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PubMed2005

Protein deficiency balance as a predictor of clinical outcome in hereditary spherocytosis.

Vertical and horizontal interactions between membrane constituents account for integrity, strength and deformability of the erythrocyte. Disruption of vertical interactions caused by membrane protein deficiencies in hereditary spherocytosis (HS), favor membrane vesiculation with development of spherocytic cells. Our aim was to evaluate the hematological and clinical presentation of HS according to the type and amount of protein deficiency. We studied 81 Portuguese individuals, 71 belonging to 21 families plus 10 unrelated subjects, and found that 51 of them were HS patients. Patients were classified as presenting mild, typical or severe HS, according to laboratory results and clinical follow-up. We performed screening tests and the standardized electrophoretic membrane protein analysis to identify and quantify protein deficiencies. We found band 3 and ankyrin deficiencies as the major causes for HS. The ratios between the value of the primary and/or secondary protein deficiencies showed significantly different values according to the severity of HS, and a significant inverse correlation with the severity of HS was observed. In mild HS, the ratios between protein deficiencies reflected equivalent protein deficiencies, while an unbalance was observed in typical HS, which was enhanced in severe HS. Our data suggest that the relative quantification of each major membrane protein and of the ratios between the values of protein deficiencies may be helpful in providing additional data about the clinical outcome of HS.

Anion Exchange Protein 1, Erythrocyte↗
PubMed1981

The neuromuscular and autonomic blocking effects of azasteroids containing choline or acetylcholine fragments.

Nine analogues of the azasteroid muscle relaxant chandonium have been tested for neuromuscular blocking activity, ganglion blocking activity, inhibitory effects on cardiac muscarinic receptors, and for effects on noradrenergic transmission. Experiments were performed in anaesthetized cats and in isolated preparations. The two bisquaternary compounds HS-626 and HS-627, choline and acetylcholine-like analogues of chandonium respectively, were approximately equipotent with chandonium as neuromuscular blocking agents in the cat, but HS-672 possessed slightly more vagal blocking action. No evidence was obtained for ganglion block. The monoquaternary analogues, HS-408 and HS-465 and two 4-aza-androstanes, (HS-522 and HS-523) were more than 100 times less active than the bisquaternary compounds as neuromuscular blocking agents, and produced vagal blockade and ganglion blockade at sub-neuromuscular blocking doses. pA2 determinations in the chick biventer cervicis muscle, the guinea-pig atria and guinea-pig ileum showed that the bisquaternary compounds chandonium, HS-626 and HS-627 were much more potent in blocking cardiac than intestinal muscarinic receptors and that HS-626 possessed the widest margin between concentrations blocking the nicotinic receptors at the neuromuscular junction and the cardiac muscarinic receptors. Evidence for the three bisquaternary compounds blocking neuronal noradrenaline reuptake was obtained only at very high concentrations. HS-626 possessed a slightly more desirable spectrum of activities than chandonium, but the degree of improvement over the parent compound is insufficient to merit extensive clinical testing.

Acetylcholine↗
PubMed2006

Viral and cellular determinants of the hepatitis C virus envelope-heparan sulfate interaction.

Cellular binding and entry of hepatitis C virus (HCV) are the first steps of viral infection and represent a major target for antiviral antibodies and novel therapeutic strategies. We have recently demonstrated that heparan sulfate (HS) plays a key role in the binding of HCV envelope glycoprotein E2 to target cells (Barth et al., J. Biol. Chem. 278:41003-41012, 2003). In this study, we characterized the HCV-HS interaction and analyzed its inhibition by antiviral host immune responses. Using recombinant envelope glycoproteins, virus-like particles, and HCV pseudoparticles as model systems for the early steps of viral infection, we mapped viral and cellular determinants of HCV-HS interaction. HCV-HS binding required a specific HS structure that included N-sulfo groups and a minimum of 10 to 14 saccharide subunits. HCV envelope binding to HS was mediated by four viral epitopes overlapping the E2 hypervariable region 1 and E2-CD81 binding domains. In functional studies using HCV pseudoparticles, we demonstrate that HCV binding and entry are specifically inhibited by highly sulfated HS. Finally, HCV-HS binding was markedly inhibited by antiviral antibodies derived from HCV-infected individuals. In conclusion, our results demonstrate that binding of the viral envelope to a specific HS configuration represents an important step for the initiation of viral infection and is a target of antiviral host immune responses in vivo. Mapping of viral and cellular determinants of HCV-HS interaction sets the stage for the development of novel HS-based antiviral strategies targeting viral attachment and entry.

