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PubMed2006

Retinal angiomatous proliferation: association with clinical and angiographic features.

AIM: It was the aim of this study to evaluate the frequency of retinal angiomatous proliferation (RAP) and its association with specific clinical and angiographic characteristics in age-related macular degeneration (AMD). METHODS: A consecutive series of 126 newly diagnosed patients with exudative AMD was reviewed retrospectively. All underwent a complete ophthalmic examination, a red-free photograph and fluorescein angiography. Most patients (85/126) underwent indocyanine green choroidal angiography (ICGA). RAP was diagnosed when a connection between the retinal vasculature and the neovascular complex was recognized angiographically. RESULTS: Out of 126 patients with recent neovascular AMD, 17 had RAP (13.5%; 95% CI 8.1-20.7). The study eye of patients with RAP had more frequent hemorrhages (88.2 vs. 59.6%; p = 0.027), hard exudates (82.4 vs. 26.6%; p < 0.001), pigment epithelium detachment (64.7 vs. 23.8%; p = 0.001) and a hot spot in ICGA (70.6 vs. 22.1%; p < 0.001) with respect to the other forms of exudative AMD. Hemorrhages were more frequently superficial, multiple and within the edge of the lesion in the RAP group. Bilateral AMD was more common in the RAP group (70.6 vs. 38.0%; p = 0.011). No statistically significant differences were found regarding sex, age and visual acuity. CONCLUSION: RAP represents a common lesion in patients with neovascular AMD referred to a tertiary care clinic. The recognition of hemorrhages, hard exudates, pigment epithelium detachment or a hot spot in ICGA can assist a correct diagnosis.

Aged↗

PubMed2000

Contrasting efficacy of dofetilide in differing experimental models of atrial fibrillation.

BACKGROUND: Rapid atrial pacing (RAP) and congestive heart failure (CHF) produce different experimental substrates for atrial fibrillation (AF). We tested the hypothesis that AF maintained by different substrates responds differently to antiarrhythmic-drug therapy. METHODS AND RESULTS: The class III antiarrhythmic agent dofetilide was given intravenously at doses of 10 (D10) and 80 (D80) microg/kg to dogs with AF induced either (1) after 7 days of RAP at 400 bpm or (2) in the presence of CHF induced by rapid ventricular pacing. Dofetilide terminated AF in all CHF dogs, but D10 failed to terminate AF in any RAP dog, and D80 terminated AF in only 1 of 5 RAP dogs (20%) (P<0.01 for efficacy in CHF versus RAP dogs). Dofetilide was highly effective in preventing AF induction by atrial burst pacing in dogs with CHF but was totally ineffective in dogs with RAP. Dofetilide increased atrial effective refractory period and AF cycle length to a greater extent in CHF dogs. Epicardial mapping with 248 bipolar electrodes showed that CHF-related AF was often due to macroreentry, with dofetilide terminating AF by causing block in reentry circuits. RAP-related AF was due to multiple-wave front reentry, with dofetilide slowing reentry and decreasing the number of simultaneous waves, but not sufficiently to stop AF. CONCLUSIONS: The mechanism underlying AF importantly influences dofetilide efficacy. The dependence of drug efficacy in AF on the underlying mechanism has potentially significant implications for antiarrhythmic drug use and development and may explain the well-known therapeutic resistance of longer-duration AF.

Animals↗

PubMedDate not supplied

Role of renal hemodynamics and arterial pressure in aldosterone "escape".

This study examined the importance of changes in renal hemodynamics and renal artery pressure (RAP) in allowing the kidneys to escape from the chronic sodium-retaining effects of aldosterone (Aldo). In five dogs in which RAP was permitted to increase during Aldo infusion (14 micrograms/kg/day), sodium excretion (UNaV) and fractional sodium excretion (FENa) decreased markedly on Day 1 and then returned to control on Days 2 to 4 of Aldo infusion as RAP and glomerular filtration rate (GFR) increased 15 to 19 mm Hg and 20% to 24%, respectively, and remained near these levels during 7 days of Aldo infusion. In seven dogs in which RAP was prevented from increasing with an electronically servo-controlled aortic occluder, UNaV decreased from 256 +/- 3 to 117 +/- 9 mEq/day on the first day and remained at 70 to 80 mEq/day below sodium intake for 7 days of Aldo infusion. Cumulative sodium balance and sodium iothalamate space increased 610 +/- 39 mEq and 3729 +/- 397 ml when RAP was servo-controlled, causing ascites in most of the dogs, while mean arterial pressure did not plateau but continued to rise to 59 +/- 3 mm Hg above control after 7 days of Aldo infusion. When the servo-controller was stopped and RAP was allowed to rise while Aldo infusion was continued, GFR rose to 126% to 136% of control, FENa increased markedly, UNaV increased to 579 +/- 64 mEq/day on the first day, and the dogs returned to normal sodium balance. These data indicate that an increase in RAP, which raises GFR and FENa, is essential in allowing the kidneys to escape from the chronic sodium-retaining action of Aldo and to achieve sodium balance and a stable level of arterial pressure without severe volume expansion and ascites.

