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Biomedical subjects

F Norris

Publications and source records attributed to F Norris.

At least 19 recordsLinked to original sources
PubMed2004

Eczema and early solid feeding in preterm infants.

AIMS: To establish whether development of eczema is influenced by feeding practices in preterm infants, while taking account of confounding factors. METHODS: Data were assembled from 257 infants born prematurely and studied to 12 months post-term. Logistic regression analysis was performed to establish the association between feeding practices and eczema, allowing for potential confounding factors including the infants' gender, parental atopic status, social background, and parental smoking habits. RESULTS: For the development of eczema (with or without other symptoms) by 12 months post-term, the introduction of four or more solid foods by or before 17 weeks post-term was a significant risk (odds ratio 3.49). Male infants were at significantly higher risk (odds ratio 1.84). In addition, having non-atopic parents who introduced solid foods before 10 weeks post-term or having at least one atopic parent represented a significant risk scenario (odds ratio 2.94). CONCLUSIONS: Early introduction of a diverse range of solid foods may predispose the preterm infant to eczema development by 12 months post-term. Furthermore, non-atopic parents who practice early as opposed to late introduction of solid foods may be exposing preterm infants to a greater risk of eczema by 12 months post-term.

Adolescent↗
PubMed1999

Inhibition of carbohydrate-mediated glucagon-like peptide-1 (7-36)amide secretion by circulating non-esterified fatty acids.

Two studies were performed to assess the entero-insular axis in simple obesity and the possible effect of variations in the level of circulating non-esterified fatty acids (NEFA) on one of the components of the entero-insular axis, glucagon-like peptide-1 [(7-36) amide]. In the first study, we compared the entero-pancreatic hormone response to oral carbohydrate in obese and lean women. Obese subjects demonstrated hyperinsulinaemia and impaired glucose tolerance but this was not associated with an increased secretion of either glucose-dependent insulinotropic polypeptide or glucagon-like peptide-1 (GLP-1). These findings therefore provide no support for the hypothesis that overactivity of the entero-insular axis contributes to the hyperinsulinaemia seen in obesity. Indeed, the plasma GLP-1 response to carbohydrate was markedly attenuated in obese subjects, confirming previous observations. In the second study, in which carbohydrate-stimulated GLP-1 responses were again evaluated in obese and lean women, circulating NEFA levels were modulated using either heparin (to increase serum NEFA) or acipimox (to reduce serum NEFA). Treatment with acipimox resulted in complete suppression of NEFA levels and in a markedly higher GLP-1 response than the response to carbohydrate alone or to carbohydrate plus heparin. We suggest that higher fasting and postprandial NEFA levels in obesity may tonically inhibit nutrient-mediated GLP-1 secretion, and that this results in attenuation of the GLP-1 response to carbohydrate. However, although serum NEFA levels post-acipimox were similarly suppressed in both lean and obese subjects, the GLP-1 response was again significantly lower in obese subjects, suggesting the possibility of an intrinsic defect of GLP-1 secretion in obesity. The reduction of GLP-1 levels in obesity may be important both in relation to its insulinotropic effect and to its postulated role as a satiety factor.

Adult↗
PubMed1999

The effect of circulating non-esterified fatty acids on the entero-insular axis.