Animals↗
PubMed2000

Herpes simplex virus types 1 and 2 differ in their interaction with heparan sulfate.

Cell surface heparan sulfate (HS) serves as an initial receptor for many different viruses, including herpes simplex virus types 1 and 2 (HSV-1 and 2, respectively). Glycoproteins C and B (gC and gB) are the major components of the viral envelope that mediate binding to HS. In this study, purified gB and gC homologous proteins as well as purified HSV-1 and HSV-2 virions were compared for the ability to bind isolated HS receptor molecules. HSV-1 gC and HSV-2 gC bound comparable amounts of HS. Similarly, HSV-1 gB and its HSV-2 counterpart showed no difference in the HS-binding capabilities. Despite the similar HS-binding potentials of gB and gC homologs, HSV-1 virions bound more HS than HSV-2 particles. Purified gC and gB proteins differed with respect to sensitivity of their interaction with HS to increased concentrations of sodium chloride in the order gB-2 > gB-1 > gC-1 > gC-2. The corresponding pattern for binding of whole HSV virions to cells in the presence of increased ionic strength of the medium was HSV-2 gC-neg1 > HSV-1 gC(-)39 > HSV-1 KOS 321 > HSV-2 333. These results relate the HS-binding activities of individual glycoproteins with the cell-binding abilities of whole virus particles. In addition, these data suggest a greater contribution of electrostatic forces for binding of gB proteins and gC-negative mutants compared with binding of gC homologs and wild-type HSV strains. Binding of wild-type HSV-2 virions was the least sensitive to increased ionic strength of the medium, suggesting that the less extensive binding of HS molecules by HSV-2 than by HSV-1 can be compensated for by a relatively weak contribution of electrostatic forces to the binding. Furthermore, gB and gC homologs exhibited different patterns of sensitivity of binding to cells to inhibition with selectively N-, 2-O-, and 6-O-desulfated heparin compounds. The O-sulfate groups of heparin were found to be more important for interaction with gB-1 than gB-2. These results indicate that HSV-1 and HSV-2 differ in their interaction with HS.

Genetic Variation↗
PubMed2000

Loading of DNA-binding factors to an erythroid enhancer.

The HS-40 enhancer is the major cis-acting regulatory element responsible for the developmental stage- and erythroid lineage-specific expression of the human alpha-like globin genes, the embryonic zeta and the adult alpha2/alpha/1. A model has been proposed in which competitive factor binding at one of the HS-40 motifs, 3'-NA, modulates the capability of HS-40 to activate the embryonic zeta-globin promoter. Furthermore, this modulation was thought to be mediated through configurational changes of the HS-40 enhanceosome during development. In this study, we have further investigated the molecular basis of this model. First, human erythroid K562 cells stably integrated with various HS-40 mutants cis linked to a human alpha-globin promoter-growth hormone hybrid gene were analyzed by genomic footprinting and expression analysis. By the assay, we demonstrate that factors bound at different motifs of HS-40 indeed act in concert to build a fully functional enhanceosome. Thus, modification of factor binding at a single motif could drastically change the configuration and function of the HS-40 enhanceosome. Second, a specific 1-bp, GC-->TA mutation in the 3'-NA motif of HS-40, 3'-NA(II), has been shown previously to cause significant derepression of the embryonic zeta-globin promoter activity in erythroid cells. This derepression was hypothesized to be regulated through competitive binding of different nuclear factors, in particular AP1 and NF-E2, to the 3'-NA motif. By gel mobility shift and transient cotransfection assays, we now show that 3'-NA(II) mutation completely abolishes the binding of small MafK homodimer. Surprisingly, NF-E2 as well as AP1 can still bind to the 3'-NA(II) sequence. The association constants of both NF-E2 and AP1 are similar to their interactions with the wild-type 3'-NA motif. However, the 3'-NA(II) mutation causes an approximately twofold reduction of the binding affinity of NF-E2 factor to the 3'-NA motif. This reduction of affinity could be accounted for by a twofold-higher rate of dissociation of the NF-E2-3'-NA(II) complex. Finally, we show by chromatin immunoprecipitation experiments that only binding of NF-E2, not AP1, could be detected in vivo in K562 cells around the HS-40 region. These data exclude a role for AP1 in the developmental regulation of the human alpha-globin locus via the 3'-NA motif of HS-40 in embryonic/fetal erythroid cells. Furthermore, extrapolation of the in vitro binding studies suggests that factors other than NF-E2, such as the small Maf homodimers, are likely involved in the regulation of the HS-40 function in vivo.

