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PubMed1977

Acid and endocrine responses to meals varying in pH in normal and duodenal ulcer subjects.

Recent studies suggest that duodenal ulcers may develop because of increased drive to secrete acid and decreased effectiveness of feedback mechanisms that inhibit acid output. This study was designed to compare gastric acid, gastrin, gastric inhibitory peptide (GIP) and secretin responses to meals (varying in pH) in 12 normal subjects and nine duodenal ulcer patients. Acid secretion was measured by an intragastric titration method which allows actual measurement of acid response to food within the stomach (ten per cent amino acid meal (AAM) adjusted to various pH levels, 7-1.5). Blood samples were collected at each pH level for radioimmunoassay of gastrin, secretin and GIP. Gastric acid and gastrin responses to AAM were found to be significantly greater in duodenal ulcer patients than in normal subjects. In duodenal ulcer patients, acid response to AAM at pH 7 or 5.5 reached 82% of Histalog maximum. Decreasing the pH of the meal resulted in a stepwise reduction in both acid secretion and gastrin in normal subjects and duodenal ulcer patients. At pH 1.5, acid inhibition was complete, but gastrin inhibition was partial. Secretin increased significantly at pH 1.5; there was no difference in secretin release between the groups. Plasma GIP was highest at pH 7 in all individuals. Use of a marker substance showed 80% recovery of AAM at pH 7-4; below pH 4, recovery rose to about 90%. We conclude that gastric acid and gastrin release are pH-dependent in normal and duodenal ulcer subjects. Inhibition of gastric secretion by acidified meals is associated with a pH-dependent suppession of gastrin and GIP levels and elevation of plasma secretin. This study confirms increased acid and gastrin responses in duodenal ulcer patients but shows no evidence of defective feedback inhibition of gastric secretion and gastrin release.

Adult↗
PubMed2003

[Pathogenesis of type 2 diabetes mellitus].

"Common" type 2 diabetes mellitus is a multifactorial disease. Hyperglycemia is related to a decrease in glucose peripheral uptake, and to an increase in hepatic glucose production, due to reduced insulin secretion and insulin sensitivity. Multiple insulin secretory defects are present, including loss of basal pulsatility, lack of early phase of insulin secretion after intravenous glucose administration, decreased basal and stimulated plasma insulin concentrations, excess in prohormone secretion, and progressive decrease in insulin secretory capacity with time. These genetically determined abnormalities appear early in the course of the disease. Insulin resistance affects muscle, liver, and adipose tissue. For the same plasma insulin levels, peripheral glucose uptake and hepatic glucose production suppressibility are lower in diabetic patients than in controls. It results from aging of the population and from "western" lifestyle, with progressive increase in mean body weight, due to excess in energy intake, decreased energy expenses and low physical activity level. NEW ASPECTS: The role of beta-cell dysfunction, as well as the interplay between insulin secretory defect and insulin resistance are now better understood. In subjects with normal beta-cell function, increase in insulin needs secondary to insulin resistance is compensated by an increase in insulin secretion adjusted to maintain plasma glucose levels to normal. In subjects genetically predisposed to type 2 diabetes, failure of beta-cell to compensate for increased needs is responsible for a progressive elevation in plasma glucose levels, then for overt type 2 diabetes. This adaptative phenomenon is called beta-cell compensation of insulin resistance. The lack of compensation is responsible for type 2 diabetes. When permanent hyperglycemia is present, progressive insulin secretory failure with time ensues, due to glucotoxicity and to lipotoxicity. PERSPECTIVES: Simple changes in lifestyle, such regular moderate physical activity, and control of body weight, should permit to avoid the explosion in prevalence of type 2 diabetes. This has been evidenced by the results of prospective studies aiming at preventing conversion from impaired glucose tolerance to diabetes. In patients with permanent hyperglycemia not controlled by lifestyle changes, metabolic defects are the targets of specific therapy intervention with antidiabetic oral agents, such as insulin secretagogues, insulin sensitizers, and inhibitors of hepatic glucose production.

Diabetes Mellitus, Type 2↗
PubMed1990

Sulphonylurea effects on insulin secretion in islets desensitized to glucose.

