Biomedical subjects

K Hall

Publications and source records attributed to K Hall.

At least 55 records · Page 3Linked to original sources

PubMed1999

Directed evolution of light-activated drugs.

Photodynamic therapy is a new technology that uses light-activated molecules to target drug action to diseased areas while sparing healthy tissue. Unfortunately, the present arsenal of photosensitive molecules is limited in both number and scope. We hypothesize that new photosensitive molecules could be developed using directed molecules evolution. This paper outlines a possible selection mechanism to evolve molecules activated by a desired wavelength of light.

Directed Molecular Evolution↗

PubMed1999

Locating ectopic foci.

INTRODUCTION: Successful radiofrequency ablation of an ectopic focus requires accurate localization of the region of enhanced automaticity. Present localization techniques require detailed electrical mapping that is time-consuming and involves much trial and error. Here, we propose two new localization techniques which were used to locate a pacemaker in a computer simulation. METHODS AND RESULTS: We suggest that an ectopic focus can be located by measuring the activation sequence of three or more intracardiac electrodes subsequent to an ectopic depolarization. Furthermore, the resetting response of an ectopic pacemaker can be used to estimate the distance from the stimulation electrode to the ectopic focus. We derive simple geometric localization strategies based on these ideas and examine the sensitivity of the strategies with respect to measurement uncertainties and electrode arrangements. Our localization strategies were tested using a numerical simulation of a pacemaker in a sheet of excitable media described by modified FitzHugh-Nagumo equations. The strategy based on electrode activation sequences located the pacemaker region in a homogeneous isotropic sheet after an average of 2.2 +/- 0.8 iterates in 10 out of 10 trials starting from random initial catheter positions. In the case of an inhomogeneous anisotropic sheet, the pacemaker was located after an average of 4 +/- 3 iterates in 9 out of 10 trials. The localization strategy based on resetting successfully found the pacemaker in a homogeneous isotropic sheet after an average of 1.2 +/- 0.4 iterates in 5 out of 5 trials and localized the pacemaker in an inhomogeneous anisotropic sheet after an average of 1.4 +/- 0.5 iterates in 5 out of 5 trials. CONCLUSIONS: Simple geometric strategies can be used to locate an ectopic focus. Although our basic localization strategies are sensitive to the electrode arrangement and measurement uncertainties, we show that iteration of our techniques quickly locates the pacemaker.

Cardiac Pacing, Artificial↗

PubMed1999

Effect of oxidative stress on DNA damage and beta-amyloid precursor proteins in lymphoblastoid cell lines from a Nigerian population.

The epsilon 4 allele of apolipoprotein E (APOE) is strongly associated with late-onset Alzheimer's disease (AD) in Caucasian populations, but our studies suggest that APOE epsilon 4 is not a risk factor for AD in Nigerian blacks and is a weak risk factor in African-Americans. The prevalence of AD is lower in Nigerians than in African-Americans. Increased oxidative damage to macromolecules in brain tissue by reactive oxygen species (ROS) has been reported in AD. Here we examined the effects of endogenous and induced oxidative stress on total (nuclear and mitochondrial) DNA damage in lymphoblastoid cell lines (5 probable AD and 3 controls) from Ibadan, Nigeria. Cells were exposed to 200 microM t-butyl peroxide (a generator of ROS) for 4 hours. Total DNA was isolated and digested with nuclease P1 and alkaline phosphatase. DNA fragments were separated by HPLC and the levels of 8-hydroxy-2'-deoxyguanosine (OH8dG, an indicator of DNA damage) and deoxyguanosine (dG) determined. We did not detect a significant difference in the OH8dG/dG ratio in untreated or treated cell lines in the two groups, and this was independent of APOE genotype. We also examined, by Western blotting, the level of beta-amyloid precursor protein (APP) which is involved in AD. The level of the heat shock protein (HSP-70) was examined as a control. There was a slight decrease in levels of APP and HSP-70 following treatment. Studies in cell lines from Caucasian subjects have shown an increase in mitochondrial DNA damage following oxidative challenge. Our preliminary results suggest that African populations are less vulnerable to chemical-induced oxidative DNA damage.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1999

Effect of protein intake on plasma and erythrocyte free amino acids and serum IGF-I and IGFBP-1 levels in rats.