Aldosterone↗

PubMed2001

Nitric oxide dependency of arterial pressure-induced changes in renal interstitial hydrostatic pressure in dogs.

A direct relationship between renal arterial pressure (RAP) and renal interstitial hydrostatic pressure (RIHP) has been shown under conditions of efficient renal blood flow autoregulation. Experiments were performed in six anesthetized dogs to evaluate whether these RIHP responses to changes in RAP were modified during nitric oxide (NO) inhibition with nitro-L-arginine (NLA) or after administration of NO donor agents. A microtip catheter transducer was placed underneath the renal capsule to measure RIHP. Stepwise reductions in RAP (140 to 80 mm Hg) during control conditions resulted in decreases in RIHP from its basal value of 4.7+/-1.1 mm Hg with a slope of 0.04+/-0.026 mm Hg. mm Hg(-)(1) along with decreases in urinary nitrate/nitrite excretion rate (U(NOx)V). Renal cortical and medullary blood flows, measured by laser-Doppler flowmetry, exhibited high autoregulatory efficiency over this RAP range. The changes in RIHP during alterations in RAP were positively correlated (r=0.743; P:<0.001) with the changes in U(NOx)V but not with cortical or medullary blood flow. NLA infusion decreased RIHP to 1.9+/-0.5 mm Hg and also reduced U(NOx)V from 1.8+/-0.2 to 0.9+/-0.01 nmol. min(-)(1). g(-)(1). Infusion of NO donors restored RIHP (4.3+/-0.9 mm Hg) and U(NOx)V (1.5+/-0.2 nmol. min(-)(1). g(-)(1)). During NLA infusion, the RIHP responses to reductions in RAP were markedly attenuated and were not restored even during constant-rate infusion of NO donors. The results suggest that changes in RIHP in response to alterations in RAP are associated with changes in intrarenal NO, suggesting a direct effect of NO to regulate RIHP.

Animals↗

PubMed2000

Cloning of novel soluble gp130 and detection of its neutralizing autoantibodies in rheumatoid arthritis.

In an attempt to isolate disease-associated autoantigens in rheumatoid arthritis (RA), we cloned a new autoantigen named gp130-RAPS, which is a novel soluble form of the IL-6 signal-transducing molecule gp130. gp130-RAPS is a 50-kDa protein translated from alternatively spliced mRNA and has a truncated form of gp130 with a unique sequence, Asn-Ile-Ala-Ser-Phe (NIASF), in its COOH-terminus. We observed serum antibodies to this NIASF sequence frequently in patients with RA, but not in those with other systemic rheumatic diseases or in healthy subjects. In RA, detection of those antibodies was significantly associated with disease activity indices such as serum C-reactive protein (CRP) levels, erythrocyte sedimentation rate, blood platelet counts, and serum IL-6 concentration. In vitro experiments revealed that gp130-RAPS inhibited IL-6 activity, and this inhibition was neutralized by antibodies to the COOH-terminus of gp130-RAPS derived from patients with RA. Thus, autoantibody to gp130-RAPS may play an important role in the progression of RA by promoting IL-6 activity. Inspection of autoantibodies to gp130-RAPS may become a practical clinical test for RA. gp130-RAPS and its autoantibody provide a new clue to the complicated pathogenesis of RA.

Animals↗

PubMed2006

How can the response to volume expansion in patients with spontaneous respiratory movements be predicted?