Prolonged, continuous exposure of the islets of Langerhans to high glucose concentrations results in desensitization of the beta cell to glucose stimulation. This study tested the ability of a sulphonylurea to stimulate insulin secretion in this setting. Normal isolated rat islets were cultured for 18-20 h in RPMI-1640 with 300 mg/dl glucose to induce desensitization or with 100 mg/dl as a control. Islets were then placed into a perifusion system and perifused with 60 mg/dl glucose followed by a stimulus. After preincubation at 300 mg/dl, a significant 50% suppression of glucose-induced insulin secretion compared with secretion in the control group preincubated at 100 mg/dl glucose was observed (p less than 0.025-0.001). This confirmed the occurrence of desensitization to glucose in this in vitro model. In contrast, stimulation of insulin secretion by glyburide (500 ng/ml) was unaffected compared with control. We also tested whether glyburide corrects the defective response to glucose stimulation in glucose-desensitized islets. Control islets (preincubated at 100 mg/dl) were stimulated with 300 mg/dl glucose or with this glucose concentration plus glyburide. Peak incremental insulin responses were similar (0.81 +/- 0.07 and 0.77 +/- 0.12 microU/ml.islet). After preincubation at 300 mg/dl, perifusion with 300 mg/dl glucose alone or with glyburide was associated with smaller, but similar, peak insulin responses (0.53 +/- 0.13 and 0.62 +/- 0.06 microU/ml.islet). In conclusion, islets in which the insulin-secretory response is compromised by desensitization to glucose are nevertheless completely responsive to the direct stimulatory effects of a sulphonylurea. However, the sulphonylurea does not correct the defect in glucose-induced insulin secretion.

Animals↗
PubMed2000

Ions, genes and insulin release: from basic science to clinical disease. Based on the 1998 R. D. Lawrence Lecture.

In 1968, reports of the first microelectrode recordings of insulin-secreting cells were published. Thirty years later it is now established that electrical responses of beta-cells play a critical role in stimulus-secretion coupling. It is now also clear that defects in ion channel genes compromise the mechanisms which govern secretion and lead to the onset of disease. Here, the physiology of insulin release is reviewed in the context of ion channels, the ionic control of insulin release and the pathophysiology of hyperinsulinism of infancy.

Animals↗
PubMed1995

Enhanced sensitivity of pancreatic islets from preobese 2-week-old ob/ob mice to neurohormonal stimulation of insulin secretion.

Insulin secretion from perifused islets of preobese, 2-week-old, genetically obese (ob/ob) mice and their lean littermates was examined to identify early-onset abnormalities in regulation of insulin secretion by ob/ob mice. The ob/ob mice were slightly hyperinsulinemic (+20%) and hypoglycemic (-12%) at 2 weeks of age. Pancreatic islet size, DNA content, and insulin content were similar in ob/ob and lean mice. The responsiveness of islets to glucose, as determined by 20 mM glucose-induced insulin secretion, and the sensitivity of islets to glucose, as determined by the glucose threshold for insulin secretion, were unaffected by phenotype, but two insulin secretagogues that potentiate glucose-induced insulin secretion via activation of the phospholipase-C signal transduction pathway (i.e. acetylcholine, and cholecystokinin) were more effective in stimulating insulin secretion from islets of ob/ob mice than from islets of lean mice. Both responsiveness and sensitivity to acetylcholine and cholecystokinin potentiation of glucose-induced insulin secretion were enhanced in islets from ob/ob mice. Further, glucose-dependent insulinotropic polypeptide, which stimulates glucose-induced insulin secretion via activation of adenylate cyclase, interacted with acetylcholine to further augment differences in insulin secretion between islets from ob/ob and lean mice. The signal transduction pathway common to acetylcholine and cholecystokinin, and cross-talk between this pathway and the glucose-dependent insulinotropic polypeptide signal transduction pathway are loci for early-onset defects in control of insulin secretion from islets of ob/ob mice.

Acetylcholine↗
PubMedDate not supplied

Clinical importance of insulin secretion and its interaction with insulin resistance in the treatment of type 2 diabetes mellitus and its complications.