Binding Sites↗
PubMed2004

Heat shock treatment suppresses angiotensin II-induced activation of NF-kappaB pathway and heart inflammation: a role for IKK depletion by heat shock?

Heat shock (HS) proteins (Hsps) function in tissue protection through their chaperone activity and by interacting with cell signaling pathways to suppress apoptosis. Here, we investigated the effect of HS treatment on the nuclear factor (NF)-kappaB signaling pathway in the angiotensin II (ANG II) model of inflammation. Male Sprague-Dawley rats were divided into sham and HS-, ANG II-, and HS + ANG II-treated groups. HS treatment was administered 24 h before the initiation of ANG II infusion. HS treatment (42 degrees C for 15 min) decreased 7-day ANG II-induced hypertension from 191 +/- 4 to 147 +/- 3 mmHg (P < 0.01). Histological staining of hearts showed that HS treatment reduced ANG II-induced leukocyte infiltration, perivascular and interstitial inflammation, and fibrosis. Heart NF-kappaB nuclear translocation and activity, examined by Western blot analysis and electrophoretic mobility shift assay, was suppressed by HS treatment. HS treatment depleted IkappaB kinase-alpha (IKK-alpha) and phosphorylated IKK-alpha and suppressed the depletion of IkappaB-alpha and the accumulation of phosphorylated IkappaB-alpha. HS treatment blocked ANG II induced expression of IL-6 and ICAM-1 in the heart. ANG II and HS treatment induced high-level expression of Hsp27 and Hsp70 and their phosphorylation. Phosphorylated isoforms of Hsp27 and Hsp70 may play an important role in protecting the heart against ANG II-induced inflammation.

Angiotensin II↗
PubMed1999

Hippocampal chemical anatomy in pediatric and adolescent patients with hippocampal or extrahippocampal epilepsy.

We determined whether age or seizure types were associated with hippocampal neuron loss, mossy fiber (MF) and GABAergic synaptic reorganizations or postsynaptic receptor densities. Children and adolescents were grouped into: (1) nonhippocampal sclerosis (non-HS; n = 11) and (2) hippocampal sclerosis (HS; n = 11). The most important results showed that: (1) regardless of the etiology of the seizures, there were greater cell losses in Ammon's horn with older ages in years; in the non-HS group, cell losses were greater with the older ages or with longer epilepsy durations; however, in the HS patients, the cell losses were not related to the patients' ages or epilepsy durations; (2) in both HS and non-HS, CA1 had greater cell losses than CA4; (3) in HS, CA1 and CA4 had greater cell losses than those in non-HS; (4) in non-HS, MF sprouting was greater with ages or with longer epilepsy durations; by contrast, in HS, MF sprouting was not related to the patients' age or epilepsy duration; (5) densities for AMPA GluR1, GABA-Abeta and for GABA axonal terminals were positively increased with age. These findings support the hypothesis that hippocampal cell losses and aberrant synaptic reorganizations are greater in the hippocampi of adolescents than in children, even for non-HS pathologies.

Adolescent↗
PubMedDate not supplied

Urinary dopamine excretion in conscious rats: effect of carbidopa in different states of sodium balance.