BACKGROUND: Circulating non-esterified fatty acids (NEFAs) have been causally associated with impairment of glucose metabolism, although their effect on the entero-insular axis, either in obesity or health, is unknown. MATERIALS AND METHODS: Glucose, insulin, glucagon-like peptide-1 (7-36 amide) (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) responses to 100 g of carbohydrate in 400 mL water were evaluated during simultaneous modulation of circulating non-esterified fatty acids (NEFAs). A total of 10,000 units of heparin (to increase serum NEFAs) and 500 mg of acipimox (2 h before oral carbohydrate ingestion to reduce serum NEFAs) were administered to seven obese [mean +/- SEM: age 40 +/- 3.7 years; body mass index (BMI) 38.9 +/- 2.1 kg m-2] and seven lean (age 39.6 +/- 3.6 years; BMI 22.4 +/- 0.4 kg m-2) women. RESULTS: Higher fasting levels and post-heparin total integrated NEFAs (P < 0.05) and glycerol (P < 0.05) responses were seen in the obese than in the lean group. Incremental integrated GLP-1 responses to oral carbohydrate post-heparin in lean (P < 0.01) and obese (P < 0.05) subjects were significantly lower than after acipimox. Total integrated GIP (P < 0.05) and glucose (P < 0.01) responses were higher post heparin than after acipimox in obese subjects only. CONCLUSION: The inverse relationship in GIP and GLP-1 responses in the obese group after modulation of NEFAs indicates that reciprocal changes between these two hormones may exist to ensure constancy of B-cell stimulation. Our results suggest that in obese subjects compensatory secretion of GIP was incomplete and could not prevent impairment in glucose tolerance after heparin-induced rise in NEFAs. These results may be important in understanding the role of the insulinotropic hormones in carbohydrate metabolism characterized by high NEFA levels such as obesity and diabetes mellitus.

Adult↗
PubMed1999

Proinsulin and insulin responses to a mixed meal in hypertriglyceridaemic men.

AIM: To investigate the contribution of proinsulin to the "hyperinsulinaemia" of hypertriglyceridaemia. METHODS: Plasma glucose, triglyceride, immunoreactive insulin, and intact proinsulin concentrations were measured before and after a mixed meal in 11 hypertriglyceridaemic men and six healthy normotriglyceridaemic male controls. RESULTS: Hypertriglyceridaemic subjects had greater fasting (101 v 50 pmol/l) and integrated (139 v 81 x 0(-3) pmol/l/h) insulin concentrations than controls. Fasting and integrated glucose and proinsulin concentrations were similar in the two groups. CONCLUSIONS: Proinsulin does not contribute to the hyperinsulinaemia observed in hypertriglyceridaemic subjects and is therefore unlikely to contribute to the increased cardiovascular risk associated with hypertriglyceridaemia.

Adult↗
PubMed1998

1.2 A refinement of the Kunitz-type domain from the alpha3 chain of human type VI collagen.

The recombinant Kunitz-type domain (C5) of human collagen alpha3(VI) chain was previously described at 1.6 A resolution at room temperature. By changing the crystallization conditions and using synchrotron radiation, we are able to record diffraction data to 1.2 A resolution for crystals of the same space group at 291 K. The protein-water-ion model has been refined anisotropically against these new data using the program SHELXL93; the results converged to an R factor of 15.0%, with all data between 7 and 1.2 A. The final electron-density map reveals a clear chain tracing with a few disordered residues and five residues out of 58 that present alternate conformations. The Cys14-Cys38 bond presents the less frequently observed left-hand conformation (chi1 = -60 degrees). The solvent molecules and a phosphate ion are well ordered with an average B of 38 A2. The high-resolution structure reveals the N and C termini which were missing from the 1.6 A structure.

Amino Acid Sequence↗
PubMed1998

Delayed gastric emptying occurs following acarbose administration and is a further mechanism for its anti-hyperglycaemic effect.

The therapeutic effect of acarbose is generally attributed to inhibition of amylase and brush border glucosidases and consequent impaired digestion and absorption of carbohydrates. We have investigated the possibility that acarbose may also influence the rate of gastric emptying by comparing plasma glucose and gastrointestinal hormone responses to an oral sucrose load with and without acarbose in 11 healthy subjects. Gastric emptying was assessed indirectly by measuring circulating paracetamol concentrations following administration of paracetamol along with the sucrose load. Peak plasma glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) responses were reduced when sucrose was given with acarbose. There was a significant reduction in post-sucrose paracetamol levels with acarbose suggestive of a significant delay in gastric emptying. The failure of acarbose to induce change in circulating paracetamol concentrations until after 60 min is indicative of a delay in gastric emptying rather than an osmotic malabsorption. The exaggerated and sustained release of glucagon-like peptide-1 (7-36)amide (GLP-1) seen when sucrose was given with acarbose may play a part in the inhibition of gastric emptying. This study indicates that a significant delay in gastric emptying may be an added mechanism contributing to the therapeutic effect of acarbose.

