Search PubMed⌕ Search

Biomedical subjects

K Hall

Publications and source records attributed to K Hall.

At least 163 records · Page 9Linked to original sources
PubMed1990

Gastric H+,K(+)-ATPase as a therapeutic target in peptic ulcer disease.

The presence of unbuffered acid appears to be an essential contributory factor in the pathogenesis of peptic ulcer disease. Treatment has concentrated therefore on the reduction of acidity, and the last decade has seen the widespread and effective use of H2 antagonists. They are, at low doses, more successful in improving the natural history of duodenal ulcer disease than of gastric or esophageal ulceration. The H2 receptor plays a central role in activation of parietal cell acid secretion, and antagonists at this receptor block most (but not all) of the acid secretion due to even gastrinergic or muscarinic (vagal) stimulation. In hypergastrinemic states such as Zollinger-Ellison syndrome, or where acid secretion has to be inhibited by more than 20% over a 24-hr period, such as for treatment of esophagitis, NSAID damage, or gastric ulcers, the dose and frequency of administration of the currently available antagonists must be increased to achieve reliable therapy. This has led to a search for an alternative target for acid inhibitory drugs, such as the gastric acid pump, the H+,K(+)-ATPase. This article focuses on the function of this ATPase and suggests that inhibition of this pump will provide a more efficacious means of reduction of acid secretion by the stomach, hence improving and simplifying therapy of acid related diseases.

Animals↗
PubMed1990

Determination of IGF-II levels in human serum using the erythroleukemia cell line K562.

A homologous radioreceptor assay (RRA) has been developed for Insulin-like Growth Factor II (IGF II) using the human erythroleukemia cell line K562. These cells have binding sites for insulin and IGF-II but not for Insulin-like Growth Factor I (IGF I). All samples were dissociated and separated from binding proteins by gel filtration at acidic pH. In healthy adults the mean serum level of radioreceptor assayable IGF II (RRA-IGF II) and 95% confidence limits were 965 ng/ml and 717-1299 ng/ml, respectively. The mean level in GH deficient patients was significantly lower (p less than 0.001) compared with healthy subjects whereas no change was found in patients with acromegaly and uremia. Slightly lowered levels of RRA-IGF II were found in one patient with a tumor induced hypoglycemia.

Acromegaly↗
PubMed1990

"Spontaneous" transfer of stimulus control from tact to mand contingencies.

An important issue in teaching verbal behavior to persons with severe handicaps is the transfer of stimulus control from tact (e.g., naming) to mand (e.g., requesting) relationships. Previous research has shown that topographies taught as tacts frequently fail to appear as mands unless transfer between these two response classes is explicitly programmed. Procedures promoting this transfer would provide a necessary instructional tool. Transfer from tact to mand contingencies was investigated in two adults with severe mental retardation. Correct pointing responses to line drawing symbols depicting the utensils required to access previously requested food (beverage) items were assessed prior to and following tact intervention. Mands for two of three utensils emerged following tact intervention. The results suggest transfer from tact variables to the conditioned establishing operation may be facilitated by the prior development of a minimal mand repertoire.

Adult↗
PubMed1990

Exercise-induced changes in insulin-like growth factors and their low molecular weight binding protein in healthy subjects and patients with growth hormone deficiency.

Serum concentrations of insulin-like growth factors 1 and 2 (IGF-1 and IGF-2), the low molecular weight form of IGF binding protein (IGFBP-1), insulin, C-peptide and GH were determined in six healthy subjects and four patients with GH deficiency during 30 min of moderate physical exercise on the cycle ergometer. The load corresponded to 60% of individual maximal oxygen uptake. IGF-1 and IGF-2 were determined by radioimmunoassays developed with antibodies isolated from immunized hens eggyolk after separation by automated acid gel filtration of serum samples prior to assay. Significant increases in the serum concentrations (mean +/- SEM) of IGF-1 (157 +/- 24 to 196 +/- 29 micrograms l-1, P less than 0.05) and IGF-2 (451 +/- 37 to 678 +/- 85 micrograms l-1, P less than 0.01) were seen in the healthy subjects after 10 min of exercise. The mean percentage increase was 26 +/- 5% for IGF-1 and 50 +/- 11% for IGF-2. No relation to the GH release was found. In GH-deficient patients the mean IGF-2 concentration rose 48 +/- 17% from basal 216 +/- 63 micrograms l-1 to a peak concentration of 324 +/- 115 micrograms l-1 (P less than 0.01) after 30 min, while the 38 +/- 20% rise of IGF-1 from basal 36 +/- 13 micrograms l-1 to a peak concentration of 55 +/- 27 micrograms l-1 was not significant. The serum IGFBP-1 concentration did not change during exercise, while insulin and C-peptide concentrations, as well as blood glucose, decreased in both healthy subjects and GH-deficient patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Insulin-like growth factor II effects mediated through insulin-like growth factor II receptors.