Amino acid (AA) levels in plasma and erythrocytes (RBC) were determined in rats (n = 29) fed diets with 6, 21, and 35% protein, and their association with insulin-like growth factor I (IGF-I), insulin, or IGF-binding protein (IGFBP)-1 levels was studied. Free AA in plasma and RBC were determined by reversed-phase high-pressure liquid chromotography, and IGF-I, IGFBP-1, and insulin plasma levels were determined by RIA. Rats fed the low-protein (6%) diet were growth-retarded and had lower serum IGF-I levels and higher serum IGFBP-1 levels than the other two groups (P < 0.0001). In rats fed the low-protein diet, most of the nonessential AA (NEAA) in both plasma and RBC increased, whereas the essential AA (EAA), with the exception of threonine, decreased. When the groups were combined, both RBC and plasma EAA-to-NEAA ratios were positively correlated to IGF-I (r = 0.76 and 0.80, respectively; P < 0.0001) and inversely correlated to IGFBP-1 levels (r = -0.67, P < 0.001 and r = -0.78, P < 0.0001, respectively). A significant inverse correlation was found between RBC glutamate and IGF-I (r = -0.85, P < 0.0001, n = 25) and insulin (r = -0.72, P < 0.001, n = 21), and a positive correlation was found for IGFBP-1 (r = 0.78, P < 0.0001, n = 24). In multiple regression analysis, only IGF-I remained as an independent variable. Threonine was the only EAA with a significant inverse correlation to insulin (r = -0.66, P < 0.001). We hypothesize that AA metabolism is associated to changes in IGF-I, insulin, and IGFBP-1 levels in rats on different protein intakes.

Aging↗

PubMed1999

Serum levels of insulin-like growth factor I in 152 patients with growth hormone deficiency, aged 19-82 years, in relation to those in healthy subjects.

Serum insulin-like growth factor I (IGF-I) levels within normal range for age have been reported to be common in adults with GH deficiency (GHD). Therefore, serum IGF-I levels were determined in 152 consecutive patients (71 women and 81 men) with evidence of hypothalamic-pituitary disorders or previous cranial radiation, who fulfilled the presently used criteria for GHD i.e. peak GH response below 3 microg/L at stimulation test. Patients treated for acromegaly were excluded. Forty-three patients, aged 19-63 yr, had childhood onset GHD, and 109, aged 23-82 yr, had adult-onset GHD. Their IGF-I levels were expressed in SD scores in relation to normal reference values based on 448 healthy subjects, aged 20-96 yr (247 women and 201 men). In healthy subjects a linear inverse correlation, without gender difference, was found between logarithmic transformed IGF-I levels and age (r = -0.774; P < 0.001). In contrast, no age dependency was found in GHD patients. All patients with childhood-onset GHD had IGF-I values below -2 SD, significantly lower than those in adult-onset GHD patients (-6.2 +/- 0.3 vs. -3.2 +/- 0.2 SD score; P < 0.001). In patients with adult-onset GHD, 34% of the IGF-I levels were within normal range, increasing to 40% in the subgroup above 60 yr of age, in whom 86% were diagnosed with hypothalamic-pituitary tumors. Normal IGF-I was more common in men than in women, but no difference was observed between patients with panhypopituitarism and those with partial pituitary insufficiency. High frequencies of IGF-I levels within the normal range were found in GHD patients with pituitary tumors (20 of 57 nonsecreting pituitary adenomas, 5 of 15 prolactinomas, 6 of 12 Cushing's disease, and 4 of 25 craniopharyngiomas), but in only 2 of 43 patients with GHD due to other causes. In conclusion, an IGF-I level below -2 SD seems to be of diagnostic value in GHD with onset in childhood or early adulthood, whereas values within normal range are common in patients over 60 yr of age, especially those with pituitary tumors. The outcome of GH replacement therapy may reveal whether the addition of IGF-I as a diagnostic criterion is of predictive value in older patients.

Adult↗

PubMed1999

Quantitative analysis of MRI signal intensity in new variant Creutzfeldt-Jakob disease.

