretion is inhibited in a more linear pattern.     

Development of cells containing catecholamines and somatostatin-like immunoreactivity in neural crest cultures: relationship of DNA synthesis to phenotypic expression

The goal of our work is to understand the mechanisms which regulate the differentiation of embryonic neural crest cells into a number of adult cell types, including several classes of neurons. As one aspect of this analysis, the relationship between DNA synthesis and the ontogeny of cells with catecholamines and somatostatin-like immunoreactivity (SLI) in neural crest cell cultures has been investigated. Most of the precursors of the catecholamine- and SLI-positive cells carry out DNA synthesis. As these cells differentiate, their ability to carry out DNA synthesis declines. However, a small percentage of cells continue to synthesize DNA after they become catecholamine or SLI positive. There is no apparent difference between the temporal pattern of DNA synthesis in the precursors of catecholamine-positive cells with SLI and those without SLI. Thus, the time of withdrawal from the cell cycle does not distinguish the lineage of cells that are catecholamine and SLI positive from those that are catecholamine positive and SLI negative.     

Extracellular Somatostatin Measured by Microdialysis in the Hippocampus of Freely Moving Rats: Evidence for Neuronal Release

Abstract: Intracerebral microdialysis combined with a sensitive and specific radioimmunoassay was used to monitor the neuronal release of somatostatin (somatostatin-like immunoreactivity, SLI) in the dorsal hippocampus of freely moving rats. The sensitivity of the radioimmunoassay was optimized to detect <1 fmol/ml. The basal concentration of SLI in 20-min dialysate fractions (5 μl/min) collected 24 h after probe implantation was stable over at least 200 min. The spontaneous efflux dropped by 54 ± 6.4% ( p < 0.05) when Ca²⁺ was omitted and 1 m M EGTA added to the Krebs-Ringer solution and by 65.5 ± 3.2% ( p < 0.05) in the presence of 1 μ M tetrodotoxin. Depolarizing concentrations of the Na⁺ channel opener veratridine (6.25, 25, 100 μ M ) induced 11 ± 2 ( p < 0.05), 17 ± 2 ( p < 0.05), and 21 ± 5 ( p < 0.01) fold increase in SLI concentration, respectively, during the first 20 min of perfusion. The effect of 100 μ M veratridine was blocked by coperfusion with 5 μ M tetrodotoxin ( p < 0.01) and reduced by 79% ( p < 0.01) in the virtual absence of Ca²⁺. Neuronal depolarization by 20 min of perfusion with Krebs-Ringer solution containing 25 and 50 m M KCl and proportionally lowered Na⁺ increased the dialysate SLI 4.4 ± 1 ( p < 0.05) and 17 ± 3 ( p < 0.01) fold baseline, respectively. Ten micromolar ouabain, a blocker of Na⁺,K⁺-ATPase, increased the dialysate SLI 15-fold baseline, on average ( p < 0.05), during 80 min of perfusion. The results demonstrate the suitability of brain microdialysis for monitoring the neuronal release of SLI and for studying its role in synaptic transmission.     

胶原合成介导的软骨细胞的光生物调节作用

目的:了解低强度激光照射对软骨细胞增殖的影响及其机制。方法:选取3周龄新西兰白兔分离培养软骨细胞,在2.5%新生牛血清中培养,用半导体激光(650 nm,2.96 mW/cm2)(sem iconductor laser irrad iation,SLI)照第4代软骨细胞,每天分别照射1 m in、3 m in、5 m in、7 m in、10 m in、20 m in,共6 d。收集激光照射后第2 d、4 d、6 d、8 d、10 d和12 d的细胞培养液,用氯胺T消化法检测羟脯氨酸(H rp)的含量。在培养至第13 d时,用XTT法检测细胞的活性,了解细胞的增殖情况。结果:在2.5%新生牛血清中,SLI对软骨细胞具有明显的光生物调节作用:(1)在培养至第13 d时,所有剂量组在照射后XTT吸光度值均有不同程度的增高,其中3 m in、5 m in、7 m in和10 m in组的增高较为明显(P<0.01);(2)两因素重复测定资料的方差分析结果显示,SLI照射后软骨细胞合成胶原的能力在逐步增加,而对照组在培养至第2周开始H rp含量明显下降。结论:SLI照射可促进2.5%新生牛血清中兔软骨细胞增殖,这个过程可能是通过促进胶原合成实现的。     