Acarbose↗
PubMed1998

A randomized trial of a brief HIV risk reduction counseling intervention for women.

There is an urgent need for the development and implementation of effective and feasible behavioral HIV and STD interventions. The purpose of the present randomized controlled trial was to evaluate the effectiveness of a single-session, skill-based sexual risk reduction intervention for women. Participants were assessed at baseline and at 1 month and 3 months following the intervention on measures of AIDS knowledge, behavioral intentions, self-efficacy, and sexual risk behavior. Compared with women in an AIDS-education-only condition, women receiving the skill-based intervention reported significantly higher rates of condom use at 3-month follow-up. Results suggest that brief sexual risk reduction programs are feasible and effective within a community setting.

Adult↗
PubMed1997

Expression of protein-tyrosine phosphatases in the major insulin target tissues.

Protein-tyrosine phosphatases (PTPs) are key regulators of the insulin receptor signal transduction pathway. We have performed a detailed analysis of PTP expression in the major human insulin target tissues or cells (liver, adipose tissue, skeletal muscle and endothelial cells). To obtain a representative picture, all tissues were analyzed by PCR using three different primer sets corresponding to conserved regions of known PTPs. A total of 24 different PTPs were identified. A multiprobe RNase protection assay was developed to obtain a semiquantitative measure of the expression levels of selected PTPs. Surprisingly, PTP-LAR, previously suggested to be a major regulator of the insulin receptor tyrosine kinase, was expressed in extremely low levels in skeletal muscle, whereas the related receptor-type PTP-sigma and PTP-alpha were expressed in relatively high levels in all four tissues. The low levels of LAR PTP mRNA in skeletal muscle were further confirmed by Northern blot analysis.

Adipose Tissue↗
PubMed1997

Zyme, a novel and potentially amyloidogenic enzyme cDNA isolated from Alzheimer's disease brain.

The deposition of the beta amyloid peptide in neuritic plaques and cerebral blood vessels is a hallmark of Alzheimer's disease (AD) pathology. The major component of the amyloid deposit is a 4.2-kDa polypeptide termed amyloid beta-protein of 39-43 residues, which is derived from processing of a larger amyloid precursor protein (APP). It is hypothesized that a chymotrypsin-like enzyme is involved in the processing of APP. We have discovered a new serine protease from the AD brain by polymerase chain reaction amplification of DNA sequences representing active site homologous regions of chymotrypsin-like enzymes. A cDNA clone was identified as one out of one million that encodes Zyme, a serine protease. Messenger RNA encoding Zyme can be detected in some mammalian species but not in mice, rats, or hamster. Zyme is expressed predominantly in brain, kidney, and salivary gland. Zyme mRNA cannot be detected in fetal brain but is seen in adult brain. The Zyme gene maps to chromosome 19q13.3, a region which shows genetic linkage with late onset familial Alzheimer's disease. When Zyme cDNA is co-expressed with the APP cDNA in 293 (human embryonic kidney) cells, amyloidogenic fragments are detected using C-terminal antibody to APP. These co-transfected cells release an abundance of truncated amyloid beta-protein peptide and shows a reduction of residues 17-42 of Abeta (P3) peptide. Zyme is immunolocalized to perivascular cells in monkey cortex and the AD brain. In addition, Zyme is localized to microglial cells in our AD brain sample. The amyloidogenic potential and localization in brain may indicate a role for this protease in amyloid precursor processing and AD.

Adult↗
PubMed1997

Elevated post-prandial gastric inhibitory polypeptide concentrations in hypertriglyceridaemic subjects.