High signal intensity within the posterior thalamus (pulvinar nucleus) has been noted on MRI in patients with new variant Creutzfeldt-Jakob disease (nvCJD). In this study MRI examinations from three patients with proven nvCJD were compared with MRI examinations from a control group of 14 age-matched subjects with no neurological abnormalities. Mean signal intensity from seven target areas (periaqueductal tissue, posterior thalamus, dorsomedial thalamus, anterior thalamus, putamen, caudate head and frontal white matter) was calculated in each case. Absolute signal intensity measurements were not significantly different between the groups. Patients with nvCJD showed significantly higher signal intensity within dorsomedial thalamus, posterior thalamus and periaqueductal region than control patients when these measurements were normalized to the signal intensity of normal appearing white matter. Highly significant differences in posterior thalamus/putamen signal intensity ratio (PPR) and posterior thalamus/caudate ratio (PCR) were observed between the groups. For proton density images, PPR and PCR were greater than 1 for all nvCJD patients and less than 1 for all control patients. Both PPR and PCR are simple to calculate and offer a simple, non-invasive indicator of nvCJD.

Adolescent↗

PubMed1999

Growth hormone treatment of osteoporotic postmenopausal women - a one-year placebo-controlled study.

OBJECTIVES: To study the effect of 12 months of growth hormone (GH) treatment on bone markers, bone mineral density (BMD), lean body mass (LBM) and body fat mass (BF) in postmenopausal osteoporotic women. DESIGN: Sixteen patients were randomised to a double-blind randomised placebo-controlled one-year study with daily s.c. injections of GH or placebo. After the first year 14 patients (8 placebo treated, 6 GH treated) were recruited to GH treatment during the second year. All patients were also supplemented with 0.5 g calcium per oral. METHODS: Bone mineral density and body composition were assessed by dual energy X-ray absorptiometry. Biochemical bone markers were analysed by RIA or HPLC techniques. Diurnal GH profiles were performed with continuous venous blood sampling. RESULTS: Sixteen patients started in the placebo-controlled study. In all, twelve patients completed one year and only four patients completed two years of GH treatment. At baseline 3 patients had serum insulin-like growth factor-I (S-IGF-I) levels below -2 S.D. for age. Maximal diurnal GH levels tended to correlate negatively with S-IGF-I (P=0.076). S-IGF-I was unrelated to BMD. Serum IGF-binding protein-1 (S-IGFBP-1) correlated negatively with femoral neck BMD (r=-0.61, P=0.012). The intended GH dose of 0.05U/kg/day or a maximum of 3U/day s.c. was reduced to 0.024+/-0.004U/kg/day, equal to 0.5-2.7U/day due to frequent side effects, and four patients were excluded. After one year of GH treatment BF increased slightly, LBM and BMD in total body and lumbar spine were unchanged but femoral neck BMD had decreased 3.4+/-1.6% (P<0.05). The mean S-IGF-I increase was 32% (range -38-138%). Mean levels of the bone formation markers S-osteocalcin and S-procollagen type I propeptide increased maximally by 88 and 36% respectively after 9-12 months while the bone resorption markers were unchanged. In the placebo-treated group there were no significant alterations. CONCLUSIONS: The effects on S-IGF-I, bone markers and LBM were small although GH-related side effects were common. The reason for this apparent partial resistance to the anabolic effects of GH is not clear but nutritional deficits may be involved. Assessment of the effects of GH on bone mass and fracture rate requires longer study periods than one year.

Absorptiometry, Photon↗

PubMed1999

Applications of comparative genomic hybridisation in constitutional chromosome studies.

G band cytogenetic analysis often leads to the discovery of unbalanced karyotypes that require further characterisation by molecular cytogenetic studies. In particular, G band analysis usually does not show the chromosomal origin of small marker chromosomes or of a small amount of extra material detected on otherwise normal chromosomes. Comparative genomic hybridisation (CGH) is one of several molecular approaches that can be applied to ascertain the origin of extra chromosomal material. CGH is also capable of detecting loss of material and thus is also applicable to confirming or further characterising subtle deletions. We have used comparative genomic hybridisation to analyse 19 constitutional chromosome abnormalities detected by G band analysis, including seven deletions, five supernumerary marker chromosomes, two interstitial duplications, and five chromosomes presenting with abnormal terminal banding patterns. CGH was successful in elucidating the origin of extra chromosomal material in 10 out of 11 non-mosaic cases, and permitted further characterisation of all of the deletions that could be detected by GTG banding. CGH appears to be a useful adjunct tool for either confirming deletions or defining their breakpoints and for determining the origin of extra chromosomal material, even in cases where abnormalities are judged to be subtle. We discuss internal quality control measures, such as the mismatching of test and reference DNA in order to assess the quality of the competitive hybridisation effect on the X chromosome.