Type 2 diabetes primarily develops from pathogenic defects in the mechanisms of insulin secretion and hepatic and peripheral insulin action. The consequent disruption of normal glucose metabolism involves a number of organ systems and is ultimately manifested in fasting and daytime hyperglycemia. Chronically elevated blood glucose concentrations determine the progression of the disease by further exacerbating insulin resistance and causing beta-cell exhaustion in addition to decreasing their responsiveness to glucose. The beta-cell secretory dysfunction is characterized by the lack of the early phase of glucose-induced insulin secretion and the insufficient and delayed late phase of secretion. Glycemic levels in patients with type 2 diabetes are directly related to the risk of developing microvascular and macrovascular complications, the main cause of the morbidity and mortality associated with this disease. The goal of treatment is to decrease the risk and delay the progression of these complications by improving glycemic control. Current oral antidiabetic agents, used as monotherapy or in combination, include traditional insulin secretagogues, insulin sensitizers and inhibitors of carbohydrate absorption. A greater understanding of the pathophysiology of type 2 diabetes and recent findings on the significance of meal-related glycemia to overall glycemic control are expanding the therapeutic options for treating this disease.

Blood Glucose↗
PubMed2000

Effect of hemipancreatectomy and of pancreatic diversion on the tolerance to a glucose load in humans.

BACKGROUND: The role of the pattern, quantity and site of insulin secretion in the tolerance to a glucose challenge is not fully evaluated in humans because it is difficult to obtain appropriate clinical models. DESIGN: To address this issue, we studied subjects with reduced pancreatic mass (hemipancreatectomized, HEMI), systemic insulin delivery (pancreas transplant recipients, PTX), and two control groups (healthy, CON; and with uveitis on the same immunosuppression as PTX, UVE), with an hyperglycaemic clamp (study 1, + 4.2 mmol L-1), using a repeat experiment (study 2) with a fixed glucose infusion, calculated to increase by 35% that in study 1. RESULTS: In study 1, CON increased glucose uptake to 20 +/- 3 micromol kg-1 min-1 after a biphasic insulin response. In study 2, CON further increased the glucose uptake via an increment in prehepatic insulin secretion that stimulated insulin sensitivity without changes in peripheral insulin and glucose concentrations. HEMI and PTX had 35% less glucose uptake in study 1, compared to CON, and increased glucose concentrations (+ 1.6 mmol L-1) in study 2. UVE had an intermediate defect. The causes of intolerance were different: HEMI had a defective first-phase insulin secretion (50% peripheral insulin concentrations) but maintained insulin sensitivity; PTX had normal peripheral insulin but only one-third of the insulin sensitivity of CON. CONCLUSIONS: Hemipancreatectomy and systemic insulin delivery impair first-phase insulin secretion; second-phase peripheral insulinization (HEMI); insulin sensitivity (PTX); and a mechanism evidentiated in study 2 of CON that increases insulin sensitivity in response to prehepatic insulin secretion (both groups). Failure of these mechanisms is largely compensated by hyperglycaemia.

Adult↗
PubMed2000

Mitochondrial glutathione replacement restores surfactant synthesis and secretion in alveolar epithelial cells of ethanol-fed rats.

BACKGROUND: Chronic alcohol abuse increases the incidence and severity of acute lung injury in critically ill patients. Previously we determined that ethanol ingestion in rats dramatically decreased alveolar epithelial cellular levels of glutathione and surfactant synthesis and secretion in vitro. Previous studies in alcoholic liver disease suggest that mitochondrial glutathione levels, and not cellular levels per se, are involved in the pathogenesis of ethanol-mediated hepatotoxicity. Therefore, we hypothesized that alveolar epithelial mitochondrial glutathione depletion mediates the observed defects in surfactant synthesis and secretion in ethanol-fed rats. METHODS: Male Sprague-Dawley rats were fed the Lieber-DeCarli liquid diet with or without ethanol (36% of total calories) for 6 weeks. In some experiments, ethanol-fed rats were then switched to the control diet for 1 week, with or without glutathione supplementation with either N-acetylcysteine (NAC) or procysteine (PRO). Alveolar epithelial type II cells were then isolated and glutathione levels (cytosolic and mitochondrial) and surfactant production (synthesis and secretion) were determined. RESULTS: Ethanol ingestion decreased (p < 0.05) mitochondrial and cytosolic levels of glutathione, and surfactant synthesis and secretion in isolated type II cells when compared to cells from control-fed rats. NAC treatment restored (p < 0.05) cytosolic but not mitochondrial glutathione levels (p > 0.05), and had no effect (p > 0.05) on surfactant synthesis and secretion in type II cells isolated from ethanol-fed rats. In contrast, PRO treatment restored (p < 0.05) cytosolic and mitochondrial glutathione levels, and normalized (p < 0.05) surfactant synthesis and secretion in type II cells isolated from ethanol-fed rats. CONCLUSIONS: These results suggest that mitochondrial, and not simply cytosolic, replacement of glutathione is necessary to improve surfactant function in critically ill patients with a history of alcohol abuse.