1. We investigated whether abnormalities of gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (7-36 amide) (GLP-1) contribute to the hypertriglyceridaemia and hyperinsulinaemia in hypertriglyceridaemic subjects. Serum triglycerides and plasma glucose GIP, GLP-1 and immunoreactive insulin (IRI) concentrations were measured before and after a mixed meal in 15 hypertriglyceridaemic patients and in eight healthy normotriglyceridaemic control subjects. 2. Integrated post-prandial GIP concentrations were greater than in controls (P < 0.05) and correlated positively with both fasting and integrated post-prandial triglyceride concentrations (P < 0.05 for both). Fasting and integrated post-prandial IRI levels were higher in hypertriglyceridaemic subjects than in controls (P < 0.02 and P < 0.05 respectively) and correlated positively with fasting triglycerides (P < 0.02 and P < 0.001 respectively) and integrated post-prandial triglycerides (P < 0.005 and P < 0.05 respectively). There was no correlation between GIP concentrations and either fasting or post-prandial IRI levels. Fasting and post-prandial concentrations of GLP-1 were similar in patients and controls. 3. Hypertriglyceridaemic subjects have post-prandial hyperGIPaemia in addition to the well-documented hyperinsulinaemia. We found no association between GIP and insulin. There is, however, clear evidence for an association between post-prandial GIP concentrations and triglyceride levels. We suggest that this association may depend on changes in lipoprotein lipase activity and that there may be a feedback loop between GIP and triglyceride lipolysis.

Adult↗
PubMed1996

Inhibitory properties of separate recombinant Kunitz-type-protease-inhibitor domains from tissue-factor-pathway inhibitor.

Tissue-factor-pathway inhibitor (TFPI) is a multivalent inhibitor with three tandemly arranged Kunitz- type-protease-inhibitor (KPI) domains. Previous studies [Girard, Y. J., Warren, L. A., Novotny , W. F., Likert, K. M., Brown, S. G., Miletich, J. R & Broze, G. J. (1989) Nature 338, 518-520] by means of site-directed mutagenesis indicated that KPI domain 1 interacts with factor VIIa, that KPI domain 2 interacts with factor Xa, and that KPI domain 3 is apparently without inhibitory function. To elucidate the reaction mechanism of this complex inhibitor, we followed a different approach and studied the inhibitory properties of fragments of TFPI obtained by expression in yeast. Results obtained with TFPI-(1-161)-peptide and separate recombinant TFPI-KPI domains 1, 2 and 3 showed that KPI domain 1 inhibited factor VIIa/tissue factor (Ki = 250 nM), KPI domain 2 inhibited factor Xa (Ki = 90 nM), and that KPI domain 3 was without detectable inhibitory function. Studies with separate KPI domains also showed that KPI domain 2 was mainly responsible for inhibition of trypsin (Ki = 0.1 nM) and chymotrypsin (Ki = 0.75 nM), whereas KPI domain 1 inhibited plasmin (Ki = 26 nM) and cathepsin G (Ki = 200 nM). The structural basis for the interaction between serine proteases and KPI domains is discussed in terms of putative three-dimensional models of the proteins derived by comparative molecular-modelling methods. Studies of factor Xa inhibition by intact TFPI (Ki approximately 0.02 nM) suggested that regions other than the contact area of the KPI domain, interacted strongly with factor Xa. Secondary-site interactions were crucial for TFPI inhibition of factor Xa but was of little or no importance for its inhibition of trypsin.

Amino Acid Sequence↗
PubMed1996

The entero-insular axis in polycystic ovarian syndrome.