Chromosome Banding↗

PubMed1999

Determinants of circulating insulin-like growth factor-I.

Total IGF-I level in serum is a sensitive index during growth hormone (GH) replacement therapy of adults, since GH stimulates the hepatic expressions of both insulin-like growth factor (IGF-I) and acid-labile subunit (ALS) and the major part of IGF-I in the circulation is found in a ternary complex together with ALS and IGFBP-3. However, other regulators of the proteins constituting the ternary complex may influence IGF-I levels. In healthy subjects the serum IGF-I levels are low at birth, rise during childhood, with peak levels during puberty, and decline with increasing age. This pattern has been attributed to the age-dependent GH production, but it is unknown whether the wide range of IGF-I levels within each age interval is due to GH production or GH sensitivity. In elderly twins approximately 60% of IGF-I levels are genetically determined. The remaining environmental dependency of IGF-I is partly due to nutrition. Both caloric and protein content of the diet is of importance. Thus, low IGF-I levels are found in GH deficient patients as well as in patients with GH resistance due to malnutrition or GH receptor defects. It is essential that IGF-I determination is performed by assays in which IGFBPs do not interfere, and that IGF-I concentration is evaluated in relation to age, i.e. expressed in SD score, and the number of individuals constituting the reference intervals improves the sensitivity and specificity. Although determination of IGF-I is recommended in assessing GH deficiency in children, its diagnostic value in patients with adult onset of GH deficiency is not agreed upon. In the age group above 40-80 years many patients with pituitary/hypothalamic disorders and GH peaks below 3 microg/l during provocation tests have normal IGF-I levels. It is not clarified, whether the IGF-I levels within normal range for age is due to endogenous basal GH production being sufficient or other factors stimulating IGF-I, IGFBP-3 or ALS expressions.

Aging↗

PubMed1999

Far upstream regulatory elements enhance position-independent and uterus-specific expression of the murine alpha1(I) collagen promoter in transgenic mice.

The stage- and tissue-specific expression of many eukaryotic genes is regulated by cis-regulatory elements, some of which are located in proximity to the start site of transcription whereas others have been identified at considerable distances. In previous studies we have identified far upstream DNase I-hypersensitive sites in the murine alpha1(I) collagen (Col1a1) gene, which may play a role in the regulation of this abundantly expressed gene. Here we have cloned several of these sites into reporter gene constructs containing the Col1a1 promoter driving the green fluorescent protein (GFP) reporter gene and tested their possible functions in transfection experiments and transgenic mice. In transient and stable transfections none of the hypersensitive sites had a significant effect on Col1a1 promoter activity, indicating that they do not contain a classical transcriptional enhancer. In transgenic animals one element located at -18 to -19.5 kb enhanced the position-independent activity of the linked Col1a1 promoter and may be part of a locus control region. Another element located at -7 to -8 kb specifically enhanced reporter gene expression in the uteri of transgenic mice, suggesting that it contains a novel transcriptional enhancer that may be involved in the regulation of type I collagen expression in tissue remodeling in the uterus during the estrous cycle. Our studies also demonstrate the versatility of the GFP reporter gene for use in transgenic animals because it can be analyzed in live animals, whole mount embryos, histological thin sections, or primary cell cultures, and it can be quantified very sensitively in tissue or cell extracts using a fluorometer.

Animals↗

PubMed1998

Role of hypoxia-induced Bax translocation and cytochrome c release in reoxygenation injury.