Urinary dopamine excretion was studied in seven different groups of rats (n = 6-12) with the following treatment regimens: normal chow and tap water (controls, CON), single administration of furosemide 20 mg/kg i.p. on day 1 and subsequent feeding of low sodium chow (low salt, LS), normal chow and 1% NaCl as drinking water (high salt, HS), normal chow and 1% NaCl plus deoxycorticosterone acetate 1 mg/kg/day i.p. (high salt plus DOCA, HS+DOCA); carbidopa 20 mg/kg/day p.o. (CDP) was administered in animals on normal chow (CON+CDP), in high salt rats (HS+CDP), and in rats on high salt plus DOCA (HS+DOCA+CDP). On day 5, rats were placed in metabolic cages with free access to their respective drinking solution; chow was withheld. Urine was collected for 24 h and analyzed for sodium, creatinine, and dopamine. Urinary dopamine excretion rates did not change in proportion to large differences in sodium excretion in LS, HS, and HS+DOCA animals compared to CON. Only when urinary dopamine excretion of HS rats was compared to the LS group there was a moderate, but significant increase of 27%. In the groups treated with CDP renal dopamine excretion was decreased by approximately 60% in comparison to the groups with the respective treatment condition but without CDP. Urinary sodium output was unchanged by CDP in CON+CDP animals compared to CON. In HS+CDP and HS+DOCA+CDP groups renal sodium excretion was reduced by half compared to the HS and HS+DOCA groups, respectively. However, this effect was accompanied by a similar, approximately 55% reduction of oral volume and sodium intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Role of endogenous atrial natriuretic peptide in DOCA-salt hypertensive rats. Effects of a novel nonpeptide antagonist for atrial natriuretic peptide receptor.

BACKGROUND: To explore roles of endogenous atrial natriuretic peptide (ANP) in blood pressure and volume regulation, we examined the effects of a newly developed ANP antagonist, HS-142-1 (HS) in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. METHODS AND RESULTS: We examined 1) the effects of HS on ANP- or brain natriuretic peptide (BNP)-induced reductions in renal vascular resistance (RVR) of rat isolated perfused kidneys, 2) the effects of HS on cyclic GMP (cGMP) production in rat cultured vascular smooth muscle cells pretreated with ANP or BNP, and 3) the renal and systemic effects of HS in DOCA-salt-treated rats and control rats. We found that 1) HS dose-dependently reversed ANP- or BNP-induced decreases in RVR; 2) ANP or BNP at 100 nM caused an eightfold increase in cGMP production. These increases in cGMP were inhibited by HS in a dose-dependent fashion, and 300 micrograms/ml HS decreased cGMP to the control level. HS alone did not influence RVR or cGMP production; and 3) DOCA-salt rats showed higher plasma concentrations of ANP (198 versus 75 pg/ml) and BNP (23.7 versus 2.7 pg/ml, each p < 0.01) than the control rats. Bolus administration of 8 mg/kg HS elevated blood pressure by 8% (p < 0.01). This rise in blood pressure was attributed to an increase in systemic vascular resistance (+14%, p < 0.05). Conversely, urinary excretion of sodium (-41%), glomerular filtration rate (-27%), and plasma (-77%) and urinary cGMP (-69%, each p < 0.01) were decreased by administration of 8 mg/kg HS. These effects were dose dependent in DOCA-salt rats but slight or negligible in the control rats. CONCLUSIONS: These results suggest that endogenous ANP and BNP may be involved in the regulation of blood pressure and body fluid volume in DOCA-salt rats in which ANP and BNP secretion is augmented.

Animals↗
PubMed2005

A novel mechanism contributing to development of Dahl salt-sensitive hypertension: role of the transient receptor potential vanilloid type 1.