Animals↗
PubMed1992

On the mechanism of impaired distal acidification in hyperkalemic renal tubular acidosis: evaluation with amiloride and bumetanide.

It has been postulated that a distinctive type of hyperkalemic distal renal tubular acidosis (DRTA), referred to as voltage-dependent DRTA, results from diminished potassium and hydrogen ion secretion in the distal nephron, which is due to a suboptimal voltage (lumen negative) as a result of impaired sodium reabsorption. To test for the presence of a voltage-dependent DRTA, we used amiloride (20 mg oral, single dose) and bumetanide (2 mg oral, single dose) to inhibit and to stimulate voltage-dependent potassium and hydrogen ion secretion, respectively. Eighteen patients with hyperkalemic DRTA and seven controls with a comparable degree of renal impairment were studied. Patients were subdivided in two groups on the basis of their ability to lower their urine pH during spontaneous acidosis. Patients in Group I lowered their urine pH to the level of controls (5.29 +/- 0.06 and 5.37 +/- 0.11, respectively) whereas patients in Group II could not lower their urine pH below 5.5 (6.38 +/- 0.11). Patients in Group I and Group II had a similar degree of metabolic acidosis and hyperkalemia whereas controls had neither acidosis or hyperkalemia. Most patients in Group II and all patients in Group I had low plasma aldosterone levels. The administration of amiloride resulted in an increase in urine pH and a decrease in potassium excretion in all three groups. The finding that amiloride, presumably by obliterating the transtubular voltage as a result of blockade of sodium transport, inhibited potassium excretion to about the same extent in both groups of patients and in controls argues against the existence of a voltage-dependent defect. Bumetanide produced a fall in urine pH below 5.5 and an increase in potassium excretion in controls and Group I patients. In Group II patients, bumetanide failed to elicit a fall in urine pH below 5.5 but resulted in an increase in potassium excretion similar to that seen in controls and Group I patients. These findings suggest that a derangement other than a voltage-dependent defect is responsible for the inability, characteristic of Group II patients, to lower their urine pH. It was concluded that the impairment in urinary acidification observed in patients with this subtype of hyperkalemic DRTA is due to a defect in collecting tubule hydrogen secretion that results from H+ ATPase dysfunction rather than from a voltage-dependent defect.

Acidosis, Renal Tubular↗
PubMed1991

A cytoskeleton-related gene, uso1, is required for intracellular protein transport in Saccharomyces cerevisiae.

The Saccharomyces cerevisiae mutant strains blocked in the protein secretion pathway are not able to induce sexual aggregation. We have utilized the defect of aggregation to concentrate the secretion-deficient cells and identified a new gene which functions in the process of intracellular protein transport. The new mutant, uso1, is temperature sensitive for growth and protein secretion. At the restrictive temperature (37 degrees C), uso1 mutant accumulated the core-glycosylated precursor form of the exported protein invertase in the cells. Ultrastructural study of the mutant fixed by the freeze-substitution method revealed expansion of the nuclear envelope lumen and accumulation of the ER at the restrictive temperature. Abnormally oriented bundles of microtubules were often found in the nucleus. The USO1 gene was cloned by complementation of the uso1 temperature-sensitive growth defect. DNA sequence analysis revealed a hydrophilic protein of 1790 amino acids with a COOH-terminal 1,100-amino acid-long alpha-helical structure characteristic of the coiled-coil rod region of the cytoskeleton-related proteins. These observations suggest that Uso1 protein plays a role as a cytoskeletal component in the protein transport from the ER to the later secretory compartments.