We investigated mechanisms of cell death during hypoxia/reoxygenation of cultured kidney cells. During glucose-free hypoxia, cell ATP levels declined steeply resulting in the translocation of Bax from cytosol to mitochondria. Concurrently, there was cytochrome c release and caspase activation. Cells that leaked cytochrome c underwent apoptosis after reoxygenation. ATP depletion induced by a mitochondrial uncoupler resulted in similar alterations even in the presence of oxygen. Moreover, inclusion of glucose during hypoxia prevented protein translocations and reoxygenation injury by maintaining intracellular ATP. Thus, ATP depletion, rather than hypoxia per se, was the cause of protein translocations. Overexpression of Bcl-2 prevented cytochrome c release and reoxygenation injury without ameliorating ATP depletion or Bax translocation. On the other hand, caspase inhibitors did not prevent protein translocations, but inhibited apoptosis during reoxygenation. Nevertheless, they could not confer long-term viability, since mitochondria had been damaged. Omission of glucose during reoxygenation resulted in continued failure of ATP production, and cell death with necrotic morphology. In contrast, cells expressing Bcl-2 had functional mitochondria and remained viable during reoxygenation even without glucose. Therefore, Bax translocation during hypoxia is a molecular trigger for cell death during reoxygenation. If ATP is available during reoxygenation, apoptosis develops; otherwise, death occurs by necrosis. By preserving mitochondrial integrity, BCL-2 prevents both forms of cell death and ensures cell viability.

Adenosine Triphosphate↗

PubMed1998

Structure and transcription regulation of the human insulin-like growth factor binding protein 4 gene (IGFBP4).

Insulin-like growth factor binding protein 4 (IGFBP-4) is locally produced by normal human bone cells and acts as a potent inhibitor of IGF action in this tissue. PTH and a cAMP analog increase the expression of IGFBP4 mRNA in human osteoblast cells. We now show that the human IGFBP4 gene is contained within 15.3 kb with the transcription initiation site located 28 bp downstream of a TATA box sequence and 286 bp upstream of the translation initiation codon. The 3'-end of the mRNA was identified at position 14281, but no conserved poly(A) addition signal was found within 30 bp upstream of this site. Deletion mutagenesis located the core promoter activity downstream of position -289, and the transcription activity disappeared at -6. Stimulation with 0.5 mM dibutyryl-cAMP resulted in a twofold increase of promoter activity. Elements responsible for the cAMP response reside between positions -869 and -6.

Amino Acid Sequence↗

PubMed1998

Insulin-like growth factor II inhibits glucose-induced insulin exocytosis.

We have investigated the effect of IGF-II on glucose-induced insulin release in the pancreatic beta-cell. Introduction of IGF-II during perifusion of the cells with 20 mM glucose abolished glucose-induced insulin release. Concomitant addition of IGF-II with 20 mM glucose caused a complete inhibition of insulin release. In addition, IGF-II inhibited Ca(2+)-induced insulin release from electropermeabilized pancreatic beta-cells. IGF-II had no effect on K(+)-or tolbutamide-induced insulin release. However, IGF-II could suppress K(+)-stimulated insulin release when cells were pretreated with the protein phosphatase inhibitor okadaic acid. The inhibitory effect of IGF-II on insulin release was not associated with significant changes in membrane potential, activity of the voltage-gated L-type Ca(2+)-channel or cytoplasmic free Ca2+ concentration. Pretreatment of the cells with pertussis toxin or the phorbol ester TPA abolished the inhibitory action of IGF-II on insulin release. Hence, the molecular mechanism whereby activation of the IGF-II/M6P receptor by IGF-II inhibits glucose-stimulated insulin exocytosis in the pancreatic beta-cell involves pertussis toxin-sensitive G proteins and is dependent on PKC activity.

Animals↗

PubMed1998

Multifunctional cytokine expression by human coronary endothelium and regulation by monokines and glucocorticoids.