To determine the role of the transient receptor potential vanilloid type 1 (TRPV1) channels in development of hypertension in Dahl salt-sensitive (DS) rats fed a high-salt diet (HS), male DS and Dahl salt-resistant (DR) rats were maintained on a low-salt diet (LS) or HS for 3 weeks. HS significantly increased systolic blood pressure in DS+HS rats compared with DS+LS, DR+HS, and DR+LS rats. Intravenous bolus injection of capsazepine (3 mg/kg), a selective TRPV1 antagonist, significantly increased mean arterial pressure in conscious DR+HS rats compared with DR+LS, DS+/-HS, and DS+/-LS rats. In contrast, capsaicin (10 or 30 microg/kg), a selective TRPV1 agonist, dose-dependently decreased mean arterial pressure in all of the groups with the most profound magnitude in DR+HS rats compared with the other 3 groups. TRPV1 expression in mesenteric resistance arteries and the renal cortex and medulla, calcitonin gene-related peptide levels in dorsal root ganglia, and calcitonin gene-related peptide-positive sensory nerve density in mesenteric resistance arteries were significantly decreased in DS+HS rats compared with DS+LS, DR+HS, and DR+LS rats. Taken together, our data indicate that the TRPV1 receptor is activated and its expression upregulated during HS intake in DR rats, which acts to prevent salt-induced increases in blood pressure. In contrast, TRPV1 expression and function are impaired in DS rats, which renders DS rats sensitive to salt load in terms of blood pressure regulation.

Animals↗
PubMed2006

Transposable element derived DNaseI-hypersensitive sites in the human genome.

BACKGROUND: Transposable elements (TEs) are abundant genomic sequences that have been found to contribute to genome evolution in unexpected ways. Here, we characterize the evolutionary and functional characteristics of TE-derived human genome regulatory sequences uncovered by the high throughput mapping of DNaseI-hypersensitive (HS) sites. RESULTS: Human genome TEs were found to contribute substantially to HS regulatory sequences characterized in CD4+ T cells: 23% of HS sites contain TE-derived sequences. While HS sites are far more evolutionarily conserved than non HS sites in the human genome, consistent with their functional importance, TE-derived HS sites are highly divergent. Nevertheless, TE-derived HS sites were shown to be functionally relevant in terms of driving gene expression in CD4+ T cells. Genes involved in immune response are statistically over-represented among genes with TE-derived HS sites. A number of genes with both TE-derived HS sites and immune tissue related expression patterns were found to encode proteins involved in immune response such as T cell specific receptor antigens and secreted cytokines as well as proteins with clinical relevance to HIV and cancer. Genes with TE-derived HS sites have higher average levels of sequence and expression divergence between human and mouse orthologs compared to genes with non TE-derived HS sites. CONCLUSION: The results reported here support the notion that TEs provide a specific genome-wide mechanism for generating functionally relevant gene regulatory divergence between evolutionary lineages. REVIEWERS: This article was reviewed by Wolfgang J. Miller (nominated by Jerzy Jurka), Itai Yanai and Mikhail S.Gelfand.

Journal Article↗
PubMed1989

Effect of an osmotic stimulus on the secretion of arginine vasopressin and adrenocorticotropin in the horse.

Arginine vasopressin (AVP) is released in response to changes in blood osmolality and is also a putative secretagogue for ACTH. However, it is unclear whether osmotically generated increases in AVP in the physiological range influence ACTH secretion. We have studied this question using our unique noninvasive technique for collecting pituitary venous blood in six normal conscious horses that received an iv infusion of hypertonic saline (HS; 5%, 0.07 ml/kg.min) for 45-60 min. Pituitary and jugular venous samples were collected every 5 min for 40 min before, during, and for 20 min after HS. During HS, mean blood osmolality rose (P less than 0.01), with a mean peak increase of 14.8 mosmol/kg (range, +6-+37 mosmol/kg). Jugular AVP rose (P less than 0.01) from 0.56 +/- 0.18 pmol/liter (mean +/- SEM) before HS to 2.16 +/- 0.86 pmol/liter during HS. Mean jugular AVP and osmolality were correlated (r = 0.82; P less than 0.05) during HS. Mean jugular ACTH concentrations increased (P less than 0.01) from 49 +/- 9 ng/liter before HS to 148 +/- 54 ng/liter during HS, while mean cortisol levels during and after HS exceeded basal levels (P less than 0.05). Pituitary AVP and ACTH concentrations exceeded jugular concentrations by up to 100-fold, and mean (P less than 0.01 for both) and peak (P less than 0.001 for both) levels increased during HS. AVP and ACTH secretion during HS were pulsatile. The mean and peak changes in pituitary AVP were significantly correlated with those in ACTH. For the six horses together, pituitary ACTH and AVP concentration changes occurred synchronously during the experiment (P less than 0.001), and the paired AVP and ACTH concentrations were highly correlated (r = 0.73; n = 129 pairs; P less than 0.001). We conclude that 1) physiological changes in AVP secretion are closely associated with comparable changes in ACTH secretion, and 2) osmotic signals that presumably activate the magnocellular neurons of the supraoptic and paraventricular nuclei may be physiologically relevant regulators of corticotrope function.