We investigated the contributions made by the entero-insular axis, proinsulin and the fractional hepatic extraction of insulin to the hyperinsulinaemia characteristic of polycystic ovarian syndrome (PCOS). We measured plasma glucose, gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (7-36 amide) (GLP-1(7-36) amide), immunoreactive insulin (IRI), intact proinsulin (IPI), and C-peptide concentrations during a 75 g oral glucose tolerance test in seven normal weight women with PCOS and eight healthy women. Women with PCOS had higher fasting (P = 0.05) and integrated (P < 0.01) IRI concentrations than controls. Fasting C-peptide levels were similar in both groups but integrated C-peptide (P < 0.05) concentrations were greater in PCOS subjects than controls. Fasting and integrated concentrations of glucose, GIP and GLP-1(7-36) amide were similar in subjects with PCOS and controls. Although fasting IPI concentrations were similar in both groups, integrated IPI concentrations were higher (P = 0.05) in patients with PCOS. Women with PCOS had similar fasting but higher (P < 0.05) integrated IRI:C-peptide molar ratios than controls. Fasting and integrated IPI:IRI molar ratios were similar in both groups. These results confirm that lean women with PCOS have peripheral hyperinsulinaemia. The mild fasting hyperinsulinaemia is due to increased pancreatic secretion, whereas the stimulated hyperinsulinaemia is due to both pancreatic hypersecretion and reduced fractional hepatic extraction of insulin. Hyperproinsulinaemia is modest and appropriate in PCOS, GIP and GLP-1(7-36) amide do not contribute to the stimulated hyperinsulinaemia in PCOS.

Adult↗
PubMed1996

Postprandial hormone and metabolic responses in simulated shift work.

This study was designed to investigate postprandial responses to a mixed meal in simulated shift work conditions. Nine normal healthy subjects (six males and three females) were studied on two occasions at the same clock time (1330 h) after consuming test meals, first in their normal environment and secondly after a 9 h phase advance (body clock time 2230 h). Plasma glucose, insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), triacylglycerol (TAG) and non-esterified fatty acids (NEFAs) were determined at intervals for 6 h after each test meal. Postprandial plasma glucose, insulin, GIP and GLP-1 profiles were evaluated by calculating areas under the curve (AUC) for the first 2 h and the last 4 h of the sampling together with total AUC. Significantly higher postprandial glucose responses (total AUC) were observed after the phase shift than before (AUC 0-360 min, 2.01 (1.51-2.19) vs 1.79 (1.56-2.04) mmol/l.min; P < 0.02; mean (range)). No significant difference was observed when the first 2 h of each response was compared, but significantly higher glucose levels were observed in the last 4 h of the study after the phase shift than before (AUC 120-360 min, 1.32 (1.08-1.42) vs 1.16 (1.00-1.28) mmol/l.min; P < 0.05). Similar results were obtained for insulin (AUC 0-360 min, 81.72 (30.75-124.97) vs 58.98 (28.03-92.57) pmol/l.min; P < 0.01; AUC 120-360 min, 40.73 (16.20-65.25) vs 25.71 (14.25-37.33) pmol/l.min; P < 0.02). No differences were observed in postprandial plasma GIP and GLP-1 responses before and after the phase shift. Postprandial circulating lipid levels were affected by phase shifting. Peak plasma TAG levels occurred 5 h postprandially before the phase shift. Postprandial rises in plasma TAG were significantly delayed after the phase shift and TAG levels continued to rise throughout the study. Plasma postprandial NEFA levels fell during the first 3 h both before and after the phase shift. Their rate of return to basal levels was significantly delayed after the phase shift compared with before. This study demonstrates that a simulated phase shift can significantly alter pancreatic B-cell responses and postprandial glucose and lipid metabolism.

Adult↗
PubMed1995

The 1.6 A structure of Kunitz-type domain from the alpha 3 chain of human type VI collagen.

The C-terminal Kunitz-type domain from the alpha 3 chain of human type VI collagen (C5), a single 58 amino acid residue chain with three disulfide bridges, was cloned, expressed and crystallized in a monoclonic form, space group P2(1), with a = 25.7 A, b = 38.2 A, c = 28.8 A and beta = 109 degrees. The structure was resolved by molecular replacement, using Alzheimer's protein precursor inhibitor and bovine pancreatic trypsin inhibitor three-dimensional structures as search models. The molecule with one sulfate ion and 43 associated water molecules was refined by XPLOR to an R-factor of 18.9% at 1.6 A. The molecule was not degraded by trypsin and did not inhibit trypsin or tested serine proteases. As opposed to the other Kunitz family members, C5 demonstrates left-handed chirality of the Cys14-Cys38 disulfide bond. Inversion of the Thr13 carbonyl and bulky side-chains at the interface with trypsin in a model of the C5-trypsin complex may explain the lack of inhibition of trypsin.