Insulin-like growth factor II (IGF-II) resembles the homologous peptide insulin-like growth factor I (IGF-I) in that it stimulates cellular growth in vitro. This effect is generally believed to be mediated through IGF type 1 receptors; the role of the IGF type 2 receptor remains, as yet, unknown. IGF-II has been shown to stimulate clonal expansion in cells from the human erythroleukaemia cell line K562, which displays binding of IGF-II and insulin but not IGF-I. This IGF-II effect was dose-dependent and correlated to the amount of specific binding; IGF-I did not stimulate growth. A similar effect on clonal growth was observed in the human T-cell line Jurkat. Furthermore, IGF-II was found to stimulate the cytotoxic activity of natural killer cells (as does interleukin 2). This effect was not inhibited by addition of IGF binding protein 1. Thus, it can be concluded that IGF-II, besides demonstrating standard IGF properties, exhibits unique biological effects in certain cells.

Cell Line↗
PubMed1990

Administration of high-dose octreotide (Sandostatin) by continuous subcutaneous infusion for the treatment of acromegaly.

Patients with active acromegaly were treated with octreotide (SMS 201-995, Sandostatin; Sandoz Pharmaceuticals) given in high dosage by continuous subcutaneous administration (CSI). Serum growth hormone (GH) and insulin-like growth factor 1 (IGF-1) concentrations were rapidly and consistently reduced to the normal range and maintained for up to 14 weeks of study. Maximal inhibition of GH and IGF-1 secretion was obtained at a dose of 600 micrograms/24 h; all except 1 of the 7 patients were able to tolerate a higher dose of 1,600 micrograms/24 h. A single patient failed to show GH suppression at any dosage of octreotide. Computed tomographic evidence of tumour shrinkage was not demonstrated in these 7 patients, although in 2 patients subsequently studied by us definite tumour shrinkage was observed. These data show that the administration of octreotide by CSI is a highly satisfactory method for persistently lowering GH and IGF-1 concentrations in acromegalic patients sensitive to this drug.

Acromegaly↗
PubMed1990

Physical and psychological capabilities during substitution therapy with recombinant growth hormone in adults with growth hormone deficiency.

In a double-blind cross-over study with recombinant methionyl growth hormone (GH) and placebo during 12 weeks, the effect of GH substitution therapy (0.5-06 IU.kg-1.week-1) on physical performance, muscle strength, bone mineral density, and mood and cognitive functions was investigated in 6 GH-deficient adults. During GH substitution serum concentrations of insulin-like growth factor-I and procollagen-III peptide increased in all 6 patients, whereas concentrations of serum urea decreased. Five of the patients identified the GH period and reported improved well-being with increased mental alertness and vitality and improved physical capacity and muscle strength. There was, however, no change of the isokinetic muscle strength during GH substitution therapy, and the working capacity on the bicycle ergometer was just slightly improved in some patients. The bone mineral density was low and unchanged in all patients. Mood and cognitive functions did not change during GH therapy. A reversible fluid retention was observed in one patient during the GH period. In conclusion, short-term GH substitution therapy to GH-deficient adults induced a subjective improvement of general well-being. Longer treatment periods will be necessary to establish the effect on physical capacity, muscle strength, bone mineral density, and mood and cognitive functions.

Adult↗
PubMed1990

Immunoreactive insulin-like growth factor II in urine.

Insulin-like growth factor II and insulin-like growth factor binding protein-1 were identified and quantified in the urine of 23 healthy subjects between 17 and 76 years of age. IGF-II was measured after separation by gel chromatography at low pH and compared with IGF-I levels in the same samples, whereas IGF binding protein-1 was measured in dialysed urine. Urinary IGF-II was found at much higher concentrations than IGF-I (mean +/- SEM: 717 +/- 69 vs 110 +/- 5 ng/mmol creatinine). The chromatographic profile indicates that pro-IGF-II may also be present. The concentrations of IGF-II appear to be less variable than the other reported parameters. The mean IGF binding protein-1 concentrations in these urine samples was 414 +/- 83 ng/mmol creatinine. IGFs in the urine are in part bound to binding proteins.