Adrenocorticotropic Hormone↗
PubMed2004

Temporal lobe volumes in patients with hippocampal sclerosis with or without cortical dysplasia.

BACKGROUND: Recent MRI-based volume reconstruction studies in intractable temporal lobe epilepsy (TLE) due to hippocampal sclerosis (HS) suggested atrophy that extends to the adjacent neocortical areas. OBJECTIVE: To study the extent of temporal lobe volume (TLV) abnormalities in patients with pathologically confirmed HS (with or without cortical dysplasia [CD]) who underwent anterior temporal lobectomy for the treatment of drug-resistant TLE. METHODS: Fifty patients (right TLE: n = 24; left TLE: n = 26) were found to have HS (hippocampal cell loss of >30%). Associated neocortical CD was seen in 20 patients (43%). MRI-based TLVs and hippocampal and hemispheric volume reconstructions in all patients were compared between pathologic groups and with volumes acquired from 10 age-matched control subjects. RESULTS: TLVs ipsilateral to the epileptogenic zone in patients with TLE were smaller than TLVs in control subjects (p < 0.01). In patients with left TLE, TLVs ipsilateral to the epileptogenic zone were smaller than contralateral TLVs (left: 66.6 +/- 8.3 cm3, right: 74.9 +/- 10.0 cm3; p < 0.001). In patients with right TLE, there were no significant asymmetries. The contralateral TLVs (regardless of the side of surgery) were smaller in the HS + CD group than the HS group (HS + CD group: 74.9 +/- 8.6 cm3, HS group: 79.7 +/- 6.6 cm3; p < 0.05). Patients with HS + CD had a tendency to have less hippocampal atrophy and slightly smaller TLVs ipsilateral to the epileptogenic zone, accounting for significantly smaller TLV/hippocampal volume ratios compared with patients with HS alone. CONCLUSIONS: Drug-resistant TLE due to HS is associated with extrahippocampal temporal lobe atrophy. The presence of bilateral temporal lobe atrophy is suggestive of a more widespread (bilateral) temporal lobe involvement in patients with HS and CD.

Adolescent↗
PubMed2002

Increased responsiveness of hypoxic endothelial cells to FGF2 is mediated by HIF-1alpha-dependent regulation of enzymes involved in synthesis of heparan sulfate FGF2-binding sites.