Human endothelium is capable of expressing a variety of molecules, including cytokines and growth factors, critical to inflammation. This aspect of coronary endothelium has not been studied in detail. In this study, we report, for the first time, expression of multifunctional cytokines by human coronary artery endothelial cells (HCAEC) and their regulation by inflammatory cytokines and glucocorticoids. We also compared expression of cytokine transcripts in two additional cell lines derived from pulmonary artery (HPAEC) and umbilical vein (HUVEC) endothelium. HCAEC expressed transcripts for interleukin 5 (IL-5), IL-6, IL-8, and monocyte chemotactic protein-1 (MCP-1) constitutively. Induction of IL-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and MCP-1 was seen following treatment with TNFalpha. We found no expression of IL-1RA, IL-2, IL-4, IL-13, TNF-alpha, or IFN-gamma in HCAEC. IL-1beta and TNF-alpha synergistically induced IL-6 and GM-CSF and additively induced IL-8 and MCP-1 production, while IL-2, IL-10, IFN-alpha, and IFN-gamma had little or no additional effects. Interestingly, no IL-1alpha or IL-5 protein product was found even after maximal stimulation of HCAEC. No significant differences were seen in the profile of cytokine genes expressed by HCAEC, HPAEC, or HUVEC. Glucocorticoids inhibited IL-8 production from all three cell lines. This study demonstrates that human coronary endothelial cells are capable of expressing a wide variety of multifunctional cytokines which may be of relevance to vascular inflammation.

Cell Line↗

PubMed1998

Insulin-like growth factor-I and insulin-like growth factor binding protein-1 in a representative population of type 2 diabetic patients in Sweden.

OBJECTIVE: To study the influence of type 2 diabetes on the insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-1 (IGFBP-1) serum levels in an area-based population of type 2 patients previously described. RESULTS: The patients (n = 151) were elderly (70.6 +/- 0.7 years of age) and moderately overweight (BMI 27.0 +/- 0.4 kg/m2). Most patients (83%) were treated with either diet alone or diet in combination with sulphonylurea. Metabolic control measured as HbAlc deteriorated with duration (p < 0.001) and between groups treated with diet (HbA1c 5.8 +/- 0.6), sulphonylurea (7.5 +/- 0.2) and insulin (7.7 +/- 0.4). Mean levels of IGF-I were within reported normal range, but were lower in the insulin-treated as compared to the non-insulin-treated patients. Levels of IGF-I decreased with diabetes duration and with increased blood glucose. There was a positive correlation between IGF-I and insulin levels and also an inverse correlation between IGF-I and IGFBP-1 levels. The IGFBP-1 levels were twofold higher than reported in non-diabetic individuals. In multiple stepwise correlation analysis, 37% of the variability in IGFBP-1 could be explained by BMI, IGF-I SD score, age, IGF-I, and fasting blood glucose. CONCLUSION: Our study indicates that influence of type 2 diabetes on IGF-I bioavailability in individual patients is modulated by insulin, body weight (presumably reflecting insulin sensitivity) and metabolic control. Furthermore, increased levels of IGFBP-1 are strongly associated with decreased b-cell function in type 2 diabetes mellitus.

Aged↗

PubMed1998

Glutamate concentration in plasma, erythrocyte and muscle in relation to plasma levels of insulin-like growth factor (IGF)-I, IGF binding protein-1 and insulin in patients on haemodialysis.

Elevated insulin-like growth factor binding protein (IGFBP) levels, including IGFBP-1, occur in renal failure, and may contribute towards reduced IGF bioactivity in uraemia. The reduced IGF bioactivity may, in turn, contribute towards the disturbances in protein metabolism present in renal failure. In this study, the relationships between intra- and extracellular amino acid (AA) levels and IGF-I and/or IGFBP-1 levels were studied in 30 adult patients (aged 24-70 years) on haemodialysis who had no clinical signs of malnutrition. Blood samples (n = 30) and muscle biopsies (n = 13) were collected for determination of free AA in erythrocytes (RBC), plasma and muscle by reverse-phase HPLC while IGFBP-1, IGF-I and insulin plasma levels were determined by radioimmunoassay The patients on haemodialysis had elevated glutamate concentrations in RBC and plasma compared with healthy controls (524 +/- 26 vs 448 +/- 17 mumol/l, P < 0.05 and 45 +/- 4 vs 32 +/- 4 mumol/l, P < 0.01 respectively), although glutamate levels in muscle were within the normal range. The mean IGF-I level was slightly increased (s.d. score +0.74 +/- 0.30) but insulin levels were within the normal range. IGFBP-1 levels, which were inversely correlated to insulin (r = -0.40, P < 0.02), were elevated threefold compared with controls. No plasma AA level displayed a significant correlation with IGF-I, IGFBP-1 or insulin levels. However, glutamate concentrations in RBC were positively correlated to IGFBP-1 (r = 0.51, P < 0.01) and inversely correlated to IGF-I (r = -0.46. P < 0.01), although unrelated to insulin. Muscle glutamate, which was inversely related to RBC glutamate, displayed an opposite pattern with an inverse relation to IGFBP-1 levels (r = - 0.73, P < 0.01) and a positive correlation to IGF-I levels (r = 0.64, P < 0.02). Glutamate was the only AA to display an inverse correlation between RBC and muscle (r = -0.65, P < 0.02, n = 12). These findings lead us to propose that, in uraemia, the elevated IGFBP-I levels, which reduce the bioavailability of IGFs, are linked to glutamate uptake in muscle, resulting in accumulation of RBC glutamate. Whether there is a causal relationship or the correlation is due to some common regulator is not clarified in the present study.