Amino Acid Sequence↗
PubMed1994

Expression, purification and characterization of a Kunitz-type protease inhibitor domain from human amyloid precursor protein homolog.

The Kunitz-type protease inhibitor domain from a recently identified homolog of the Alzheimer amyloid precursor protein (APPH KPI) was expressed in yeast, purified and characterized. Its inhibition profile towards several serine proteases was studied and compared to that of APP KPI, the Kunitz domain from the Alzheimer amyloid precursor protein. APPH KPI was shown to inhibit proteases with trypsin-like specificity with an inhibitor profile resembling that of the APP KPI domain. The KPI domains from APP and APPH inhibited trypsin (Ki = 0.02 nM), and plasma kallikrein (Ki = 86 nM) with approximal equal affinity. In comparison to APP KPI (Ki = 82 nM) the KPI domain of the homolog, APPH KPI, (Ki = 8.8 nM) was a more potent inhibitor of glandular kallikrein. APPH KPI was a less potent inhibitor of chymotrypsin than APP KPI (Ki = 78 nM as compared to Ki = 6 nM), plasmin (Ki = 81 nM as compared to 42 nM), and factor XIa (Ki = 14 nM as compared to Ki = 0.7 nM). The affinity of factor XIa for APPH KPI is sufficiently high to allow for an interaction in the blood. It is, however, well possible that the physiological protease ligand for the receptor-like APPH protein has yet to be identified.

Amino Acid Sequence↗
PubMed1993

Molecular cloning of the cDNA for a human amyloid precursor protein homolog: evidence for a multigene family.

Alzheimer's disease is a degenerative neurological disorder characterized by neural loss and brain lesions associated with plaques containing large amounts of the beta/A4 amyloid peptide. Molecular cloning of the cDNA for this peptide from human brain has shown it to be derived by proteolysis from a much larger precursor called the amyloid precursor protein (APP). The biological role of the precursor is unknown, but it has been shown to be transcribed in many human tissues in addition to brain. In the present report, we describe the molecular cloning from a human placental library of a full-length cDNA for a molecule closely related to APP. This novel molecule, which we have called amyloid precursor protein homolog (APPH), shares overall domain organization with APP. It is 763 amino acids in length and appears to encode a signal peptide, a large apparent extracellular domain including a Kunitz inhibitor domain, a transmembrane region, and a short cytoplasmic domain. Northern analysis indicates that it occurs in at least two molecular forms and is transcribed in human brain, heart, lung, liver, and kidney, in addition to placenta. On the basis of its extensive sequence similarity and conservation of domain structure, APPH is the nearest relative of APP yet identified in an emerging multigene family.

Amino Acid Sequence↗
PubMed1993

Purification and characterization of the trefoil peptide human spasmolytic polypeptide (hSP) produced in yeast.

Recombinant human spasmolytic polypeptide (r-hSP) has been produced in relatively large amounts in Saccharomyces cerevisiae. The two intronless trefoil domains of the hSP-DNA were cloned separately by PCR from human genomic DNA, and the remaining parts of the gene synthesized. Recombinant plasmids were constructed to encode a fusion protein consisting of a hybrid leader sequence and the hSP sequence. The leader sequence serves to direct the fusion protein into the secretory pathway of the cell and to expose it to the Kex 2 processing enzyme system. The secreted r-hSP was found in a glycosylated and an non-glycosylated form. The two forms of r-hSP were purified from the yeast fermentation broth by a combination of ion-exchange chromatography and preparative HPLC. The overall yield from 8 litres of fermentation broth was 160 mg r-hSP and 219 mg glycosylated r-hSP corresponding to 50% and 34%, respectively. The structure of the r-hSP and the glycosylated r-hSP was determined by amino acid analysis and carbohydrate composition analysis as well as by peptide mapping, amino acid sequencing and mass spectrometric analysis.

Amino Acid Sequence↗