Amino Acid Sequence↗
PubMed2003

Insulin sensitivity and beta-cell secretion in thalassaemia major with secondary haemochromatosis: assessment by oral glucose tolerance test.

UNLABELLED: Diabetes mellitus in patients with thalassaemia major is caused by secondary haemochromatosis due to transfusional iron overload. The pathogenetic mechanisms leading from siderosis to diabetes are still poorly understood. This study aimed at assessing the influence of insulin resistance and insulin deficiency on that process. Glucose, insulin and C-peptide levels during oral glucose tolerance tests (OGTT) from 36 thalassaemic patients with normal ( n=23), impaired ( n=6), or diabetic glucose tolerance ( n=7) and 32 control subjects were examined. Insulin secretion and insulin sensitivity were assessed by established calculated indices. Fasting, 2h and integrated glucose concentration were significantly increased in thalassaemic patients with normal glucose tolerance compared to controls (5.01/4.59 mmol/l, 6.33/5.17 mmol/l, and 844.2/739.3 mmol/l per min, respectively; all P<0.03). Patients with impaired glucose tolerance presented hyperinsulinaemia and delayed peak insulin during OGTT. The C-peptide/insulin ratio was decreased in patients with abnormal glucose tolerance compared to controls (5.85/7.33 x 10(3)pmol/l per min, P<0.03). It was negatively correlated with age in patients ( r=-0.45, P<0.01), but positively in controls ( r=0.43, P<0.03). Insulin sensitivity was significantly reduced in patients with impaired glucose tolerance or diabetes compared to controls. In addition, a significant decrease in patients with normal glucose tolerance was shown by two insulin sensitivity indices (all P<0.05). In thalassaemia patients, insulin sensitivity was negatively correlated with age. Insulin secretion capacity according to the homeostasis assessment model was significantly reduced in patient groups compared to controls (Kruskal-Wallis-test, P<0.004). CONCLUSION: Insulin resistance is of central importance for the development of diabetes mellitus in patients with secondary haemochromatosis. An additional early defect in beta-cell secretion cannot be excluded.

Adolescent↗
PubMed1976

Lithium-induced impairment of urine acidification.

The purpose of this study was to clarify the means by which lithium induced a disorder of urine acidification. Rats infused with hydrochloric acid (1 mEq/kg) developed acute metabolic acidosis (blood Ph = 7.32; bicarbonate, 18 mEq/liter) with a urine pH of approximately 5.85. The addition of lithium chloride (4 mEq/kg i.p) caused an increase in the urine pH (6.38) and a further decrease in blood bicarbonate (11.0 mEq/liter). During bicarbonate loading, lithium caused the urine PCO2 to fall significantly (urine minus blood PCO2 decreased from 25.3 +/-2.8 To 14.4 +/- 2.3 mm Hg) These changes were not seen following equimolar i.p. administration of sodium chloride. Similarly, lithium administration depressed bicarbonate reabsorption by 11.1% (from 30.6 to 27.2muEq/ml of GFR) during alkali infusion, while saline caused only a 5% decrease (30.0 to 28.5muEq/ml of GFR). The combination of an increase in urine PCO2 in alkaline urine indicates that lithium produced a defect in distal nephron hydrogen ion secretion. The fall in bicarbonate reabsorption following lithium administration oculd be due to a mild hydrogen ion secretory defect located in the proximal tubule or a severe defect in the distal nephron.

Acid-Base Imbalance↗
PubMed1997

Yeast actin cytoskeleton mutants accumulate a new class of Golgi-derived secretary vesicle.