INTRODUCTION: The aim of the study was to evaluate the ability of different static and dynamic measurements of preload to predict fluid responsiveness in patients with spontaneous respiratory movements. METHODS: The subjects were 21 critically ill patients with spontaneous breathing movements receiving mechanical ventilation with pressure support mode (n = 9) or breathing through a face mask (n = 12), and who required a fluid challenge. Complete hemodynamic measurements, including pulmonary artery occluded pressure (PAOP), right atrial pressure (RAP), pulse pressure variation (DeltaPP) and inspiratory variation in RAP were obtained before and after fluid challenge. Fluid challenge consisted of boluses of either crystalloid or colloid until cardiac output reached a plateau. Receiver operating characteristics (ROC) curve analysis was used to evaluate the predictive value of the indices to the response to fluids, as defined by an increase in cardiac index of 15% or more. RESULTS: Cardiac index increased from 3.0 (2.3 to 3.5) to 3.5 (3.0 to 3.9) l minute-1 m-2 (medians and 25th and 75th centiles), p < 0.05. At baseline, DeltaPP varied between 0% and 49%. There were no significant differences in DeltaPP, PAOP, RAP and inspiratory variation in RAP between fluid responders and non-responders. Fluid responsiveness was predicted better with static indices (ROC curve area +/- SD: 0.73 +/- 0.13 for PAOP, p < 0.05 vs DeltaPP and 0.69 +/- 0.12 for RAP, p = 0.054 compared with DeltaPP) than with dynamic indices of preload (0.40 +/- 0.13 for DeltaPP and 0.53 +/- 0.13 for inspiratory changes in RAP, p not significant compared with DeltaPP). CONCLUSION: In patients with spontaneous respiratory movements, DeltaPP and inspiratory changes in RAP failed to predict the response to volume expansion.

Aged↗

PubMed1989

The role of Ca2+ and calmodulin in the regulation of atrial natriuretic peptide-stimulated guanosine 3',5'-cyclic monophosphate accumulation by isolated mouse Leydig cells.

We have investigated the role of Ca2+ and calmodulin in the stimulation of cGMP formation by mouse Leydig cells in response to rat atriopeptin-II (rAP-II). Removal of extracellular Ca2+ had no influence on the levels of cGMP accumulated by the cells stimulated with rAP-II. The amounts of testosterone produced by unstimulated and rAP-II-stimulated cells were, however, reduced by 50% in the absence of Ca2+ from the incubation medium. Addition of ionomycin to the Leydig cells led to a dose-related inhibition of rAP-II-stimulated cGMP formation, but the basal cGMP level was not affected. These experiments were carried out in the presence of a phosphodiesterase inhibitor. The inhibitory effect of ionomycin was absolutely dependent upon the presence of Ca2+ in the medium. The guanylate cyclase activity required the presence of a cation, and Mn2+, Mg2+, or Ca2+ could function as the required cation. There was no direct inhibition of the cyclase activity by Ca2+ up to as high a concentration as 8 mM. Furthermore, three structurally unrelated calmodulin antagonists, W7, trifluoperazine, and calmidazolium, but not W5, caused a dose-related inhibition of rAP-II-stimulated cGMP accumulation by the cells. The inhibitory effect of calmodulin antagonists was not exerted directly at the level of guanylate cyclase activity, since the particulate enzyme was not inhibited by any of these drugs. We conclude, therefore, that extracellular Ca2+ is not essential for rAP-II-mediated stimulation of cGMP formation by mouse Leydig cells, at least under the short term incubation conditions used. An excessive ionophoretic influx of Ca2+ into the cells impairs the ability of rAP-II to stimulate cGMP formation. Therefore, it appears that a finely regulated level of intracellular Ca2+ is required for optimal activation of atrial natriuretic peptide-responsive guanylate cyclase in mouse Leydig cells, and calmodulin plays an important role in this process.

Animals↗

PubMed1999

Trans-activation of the mouse cartilage-derived retinoic acid-sensitive protein gene by Sox9.

The transcription factor Sox9 is capable of enhancing type II collagen gene expression and may play a crucial role in chondrogenesis. To determine whether Sox9 is an inducer of the chondrocyte phenotype, we investigated the role of Sox9 in transcription of another cartilage gene encoding the cartilage-derived retinoic acid-sensitive protein (CD-RAP). CD-RAP is specifically expressed during chondrogenesis. We show here that Sox9 protein is able to bind to a SOX consensus sequence in the CD-RAP promoter. Mutation of the SOX motif led to decreased transcription of a CD-RAP promoter construct in chondrocytes. Overexpression of SOX9 resulted in a dose-dependent increased activity of CD-RAP promoter-driven reporter gene in both chondrocytes and nonchondrogenic cells. A truncated SOX9, which contains a binding domain but no trans-activation function, inhibited CD-RAP promoter activity. Overexpression of SOX9 increased the level of endogenous CD-RAP mRNA in chondrocytes, but was unable to induce endogenous gene expression in 10T1/2 mesenchymal cells or BALB/c-3T3 fibroblasts. These results suggest that Sox9 is a general transcriptional regulator of cartilage-specific genes. However, Sox9 does not appear to be able to induce the chondrocyte phenotype in nonchondrogenic cells, implying that other factors are involved in chondrogenesis.