Adult↗

PubMed1998

Differential expression of IGF-I and IGF-binding protein-1 and -2 in periportal and perivenous zones of rat liver.

IGF-I has important roles in regulating growth and metabolism. Circulating IGF-I is bound to specific binding proteins (IGFBP-1 to -6), with hepatocytes containing IGF-I, IGFBP-1 and -2 mRNA. Although many hepatic proteins are regionally expressed in the liver acinus, no studies have reported zonation of IGF protein expression. In this study we investigated the pattern of hepatic mRNA for the IGF proteins, vs the previously reported pepriportal gradient of phosphoenolpyruvate carboxykinase (PEPCK) expression. In situ hybridisation was used to analyse IGF-I, IGFBP-1, -2 and PEPCK mRNA in female Sprague-Dawley rats fed diets containing low (6%), normal (21%) or high (35%) protein. We report for the first time that IGFBP-1 and -2 and IGF-I are differentially expressed in the liver acinus. In the normal- and high-protein groups, levels of IGFBP-1 mRNA were higher in the perivenous region, i.e. the opposite gradient to PEPCK, with a higher gradient of IGFBP-1 expression in the high-protein group. In contrast, IGFBP-2 had a similar pattern to PEPCK, and a periportal gradient of IGF-I mRNA was also seen in the low-protein group. Using computerised image analysis, levels of IGFBP-1 and -2 mRNA were elevated 2- and 10-fold respectively, in the low- vs normal-protein groups. The level of IGF-I mRNA was reduced to 65% of normal, with circulating IGF-I levels at 30% and insulin levels 39% of normal. These results demonstrate that hepatocytes are a heterogeneous population with respect to regulation of IGF proteins, having specific expression patterns dependent on the position of the hepatocyte within the liver acinus.

Animals↗

PubMed1998

Risk factors and Alzheimer's disease: a comparative study of two communities.

OBJECTIVE: To determine the association between demographic, lifestyle and medical history factors to Alzheimer's disease (AD), we studied samples of two community dwelling populations with significantly different prevalence rates of AD in Indianapolis, USA (6.24%) and Ibadan, Nigeria (1.4%). METHODS: The samples were drawn from African-American community dwelling residents 65 years of age and over in Indianapolis, and Yoruba community-dwelling residents 65 years of age and over in Ibadan. A two-stage epidemiological design was used in which diagnosis of AD was by National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria. RESULTS: In Indianapolis, age (odds ratio [OR] = 1.16; 95% confidence interval [CI] = 1.11-1.21), family history of dementia (OR = 5.40; 95% CI = 1.99-14.62), low education (0-6 years, OR = 3.49; 95% CI = 1.06-11.48) and rural residence (OR = 2.49; 95% CI = 1.05-5.88) were associated with a higher risk of AD. In Ibadan, age (OR = 1.15; 95% CI = 1.12-1.18) and female gender (OR = 13.9; 95% CI = 3.85-50.28) were associated with a higher risk of AD. CONCLUSIONS: The remarkably similar odds ratios between age and AD between sites suggest that biological processes associated with ageing are essential elements in the development of AD but that genetic and environmental risk factors may alter age-specific rates. In our longitudinal study, we intend to investigate in more depth the interaction between these ageing, genetic and environmental factors.

Aged↗