Many yeast actin cytoskeleton mutants accumulate large secretory vesicles and exhibit phenotypes consistent with defects in polarized growth. This, together with actin's polarized organization, has suggested a role for the actin cytoskeleton in the vectorial transport of late secretory vesicles to the plasma membrane. By using ultrastructural and biochemical analysis, we have characterized defects manifested by mutations in the SLA2 gene (also known as the END4 gene), previously found to affect both the organization of the actin cytoskeleton and endocytosis in yeast. Defects in cell wall morphology, accumulated vesicles, and protein secretion kinetics were found in sla2 mutants similar to defects found in act1 mutants. Vesicles that accumulate in the sla2 and act1 mutants are immunoreactive with antibodies directed against the small GTPase Ypt1p but not with antibodies directed against the homologous Sec4p found on classical "late" secretory vesicles. In contrast, the late-acting secretory mutants sec1-1 and sec6-4 are shown to accumulate anti-Sec4p-positive secretory vesicles as well as vesicles that are immunoreactive with antibodies directed against Ypt1p. The late sec mutant sec4-8 is also shown to accumulate Ypt1p-containing vesicles and to exhibit defects in actin cytoskeleton organization. These results indicate the existence of at least two classes of morphologically similar, late secretory vesicles (associated with Ypt1p+ and Sec4p+, respectively), one of which appears to accumulate when the actin cytoskeleton is disorganized.

Antibody Specificity↗
PubMed1997

Age-related decrease in the opioid control of LH secretion during reproductive years in normal women.

UNLABELLED: Our previous studies showed that naloxone is unable to stimulate LH secretion in elderly men, suggesting a loss in the endogenous opioid inhibitory control of LH in senescence. METHODS: In the present study, we examined whether increasing age during the reproductive period in women is associated with alterations in the LH-releasing effect of naloxone. Studies were performed in younger (age 20-28 years, n = 8) and older (age 40-48 years, n = 8) subjects with normal menstrual cycles and normal gonadal steroid levels to avoid the interference of premenopause or menopause on gonadotropin secretion. The LH response to naloxone (4 mg as an i.v. bolus plus 10 mg infused in 2 h) was tested not only in normal conditions, but also after chronic dopaminergic stimulation with bromocriptine (5 mg/day for 7 days), because this treatment has been found able to restore normal LH responses to naloxone in elderly men. All tests were performed on the 22nd day of normal menstrual cycles. RESULTS: Naloxone induced a 100% increase in plasma LH levels in the younger group. In contrast, naloxone enhanced only by 50% LH secretion in the older subjects. When experiments were repeated after bromocriptine treatment, the effect of naloxone did not change in the younger subjects, whereas it was significantly higher in the older group. In the presence of bromocriptine, naloxone-induced LH increment in the older group was indistinguishable from that observed in the younger group. These data suggest that during the reproductive period, increasing age is associated with an impairment in the endogenous opioid control of LH secretion. In addition, age-related dopaminergic alterations independent of circulating gonadal steroid levels appear to underlie the defective endogenous opioid control of LH secretion in normally cycling women.

Adult↗
PubMed1990

[Experimental reconstruction of the trachea with free jejunal graft].

To evaluate experimentally the usefulness of the jejunum in the correction of extensive tracheal defect, circumferential tracheal defect was surgically created in 31 mongrel dogs and primarily reconstructed with microsurgical free tissue transfer of autogenous jejunal segment. A silicone T tube was inserted to maintain the lumen of the grafted jejunal segment. First, defect of 7 cervical tracheal rings was repaired with untreated 5 cm free jejunal segment in 12 dogs (group 1). Next, a pilot experiment to examine the quantity of intestinal juices from jejunal segments revealed that abrasion and cauterization of the mucosal surface decreased the secretion of intestinal juices, so defect of 7 cervical tracheal rings was repaired with 5 cm free jejunal segment the surface of whose mucosa was abraded and cauterized in 11 dogs (group 2). In all the dogs except two, primary healing was accomplished without air leakage or infection, and gross pathological examination of the trachea and graft revealed no evidence of disruption, infection or granulation. In group 1, 6 of the 12 dogs died of pneumonia or air way obstruction caused by intestinal juices from free jejunal segment within 20 days after the operation. On the other hand, only one of the 11 dogs died of pneumonia at 9 days in group 2. One of the dogs died of air way obstruction caused by mucus at 3 months. Three dogs died of filariasis at 4 weeks, 3 and 7 months, and 5 dogs were sacrificed at 2, 4, 8 weeks and 3 months. Microscopic examination of the graft demonstrated thin jejunal mucosa. The anastomosis was already covered with epithelium by the end of 2 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Lack of Histocompatibility Leukocyte Antigen-G expression in early embryos is not related to germinal defects or impairment of interleukin-10 production by embryos.