Animals↗

PubMed2000

Receptor-associated protein is important for normal processing of megalin in kidney proximal tubules.

The receptor-associated protein (RAP) has been identified as a chaperone regulating the expression and processing of the LDL receptor-related protein. RAP also binds to the related 600-kD multiligand endocytic receptor megalin expressed in many absorptive epithelia including renal proximal tubule. The present study examines the effect of RAP gene disruption on megalin expression and subcellular distribution in the proximal tubule as well as the effect on tubular protein reabsorption. It is shown that RAP is important for the normal expression and function of megalin. Megalin expression was reduced to approximately 23% estimated by immunoblotting and supported by immunocytochemistry and by the amount of megalin recovered by RAP affinity chromatography. Light- and electron microscope immunocytochemistry as well as analyses on separated membrane fractions showed significant changes in the subcellular distribution of megalin. A significant reduction in the normal brush border labeling was observed in association with increased labeling of rough endoplasmic reticulum and the smooth paramembranous endoplasmic reticulum along the basolateral membranes. RAP deficiency was associated with changes in urinary protein composition, enabling the identification of alpha-amylase as a new ligand for megalin. In addition, an increased excretion of vitamin D-binding protein, a recently identified ligand to megalin, was observed supporting changes in tubular protein reabsorption. The present data show that RAP is of crucial importance for normal processing and function of megalin, suggesting a chaperone-like function of this protein in the kidney proximal tubule.

Animals↗

PubMed1995

Impaired renal autoregulatory ability in dogs with reduced renal mass.

In normal dogs, the renal autoregulatory mechanism limits the effect of changes in renal arterial pressure (RAP) on RBF, renal outer cortical blood flow (OCBF), and GFR by adjusting the vascular tone of the preglomerular arterioles. To determine the extent to which autoregulatory ability was impaired in remnant renal tissue in dogs, the effects of variations in RAP on RBF, OCBF, and GFR were studied after sham-operation (Group 1; N = 5), 3/4 nephrectomy (Group 2; N = 5), or 7/8 nephrectomy (Group 3; N = 5). In Group 1, the RBF, OCBF, and GFR were not significantly affected by variations in RAP between 75 and 125 mm Hg, indicating intact renal autoregulatory ability. In contrast, both groups of partially nephrectomized dogs exhibited a loss of renal autoregulatory ability below 100 mm Hg (P < 0.05). As RAP rose above 100 mm Hg, dogs with 7/8 nephrectomy exhibited a greater increase than control dogs in RBF (0.586 +/- 0.211 versus -0.080 +/- 0.030 percent change in RBF/mm Hg change in RAP; P < 0.05), OCBF (0.408 +/- 0.157 versus -0.059 +/- 0.054 percent change in RBF/mm Hg change in RAP; P < 0.05), and GFR (0.784 +/- 0.230 versus 0.134 +/- 0.049 percent change in RBF/mm Hg change in RAP; P < 0.05). The ability of the renal vasculature to maintain renal function stable above 100 mm Hg was intermediate in Group 2 and not significantly different from corresponding values for Group 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Megalin (gp330) possesses an antigenic epitope capable of inducing passive Heymann nephritis independent of the nephritogenic epitope in receptor-associated protein.