Binding of basic fibroblast growth factor (FGF2) to its high affinity receptors requires the presence of specific heparan sulfate (HS) moieties on the cell surface that act as coreceptors. To determine the contribution of cell-surface HS to modulation of FGF2-dependent cell growth, we studied the changes in the cell mass and FGF2 binding of endothelial cell HS under normoxic and hypoxic conditions in vitro. Both large vein and cardiac microvascular endothelial cells cultured under hypoxic conditions demonstrated an increase in the ratio of cell-surface HS to chondroitin sulfate (CS), as well as an increase in the number of low affinity (HS-associated) binding sites for FGF2 with no change in the apparent K(d). This increase in the number of HS-FGF2 binding sites, in the absence of a significant change in FGF receptor expression, resulted in enhanced responsiveness of hypoxic, compared with normoxic, endothelial cells to FGF2 stimulation. Gene expression studies demonstrated increased expression of the key regulatory enzyme responsible for HS chain synthesis, 1,4 GlcNAc transferase (GlcNAcT-I), as well as increased expression of 2-O sulfotransferase (HS2ST), the enzyme responsible for sulfation of IdoA, a crucial part of the HS-FGF2 binding site. Transduction of cells with an adenovirus encoding a HIF-1alpha expression construct resulted in a similar increase in GlcNAcT-I and HS2ST expression. We conclude that hypoxia increases endothelial cell responsiveness to FGF2 by promoting preferential synthesis of HS rather than CS chains and increasing the number of FGF2-binding sites on HS chains. Both of these events are mediated by a HIF-1alpha-dependent increase in expression of the enzymes GlnNAcT-I and HS2ST. This shift in cell-surface HS composition results in enhanced cell sensitivity to FGF2-induced growth stimulation.

Animals↗
PubMed2003

Body mass index, but not physical activity, is associated with C-reactive protein.

UNLABELLED: Elevated high-sensitivity c-reactive protein (hs-CRP) is associated with increased risk of future first and recurrent coronary events and has been associated with both high body mass index (BMI) and low physical activity in cross sectional studies. PURPOSE: To longitudinally examine the effects of BMI and both current and previous-year physical activity on hs-CRP in healthy men and women (N = 109). METHODS: BMI and hs-CRP were measured five times (baseline and quarterly) over 1 yr. Current physical activity was assessed 12-15 times during the study via 24-h recall. Previous-year physical activity was assessed using the Baecke questionnaire at baseline. RESULTS: Mean BMI and hs-CRP were unchanged over the course of the study, but current physical activity increased on visit 3. Average hs-CRP was not related to average current physical activity or to natural changes in current physical activity across the five visits. Additionally, current physical activity on any given visit was not associated with hs-CRP on the following visit. When current physical activity, BMI, age, gender, and smoking were included in the statistical model, only BMI was significantly related to hs-CRP (P < 0.001). Average hs-CRP was significantly correlated with average BMI (r = 0.50; P < 0.001) but was not related to previous-year (Baecke) physical activity levels (r = 0.02; P = 0.89). When subjects were grouped by BMI (<25 kg.m-2, 25-29.9 kg x m-2, >30 kg x m-2) hs-CRP was significantly greater in obese (3.2 +/- 1.9 mg.L-1) and overweight (2.1 +/- 1.7 mg x L-1) than normal weight (1.1 +/- 1.0 mg.L-1) subjects (ANOVA P < 0.05). Current physical activity was similar between the three BMI groups at all times, and was unrelated to hs-CRP in all groups, throughout the study period. CONCLUSION: These data indicate that BMI, but not previous-year or current physical activity, predicts hs-CRP.

Adult↗
PubMed2006

Induction of glomerular heparanase expression in rats with adriamycin nephropathy is regulated by reactive oxygen species and the renin-angiotensin system.

Heparan sulfate (HS) in the glomerular basement membrane (GBM) is important for regulation of the charge-dependent permeability. Heparanase has been implicated in HS degradation in several proteinuric diseases. This study analyzed the role of heparanase in HS degradation in Adriamycin nephropathy (AN), a model of chronic proteinuria-induced renal damage. Expression of heparanase, HS, and the core protein of agrin (to which HS is attached) was determined on kidney sections from rats with AN in different experiments. First, expression was examined in a model of unilateral AN in a time-course study at 6-wk intervals until week 30. Second, rats were treated with the hydroxyl radical scavenger dimethylthiourea (DMTU) during bilateral AN induction. Finally, 6 wk after AN induction, rats were treated with angiotensin II receptor type 1 antagonist (AT1A) or vehicle for 2 wk. Heparanase expression was increased in glomeruli of rats with AN, which correlated with HS reduction at all time points and in all experiments. Treatment with DMTU prevented the increased heparanase expression, the loss of GBM HS, and reduced albuminuria. Finally, treatment of established proteinuria with AT1A significantly reduced heparanase expression and restored glomerular HS. In conclusion, an association between heparanase expression and reduction of glomerular HS in AN was observed. The effects of DMTU suggest a role for reactive oxygen species in upregulation of heparanase. Antiproteinuric treatment by AT1A decreased heparanase expression and restored HS expression. These results suggest involvement of radicals and angiotensin II in the modulation of GBM permeability through HS and heparanase expression.