The expression of Histocompatibility Leukocyte Antigen (HLA)-G molecules is a mandatory prerequisite for the development of pregnancy but no hypotheses have yet been advanced regarding the lack of HLA-G modulation expression in a percentage of early embryos obtained by in vitro fertilization (IVF). One possible hypothetical model assumes that the absence of regulation of HLA-G or impaired interleukin (IL)-10 secretion could be related to germinal defects. We investigated the presence of soluble HLA-G antigens in supernatants of single embryo cultures from couples admitted to a second fertilization procedure; these couples showed a complete absence of HLA-G modulation in the first cycle's embryo supernatants (0/31). The results obtained in the second IVF cycle showed embryo supernatants positive for HLA-G (14/40), suggesting that the previous lack of antigen modulation is independent of germinal defects. Furthermore, since it has been reported that oocytes and early embryos can secrete IL-10, an anti-inflammatory cytokine produced by type 2 helper T cells that induces upregulation of HLA-G expression in monocytes and trophoblasts, we investigated the levels of IL-10 and soluble HLA-G in 40 embryo culture supernatants from 21 IVF cycles. No associations were observed between the presence of IL-10 and the production and concentrations of soluble HLA-G, or between IL-10 levels and pregnancy outcome. These results indicate that the lack of HLA-G production in early embryos is not related to germinal defects or to impairment in embryo IL-10 secretion but could be ascribed to possible uncorrected fertilization processes.

Embryo, Mammalian↗
PubMed1988

Activation events in hapten-specific B cells from tolerant mice.

We have studied hapten-binding cells from the spleens of normal and tolerant adult mice in terms of their ability to enlarge, proliferate, and differentiate into antibody-secreting cells. Tolerant B cells showed clear defects in intermediate activation events in addition to a deficit in antibody-secreting cells. In these studies, isolated B cells were stimulated by T cell independent Ag with lymphokines, or with mitogens, in the absence of filler cells. The number of antibody-secreting cells generated from the tolerant population was consistently reduced by 70 to 80% of the control response to the specific Ag, fluoresceinated Brucella abortus (FL-BrA) +/- lymphokines. We found that similar numbers of normal and tolerant cells enlarged (entered cell cycle) when stimulated by FL-BrA, LPS, IL-4, or alpha-Ig coupled to dextran (alpha-Ig-dex). Ia induction stimulated by IL-4, LPS, FL-BrA, or alpha-Ig-dex was the same in normal and tolerant cells. However, DNA synthesis stimulated by FL-BrA, FL-BrA + IL-5, or suboptimal concentrations of LPS was reduced by 70% in the tolerant cell population. Proliferation in response to 50 micrograms/ml LPS or to low doses of alpha-Ig-dex was similar in normal and tolerant B cells. These data suggest that the primary defect in adult B cell tolerance is the ability to proliferate in response to Ag.

Animals↗
PubMed1984

Reduction due to ageing of TSH-stimulated thyroid hormone release in the cream hamster.

The in vitro secretion by thyroid lobes from young (2-month-old) and from "aged" (more than 21 months old) male cream hamsters was estimated by measuring the butanol-extractable 125I (BE-125I) released into the medium after 2 and 4 h of incubation in the presence or absence of thyroid stimulating hormone (TSH). Lobes were fixed at the end of incubation for examination by both light and electron microscopy. Other lobes from both groups were collected for estimation of cyclic AMP contents. BE-125I release by lobes from aged animals after TSH stimulation was significantly lower than that of young animals. Similarly, pseudopods resorbing colloid, the morphological markers of secretion, were much less prominent in the aged group than in the young group. As this observation and the reduced BE-125I release contrast with an equivalent increase of cyclic AMP in both the young and aged groups, it is suggested that the age-dependent defect resulting in reduced hormone secretion is located at a step beyond the generation of cyclic AMP in the cascade of events occurring between binding of TSH to plasma membrane receptors on the target cell and hormone release.

Aging↗