Adolescent↗
PubMed1990

Differential effects of IGF-I and insulin on glucoregulation and fat metabolism in depancreatized dogs.

The effects of equipotent glucose-lowering doses of insulinlike growth factor I (IGF-I) and insulin on tracer-determined glucose kinetics and several metabolites were compared in 14 experiments (7 in each group) in fasted, totally depancreatized dogs. This model prevented variations in insulin secretion induced by IGF-I and permitted evaluation of the effects of IGF-I on extrapancreatic glucagon. Steady-state moderate hyperglycemia (9.9 +/- 0.2 mM) was maintained by a subbasal intraportal infusion of insulin (1.29 +/- 0.17 pmol.kg-1.min-1). This was continued throughout the experiment, allowing evaluation of IGF-I effects on insulin clearance. Human recombinant IGF-I or insulin was given intravenously as a primed infusion for 90 min, followed by a 50-min recovery period. The dose of IGF-I was a 2.6-nmol/kg bolus plus 57.4 pmol.kg-1.min-1. The insulin dose required to induce the same plasma glucose decline as IGF-I (44 +/- 6 vs. 43 +/- 5%, NS) was 9-12 times lower (0.06-nmol/kg bolus + 6.4 +/- 0.6 pmol.kg-1.min-1). However, the mechanism of this decline differed with IGF-I and insulin; glucose production was much less suppressed (25 +/- 9 vs. 42 +/- 11%, P less than 0.001) and glucose utilization was more stimulated (68 +/- 18 vs. 38 +/- 19%, P less than 0.05) with IGF-I.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Mitogenically uncoupled insulin and IGF-I receptors of differentiated human neuroblastoma cells are functional and mediate ligand-induced signals.

The SH-SY5Y human neuroblastoma cell line is differentiated in vitro with nanomolar concentrations of 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Untreated cells express insulin receptors, and both type I and type II insulin-like growth factor (IGF) receptors, as has been shown by agonist binding and immunoprecipitation studies. Via interaction with its own receptor and the IGF-I receptor, insulin induced a mitogenic response in these cells. IGF-I and IGF-II are also mitogens for SH-SY5Y cells, as shown by a transient increase of the c-fos mRNA level, ornithin decarboxylase activity, thymidine incorporation, and, finally, cell division. TPA-differentiated cells do not respond mitogenically to any of these factors, although insulin and IGF-I receptors are still present on the cell surface and remain functional, as demonstrated by ligand-stimulated autophosphorylation, actin reorganization, and c-fos induction. However, other prereplicative responses, i.e., increased ornithin decarboxylase activity and c-myc mRNA levels, cannot be induced. These phenomena, may be part of a receptor uncoupling mechanism(s). The findings are discussed in terms of differentiation stage-dependent signaling of growth factor receptors. We suggest that these receptors switch from controlling cell division in replicative neuronal cells to mediating externally controlled functions related to the differentiated neuronal phenotype.

Actins↗
PubMed1989

Continuous infusion of octreotide in acromegaly.

15 patients with acromegaly were treated with continuous subcutaneous infusion of octreotide in increasing dose from 200 to 1600 micrograms per 24 h by 200 micrograms increments each week. Patients were studied during the initial 7 h of infusion, weekly at each dose level, then after 1 and 2 months at maximum dosage. 13 patients responded well, as judged by growth hormone (GH) suppression and return of insulin-like growth factor 1 to normal, although 1 patient withdrew due to adverse effects; 2 patients showed no significant reduction in GH. In the 12 responders GH level fell within the first 3 h of infusion at a mean plasma octreotide level of 0.76 (SE 0.26) micrograms/l, corresponding to 25 micrograms of infused drug. Optimum suppression of GH occurred at a dosage of 600 micrograms per 24 h, a plasma drug level of 3.5 (0.5) micrograms/l. A definite reduction in tumour size was seen on computerised tomographic scan in 2 patients. All responders noted subjective improvement in acromegalic symptoms. Adverse effects comprised gastrointestinal disturbances, which were transient and mild in 14 patients but severe in 1; biliary sludging occurred in 1 patient. No significant deterioration in carbohydrate tolerance was seen in the responders.