The Heymann nephritis antigenic complex (HNAC) consists of two glycoproteins, megalin (gp330), and the receptor-associated protein (RAP). HNAC is expressed on the surface of the glomerular epithelium where it plays a primary role in the pathogenesis of Heymann nephritis (HN). Several models were previously proposed describing how antibody binding epitopes in HNAC may contribute to the initiation and progression of HN. Although these models suggest that nephritogenic epitopes capable of initiating HN are present in both megalin and RAP, the structural relationship between these epitopes has not been established. Previously a nephritogenic epitope was identified and characterized in RAP that initiates immune complex formation in HN. In this report, the immunologic relationship between nephritogenic epitopes in megalin and RAP were examined to determine whether these epitopes are immunologically distinct or antigenically related. To this end, a polyclonal antibody to megalin was generated that does not recognize RAP by immunoblotting or immunoprecipitation and whether this antibody is capable of inducing passive HN was determined. It was found that antimegalin antibodies devoid of RAP cross-reactivity induced the formation of subepithelial immune deposits (passive HN) when injected into rats. Antibodies eluted from glomeruli of the injected rats recognized only megalin by immunoblotting a cortical extract and did not recognize a RAP fusion protein or any other renal protein. In addition, the eluted antibodies immunoprecipitated two proteolytic fragments of megalin (140 and 75 kd) identifying a pathogenic epitope within a smaller fragment of megalin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2000

The role of Helicobacter pylori and gastritis in children with recurrent abdominal pain.

BACKGROUND: Recurrent abdominal pain is a common pediatric diagnostic problem. Endoscopy is sometimes performed as part of the evaluation. Although gastritis and/or Helicobacter pylori infection is often present, it is not known if they contribute to the symptomatology. OBJECTIVES: To evaluate the role of either gastritis or H. pylori infection in the symptomatology of children with RAP. PATIENTS AND METHODS: We retrospectively studied two groups of patients, 70 children in each, who had undergone endoscopy. One group was evaluated endoscopically for RAP and the other was a heterogeneous group that underwent endoscopy for indications other than RAP. Biopsies were taken during endoscopy and Giemsa staining was performed for the presence of H. pylori. Triple therapy was given as indicated, and the children were followed for an average of 6 months. RESULTS: Microscopic gastritis was diagnosed in 39 patients (55.7%) of the RAP group and in 31 of the heterogeneous group (44.2%) (NS), and H. pylori was found in 32 patients of the RAP group and in 16 of the heterogeneous group (45.7% vs. 22.8%, P < 0.01). All children with H. pylori, except one in the heterogeneous group, had accompanying gastritis. On the other hand, gastritis without H. pylori infection was seen in 7 children in the RAP group and in 15 of the other. Endoscopy revealed macroscopic abnormalities in 52 of the 70 children with microscopic gastritis. There was a clinical improvement after triple therapy in 28 of 33 children with H. pylori-associated gastritis (84.85%), in 4 of 8 children with gastritis unassociated with H. pylori (50%), and in 8 of 15 without gastritis or H. pylori (53.3%) (P < 0.01 between the H. pylori-associated gastritis and each of the other groups). CONCLUSIONS: H. pylori infection and gastritis may be associated with RAP in a selected subgroup of children. We recommend a complete work-up, including endoscopy and invasive or non-invasive diagnostic modalities for H. pylori, and treatment of the infection.

Abdominal Pain↗

PubMed1992

A novel mechanism for controlling the activity of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein. Multiple regulatory sites for 39-kDa receptor-associated protein.

The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha 2MR/LRP) consists of two polypeptides, 515 and 85 kDa, that are noncovalently associated. A 39-kDa polypeptide, termed the receptor-associated protein (RAP), interacts with the 515-kDa subunit after biosynthesis of these molecules and remains associated on the cell surface. This molecule regulates ligand binding of alpha 2MR/LRP (Herz, J., Goldstein, J. L., Strickland, D. K., Ho, Y. K., and Brown, M. S. (1991) J. Biol. Chem. 266, 21232-21238). Titration and binding studies indicate that RAP binds to two equivalent binding sites on alpha 2MR/LRP, with a KD of 14 nM. Heterologous ligand displacement experiments demonstrated that RAP completely inhibits the binding of 125I-activated alpha 2M to human fibroblasts and to the purified alpha 2MR/LRP, with a Ki of 23 and 26 nM, respectively. A direct correlation between the degree of binding of RAP to the receptor and the degree of ligand inhibition was observed, indicating that as the RAP binding sites are saturated, alpha 2MR/LRP loses its ability to bind ligands. Thus, the amount of RAP bound to alpha 2MR/LRP dictates the level of receptor activity. A model is proposed in which alpha 2MR/LRP contains multiple ligand binding sites, each regulated by a separate RAP site.

Base Sequence↗

PubMed1992

Rapamycin and FK506 differentially inhibit mast cell cytokine production and cytokine-induced proliferation and act as reciprocal antagonists.