Plasma somatostatin-like immunoreactivity responses to a mixed meal and the heterogeneity in healthy and non-insulin-dependent (NIDDM) diabetics

Peripheral plasma somatostatin-like immunoreactivity (SLI) was estimated in non-extracted plasma using a specific somatostatin-14 (SS-14) antiserum. The basal plasma SLI level in healthy subjects (n = 18) was 43 +/- 2.9 pg/ml (mean +/- SE) and rose significantly to 8.3 +/- 2.7, 7.3 +/- 1.1 and 5.8 +/- 2.1 pg/ml above the mean basal level 20, 30, and 40 min after a mixed meal, respectively (P less than 0.05). Basal plasma SLI levels in diet (n = 8), sulfonyl urea (n = 8), and insulin groups (n = 8) of non-insulin-dependent maturity onset diabetics (NIDDM) were 50 +/- 1.6, 59 +/- 4.5, and 74 +/- 5.8 pg/ml, respectively. The basal levels for patients with NIDDM were significantly higher than those for healthy subjects (P less than 0.05). No significant increases in plasma SLI were observed after a mixed meal in any group of NIDDM subjects. Elevated plasma SLI levels are considered to be closely related to the severity of the diabetes. The ratios of SS-14 and SS-28 to the total amount of basal plasma SLI were analyzed using high pressure liquid chromatography (HPLC). The ratio of SS-14 to the total SLI was 71-80% in healthy subjects. The ratio of SS-28 to the total SLI increased from 26-30% in the diet group to 50-55% in the group on insulin. These findings suggest a possible pathophysiological role for gastrointestinal somatostatin in NIDDM.     

Effect of gamma-aminobutyric acid on bombesin-evoked release of somatostatin and gastrin from isolated rat stomach

The effect of gamma-aminobutyric acid (GABA) on basal and bombesin (BBS)-stimulated release of somatostatin (SLI) and gastrin from isolated perfused rat stomach was examined. In the control study, BBS at a dose of 10 nM significantly stimulated release of SLI and gastrin. Infusion of GABA (1-1000 nM) caused a depression of SLI release induced by BBS (10 nM) in a dose-dependent fashion. However, at doses used in this study GABA had no effect on either basal level of SLI and gastrin or BBS-elicited gastrin release. These results indicate that GABA can specifically modulate BBS-induced SLI release from rat stomach.     

Plasma somatostatin-like immunoreactivity during growth-hormone-releasing hormone therapy in non-growth-hormone-deficient children

To date, the effects of long-term growth hormone (GH)-releasing hormone [GHRH(1-29)-NH2] treatment on the plasma concentrations of somatostatin-like immunoreactivity (SLI) remain undefined. In the present study, the effect of GHRH(1-29)-NH2 therapy on plasma SLI levels has been studied in 11 non-GH-deficient children. The pattern of administration was 5 micrograms/kg body weight, given subcutaneously once every day. There was no significant change in plasma SLI levels after bolus injection of GHRH(1-29)-NH2 before and during GHRH(1-29)-NH2 therapy. However, plasma SLI rose in basal plasma and nocturnal sleep after 3 months of GHRH(1-29)-NH2 therapy and remained the same during 6 months of treatment with GHRH(1-29)-NH2. The reason for this finding is uncertain, but an increase in SLI release from the enteroinsular axis is a possible explanation. The association of our findings with the role of the circulating SLI on nutrient homeostasis and the effects of GNRH on growth velocity is discussed.     