Acromegaly↗
PubMed1989

A comparison of the biological activity of the recombinant intact and truncated insulin-like growth factor 1 (IGF-1).

A truncated form of insulin-like growth factor 1 (IGF-1), which lacked the aminoterminal tripeptide Gly-Pro-Glu has been isolated from human fetal and adult brain. This truncated IGF-1 displayed more potent cross-reactivity and biological action on brain cells than IGF-1 isolated from human serum. We now present data on a recombinant DNA-derived truncated IGF-1 lacking the aminoterminal tripeptide. Recombinant truncated IGF-1 was 1.4-5-times more potent than recombinant and natural IGF-1 in displacing [125 I]IGF-1 from human fetal and adult brain and placenta membranes. These differences were slightly enhanced when truncated IGF-1 was used as radioligand. The relative potencies compared to insulin-like growth factor 2 (IGF-2) in displacing [125I]IGF-2 from rat liver membranes were recombinant truncated IGF-1, 0.3% and recombinant IGF-1, 0.2%. Recombinant truncated IGF-1 displayed 100-fold reduced affinity for the low molecular weight binding protein (IGF-BP) isolated from human amniotic fluid when compared to recombinant IGF-1. Likewise, the IGF-BP was 100-fold less potent in inhibiting the receptor binding of recombinant truncated IGF-1 than that of recombinant IGF-1. Recombinant truncated IGF-1 was 4-times more potent than recombinant and natural IGF-1 in stimulating DNA synthesis in fetal rat brain cells. This biological activity of recombinant truncated IGF-1 was not affected by the IGF-BP at concentrations which abolished the biological activity of recombinant IGF-1. The hypothesis that IGF-BP bound intact IGF-1 represents the endocrine form of IGF-1, whereas truncated IGF-1 represents the paracrine or autocrine form of IGF-1, is proposed.

Animals↗
PubMed1989

Functional domains of the gastric HK ATPase.

The gastric H+ + K+ ATPase is a member of the phosphorylating class of transport ATPase. Based on sequence homologies and CHO content, there may be a b subunit associated with the catalytic subunit of the H+ + K+ ATPase. Its function, if present, is unknown. The pump catalyzes a stoichiometric exchange of H+ for K+, but is also able to transport Na+ in the forward direction. This suggests that the transport step involves hydronium rather than protons. The initial binding site is likely to contain a histidine residue to account for the high affinity of the cellular site. The extracellular site probably lacks this histidine, so that a low affinity for hydronium allows release into a solution of pH 0.8. Labelling with positively charge, luminally reactive reagents that block ATPase and pump activity has shown that a region containing H5 and H6 and the intervening luminal loop is involved in necessary conformational changes for normal pump activity. The calculated structure of this loop shows the presence of an a helical, b turn, and b strand sector, with negative charges close to the membrane domain. This sector provides a possible site of interaction of drugs with the H+ + K+ ATPase, and may be part of the K+ pathway in the enzyme.

Adenosine Triphosphatases↗
PubMed1989

Serum levels of insulin-like growth factor (IGF) I, II and IGF binding protein in diabetic adolescents treated with continuous subcutaneous insulin infusion.

IGF-I and IGF-II as well as the low molecular type of IGF binding protein (IGFPB) were determined in serum from 11 adolescents with insulin-dependent diabetes mellitus (IDDM) during a cross-over study with conventional and continuous subcutaneous insulin infusion (CIT and CSII) therapy. At the onset of the study the mean IGF-I level, 127 +/- 15 ng ml-1, was significantly decreased (P less than 0.001) in comparison with age-matched controls, whereas the mean IGF-II level, 1024 +/- 48 ng ml-1, was increased. A significant correlation (r = 0.70, P less than 0.05) was found between IGF-II and HbA1c levels. The mean morning level of IGFBP, 75 +/- 17 ng ml-1, at the onset of the study, was increased threefold above that in age-matched controls (P less than 0.01). There was a significant correlation between IGFBP and blood glucose values (r = 0.66, P less than 0.05). During CSII therapy a significant decrease (P less than 0.05) of the IGFBP levels was seen in subjects with a decrease in glucose levels, whereas no change was observed in IGF levels. The findings of elevated IGF-II and IGFBP levels and correlations between IGFBP and blood glucose concentration as well as IGF-II and HbA1c levels in adolescents with IDDM indicate that both IGF-II and IGFBP reflect a deranged metabolism caused by inadequate insulin administration.

Adolescent↗