We have previously demonstrated that cyclosporine (CSA) and FK506 are able to selectively inhibit cytokine production by murine mast cell lines at concentrations comparable to those observed with thymus-derived lymphocytes (T cells). The selectivity of these effects were demonstrated by the failure of CSA and FK506 to inhibit cytokine-induced mast cell proliferation at equivalent or higher concentrations. In this report, we examined the ability of rapamycin (RAP) to inhibit cytokine production and cytokine-induced proliferation by a factor-dependent murine mast cell line and compared its activity to that of the structurally related macrolide FK506. The mast cell clone, MC/9, was stimulated to produce cytokines with phorbol myristate acetate plus the calcium ionophore A23187, or to proliferate in response to exogenous cytokines such as interleukin-3 and interleukin-4, produced by the helper T cell clone D10.G4. RAP did not inhibit cytokine production by MC/9, even at concentrations greater than 1000 nM. FK506 and CSA inhibited cytokine production with IC50 of 0.8 and 16.2 nM, respectively. In contrast to its lack of effect on cytokine production, RAP potently inhibited cytokine-induced proliferation of MC/9 cells with an IC50 of 1.9 nM. Because RAP and FK506 are structurally related and yet have divergent biological effects, we examined the ability of RAP to antagonize inhibitory effects of FK506 on mast cell cytokine production and the ability of FK506 to antagonize inhibitory effects of RAP on cytokine-induced mast cell proliferation. The addition of RAP in molar excess reversed inhibition of mast cell cytokine production mediated by FK506, but not that of CSA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2002

A computational model-based validation of Guyton's analysis of cardiac output and venous return curves.

Guyton developed a popular approach for understanding the factors responsible for cardiac output (CO) regulation in which 1) the heart-lung unit and systemic circulation are independently characterized via CO and venous return (VR) curves, and 2) average CO and right atrial pressure (RAP) of the intact circulation are predicted by graphically intersecting the curves. However, this approach is virtually impossible to verify experimentally. We theoretically evaluated the approach with respect to a nonlinear, computational model of the pulsatile heart and circulation. We developed two sets of open circulation models to generate CO and VR curves, differing by the manner in which average RAP was varied. One set applied constant RAPs, while the other set applied pulsatile RAPs. Accurate prediction of intact, average CO and RAP was achieved only by intersecting the CO and VR curves generated with pulsatile RAPs because of the pulsatility and nonlinearity (e.g., systemic venous collapse) of the intact model. The CO and VR curves generated with pulsatile RAPs were also practically independent. This theoretical study therefore supports the validity of Guyton's graphical analysis.

Atrial Function, Right↗

PubMed1990

Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin.

FK-506 and the structurally related macrolide rapamycin (RAP) were investigated in comparison with cyclosporin A (CsA) for their immunosuppressive effects on murine T cells. All three agents suppressed the proliferation of splenic T cells triggered by lectins or antibodies to CD3 and Ly-6C. FK-506 or CsA also inhibited proliferation, IL-2 production, and IL-2R expression in splenic T cells activated with ionomycin + PMA. However, RAP minimally affected IL-2 production and IL-2R expression in these cells, although it reduced proliferation. Similarly, FK-506 and CsA, but not RAP, suppressed IL-2 production by activated DO.11.10 T hybridoma cells. In such a system, as well as in normal T cells stimulated with high ionomycin concentrations, FK-506 and CsA enhanced proliferation, indicating that they both abrogate negative signals associated with T cell activation. On the contrary, RAP diminished the autonomous proliferation of hybridoma cells, whereas FK-506 and CsA had little effect. The proliferative response induced in D10.G4 cells by IL-1 + ionomycin but not that induced by IL-1 + PMA was sensitive to inhibition by FK-506 and CsA. In contrast, RAP inhibited equally well both types of stimulation. Finally, T cell proliferation driven by IL-2 or IL-4 was found to be relatively resistant to FK-506 or CsA but sensitive to RAP. Altogether, these data demonstrate that FK-506 and CsA alter similar calcium-associated events of T cell activation and block T cell proliferation primarily by suppressing lymphokine production. RAP interferes with a different set of events and inhibits T cells by impairing their response to growth-promoting lymphokines.

Animals↗

PubMed1995

Rapamycin inhibits ribosomal protein synthesis and induces G1 prolongation in mitogen-activated T lymphocytes.