Starvation increases gastrointestinal somatostatin in normal and obese Zucker rats: a possible regulatory mechanism

Normal, male Sprague-Dawley (S-D) rats and female, lean and obese Zucker rats were studied in the fed state and after 48 hours of food deprivation. Somatostatin-like immunoreactivity (SLI) was measured from acetic acid extracts of oesophagus-cardia, stomach, small and large intestine, pancreas, hypothalamus, pituitary and cerebellum. Within the CNS, the highest levels of SLI were found in the hypothalamus, while in the gut, these levels were highest in the stomach and pancreas. All Zucker rats displayed higher hypothalamic levels of SLI than did S-D rats. Obese Zucker rats in the fed state differed from their lean littermates in that SLI levels were lower in oesophagus-cardia, stomach and hypothalamus, while being higher in pancreas and pituitary. The response to starvation in both obese and lean Zucker rats was qualitatively similar, and included significant increases in stomach and oesophagus-cardia SLI, but with a significant fall hypothalamic SLI. We have concluded that the increase in gastrointestinal SLI with starvation in Zucker as well as in S-D rats may represent a significant regulatory mechanism in nutrient homeostasis. We postulate that gastric SLI may decrease the availability of intestinal insulin secretagogues in the fasting state. This adaptive mechanism appears to be intact in the obese Zucker rat.     

Absence of a relationship between immunoreactive-gastrin and somatostatin-like immunoreactivity secretion in the perfused rat stomach

The possible interaction between somatostatin-like immunoreactivity (SLI) and immunoreactive-gastrin release was studied in an isolated perfused rat stomach preparation. Gastrin release was abolished by antrectomy but basal and gastric inhibitory polypeptide-stimulated SLI levels were unchanged from control experiments, implicating the corpus as the major source of SLI released into the vasculature. Perfused stomachs of vagotomized rats exhibited basal hypergastrinaemia with no alteration in basal or stimulated SLI release, suggesting an uncoupling of SLI and gastrin release. This study indicated that SLI released into the vasculature originated in the acid secretory region of the stomach and therefore may be involved in the regulation of acid secretion at the level of the parietal cell mass.     

Somatostatin release from perifused rat and human gastric mucosa

In the present study the release of somatostatin-like immunoreactivity (SLI) was evaluated in vitro from isolated rat antral and fundic mucosa and from biopsy specimens of human antral mucosa. Perifusion of antral mucosa with Earle's balanced salt solution showed a pH-dependent release of SLI. SLI release did not change in response to a reduction from pH 7 during the baseline period to pH 3, whereas a significant increase occurred when the pH was changed to 2.5 or 2, respectively. Fundic SLI release remained at baseline levels during the decrease of the pH value of the buffer solutions. Atropine at doses of 10(-6) to 10(-4) M did not alter acid-induced SLI release from the isolated antral mucosa, suggesting different mechanisms in vitro compared to the acid-induced SLI release in vivo. SLI release from human mucosa was 450 +/- 217 pg/min X mg wet weight in response to perifusion with the buffer pH 2 in 7 control subjects. No significant difference was observed in patients with duodenal ulcer or acute gastritis, whereas gastric ulcer patients had significantly lower values (66 +/- 44) compared to controls and duodenal ulcer patients. These data do not support the hypothesis that impaired somatostatin production and release might be a pathogenetic factor for gastric acid hypersecretion and development of duodenal ulcer.     

Somatostatin content and binding in small intestinal mucosa from fed, fasted, and refed rabbits

The present study is an investigation of the effects of 12- to 96-hours' starvation and 96-hours' starvation plus 48-hours' refeeding on both somatostatin-like immunoreactivity (SLI) and cytosolic somatostatin binding sites in rabbit small intestinal mucosa. The SLI concentration increased after 24 h in duodenal and jejunal mucosa, but not in ileal mucosa, and reached its highest value after 96 h of fasting. The number of specific high and low-affinity somatostatin binding sites, but not their affinity, decreased with the duration of fasting in the same gut segments, refeeding of fasted animals resulted in a return to normal control values for small intestine mucosal SLI and somatostatin binding.     

Effects of alloxan-induced diabetes on somatostatin binding to cytosolic components of rabbit gastric fundic mucosa

Diabetes was induced by administration of alloxan (150 mg/Kg) to 24 h-fasted rabbits. Somatostatinlike immunoreactivity (SLI) and cytosolic binding sites for somatostatin in gastric fundic mucosa were studied using radiolabelled Tyr¹¹-somatostatin. Three months after the onset of the disease, the specific binding of somatostatin to these sites was seen to be significantly lower, due to a reduction in the number (but not the affinity) of specific somatostatin binding sites of high-affinity and a disappearance of the specific, somatostatin binding sites of low-affinity. These changes were associated with an increase in the SLI concentration in both gastric fundic mucosa and plasma.