Agrin↗
PubMed2003

Asthmatic airway inflammation is more closely related to airway hyperresponsiveness to hypertonic saline than to methacholine.

BACKGROUND: Airway hyperresponsiveness (AHR) to direct stimuli, such as methacholine (MCh), is observed not only in asthma but other diseases. AHR to indirect stimuli is suggested to be more specific for asthma. The purpose of this study was to determine whether asthmatic airway inflammation is more closely related to AHR to hypertonic saline (HS), an indirect stimulus, than to MCh. METHODS: Sixty-four consecutive adult patients with suspected asthma (45 asthma and 19 non-asthma) performed a combined bronchial challenge and sputum induction with 4.5% saline, and MCh challenge on the next day. RESULTS: Both HS-PD15 and MCh-PC20 were significantly lower in asthma patients than in non-asthma patients. However, the sensitivity/specificity for asthma was 48.9%/100%, respectively, in the HS test and 82.2%/84.2%, respectively, in the MCh test. There was a significant relationship between HS-PD15 and MCh-PC20 and only 52.9% of patients with MCh-PC20 < or = 4 mg/mL showed HS-AHR, but 4 patients with HS-AHR showed MCh-PC20 > 4 mg/mL. There were significant correlations between both HS-PD15 and MCh-PC20 and FEV1, or sputum eosinophils, but FEV1 was more closely related to MCh-PC20 (r = 0.478, p < 0.01) than to HS-PD15 (r = 0.278, p < 0.05), and sputum eosinophils were more closely related to HS-PD15 (r = -0.324, p < 0.01) than to MCh-PC20 (r = -0.317, p < 0.05). Moreover, the IL-5 level (r = 0.285, p < 0.05) and IFN-gamma/IL-5 ratio (r = 0.293, p < 0.05) in sputum were significantly related to HS-PD15, but not to MCh-PC20. CONCLUSION: HS-AHR may reflect allergic asthmatic airway inflammation more closely than MCh-AHR.

Asthma↗
PubMed2005

Airway hyperresponsiveness to hypertonic saline as a predictive index of exercise-induced bronchoconstriction.

BACKGROUND: Changes in airway mucosal osmolarity are an underlying mechanism of bronchoconstrictive responses to exercise and hypertonic saline (HS). The purpose of this study was to examine whether an osmotic challenge test using HS can predict exercise-induced bronchospasm (EIB) in asthma patients. METHODS: Thirty-six young male asthmatic patients underwent bronchial challenge tests based on 4.5% HS, exercise (> 24h later), and methacholine (MCh) at the Chonnam National University Hospital. The relationships between responses to HS and exercise, and between MCh and exercise were evaluated. RESULTS: The maximal fall in forced expiratory volume in one second following exercise was significantly higher in the HS-responders (n=19) than in the HS-nonresponders (n=17, 35.9 +/- 4.1% vs. 17.9 +/- 2.7%, p<0.001), and there was a significant correlation between the severity of EIB and HS-airway hyperresponsiveness (AHR). When compared with the MCh-AHR test in terms of predicting EIB, the HS-AHR test showed higher specificity (71.4% vs. 42.90%), but a lower sensitivity (58.6% vs. 89.7%) and negative predictive value (29.4% vs. 50.0%). At the moderate AHR cutoff value, the MCh-AHR test had a specificity that was comparable with and predictive values that were higher than those of the HS-AHR test. CONCLUSIONS: The HS-AHR test was more specific than the MCh-AHR test, but was less sensitive and had a poorer negative predictive value, which in combination preclude the use of the HS-AHR test as a screening tool for EIB. The MCh-AHR test had a cutoff value for moderate AHR that may be more useful for predicting EIB in asthmatic patients.

Adolescent↗