We investigated the effects of rapamycin (RAP) on cell cycle progression and protein synthesis in mitogen-activated primary T lymphocytes. Stimulation of resting human T lymphocytes with phorbol ester and calcium ionophore rendered cells capable of initiating DNA synthesis within 30 h; roughly 60% of the cells entered the first G2/M phase of the cell cycle within 96 h. Addition of RAP delayed the entry into S phase by 9 h, although a similar percentage (approximately 50%) of cells entered the first G2/M phase and proliferated. On this basis, we concluded that RAP primarily induced a G1 prolongation without blocking cell cycle progression. Addition of the co-mitogens to resting T lymphocytes up-regulated the translation of ribosomal protein mRNA concurrent with activation of p70s6k. RAP inhibited this translational up-regulation of ribosomal protein mRNA as well as the activation of p70s6k without affecting translation of nonribosomal protein mRNA. RAP also prevented the synthesis and accumulation of ribosomal proteins. Further, this failure to increase ribosomal proteins, which probably reflects the failure to increase numbers of ribosomes, resulted in suppression of the synthesis of total cellular protein and a delay in the escalation of cell size. RAP-treated cells eventually initiated DNA synthesis when cell size became equivalent to that of the control cells entering S phase of the cell cycle. Thus, inhibition of protein synthesis caused by the primary inhibition of ribosomal protein mRNA translation probably explains the effect of RAP on cell cycle progression of mitogen-activated resting T lymphocytes.

Amino Acid Sequence↗

PubMed1995

Helicobacter pylori infection in recurrent abdominal pain in childhood: comparison of diagnostic tests and therapy.

OBJECTIVE: To determine the role of Helicobacter pylori infection in children with recurrent abdominal pain and the usefulness of serologic tests in screening H pylori infection and monitoring treatment of H pylori-associated gastritis. METHODS: During a 3 year period, we investigated the presence of serum immunoglobulin G (IgG) antibody to H pylori in 456 children using the high-molecular-weight cell-associated protein H pylori enzyme immunoassay kit. Among the 456 children studied, 218 (age range, 3 to 18 years; mean age, 9.5 years) had symptoms of recurrent abdominal pain (RAP syndrome) with or without vomiting, and the remaining 238 (age range, 3 to 18 years; mean age, 9.8 years) had no RAP (non-RAP syndrome). We performed upper gastrointestinal endoscopy on 111 consecutive children of the 218 with RAP syndrome and obtained mucosal biopsies for culture, histologic analysis, CLO test (Delta West, Perth, Australia), and H pylori detection by polymerase chain reaction. RESULTS: Thirty-eight (17.4%) of 218 children in the RAP group and 25 (10.5%) of 238 children in the non-RAP group were seropositive for H pylori. Of the 111 children endoscoped, 95 were found to be negative, and 12 were positive by all five assays. Specimens from 2 children were negative by culture and the CLO test but positive by the other three assays. Specimens from 1 child were negative by histologic analysis but positive by all other tests. The remaining child was positive for anti-H pylori IgG but negative by all of the other four assays. Upper gastrointestinal endoscopy detected 14 children with peptic ulcer disease (9 duodenal ulcer and 5 gastric ulcer) and 12 with antral nodular gastritis. Only 4 of the 14 diagnosed with peptic ulcer were H pylori positive by all five assays, whereas all 12 children with antral nodular gastritis were H pylori positive. Nine of the 12 H pylori-positive children were treated with a combination of bismuth subsalicylate, amoxicillin, and metronidazole for 2 weeks. Sera obtained at 2, 4, and 6 months after treatment from all 9 children showed a decrease in anti-H pylori IgG titer. Three H pylori-infected children who did not receive any treatment served as control children, and their IgG levels remained elevated or increased over time. CONCLUSION: The results from our study indicate that screening for the serum IgG antibody to H pylori is a practical method for diagnosing H pylori infection in children, and that serial measurements of the H pylori IgG antibody are useful for monitoring treatment of H pylori because of its high sensitivity and ease of performance. Only 4 of the 14 children diagnosed with peptic ulcer disease were confirmed to be infected with H pylori, whereas all 12 children with antral nodular gastritis were found to be infected by H pylori. These observations suggest that H pylori infection is more frequently associated with gastritis than with peptic ulcer disease in children, and that H pylori gastritis is a cause of RAP syndrome in children.

Abdominal Pain↗