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PubMed2026

Relationship Between Number of Acute Pancreatitis Episodes and Risk of New-onset Diabetes in the U.S.: A Real-world Data Analysis.

INTRODUCTION: Acute pancreatitis (AP) is a common inflammatory disorder that is associated with increased risk for diabetes mellitus (DM). It remains unclear whether recurrent acute pancreatitis (RAP) is associated with further increased risk of incident DM. This study aims to investigate the association between RAP and incident DM using real-world data. METHODS: We conducted a retrospective cohort study using the MerativeTM MarketScan® claims database (2016-2023), identifying patients with AP and no prior history of DM at baseline. The primary exposure of interest, RAP, was defined as one or more episodes of AP occurring ≥90 days after the index AP diagnosis, whereas one episode of AP referred to a single episode of AP (SAP) with no subsequent recurrence within 90 days following the index event. A multivariable stratified Cox proportional hazards regression models were used to determine the association between RAP and incident DM, identified using ICD-10 codes. RESULTS: In total, 16,184 individuals with AP (mean [SD] age: 45.8 [12.3]) contributed 40,712 person-years of follow-up, during which 1,477 incident cases of DM were documented. Individuals with RAP had an increased risk of incident DM compared with those with a SAP(adjusted HR, 1.92; 95% CI, 1.61-2.29). The risk increased significantly with the frequency of RAP. In comparing the modifying effect of patient demographics and comorbidities, a stronger association between RAP and incident DM was observed in females (adjusted HR, 2.44; 95% CI, 1.87-3.19) than in males (adjusted HR, 1.64; 95% CI, 1.30-2.07; Pinteraction=0.03). Also, stronger associations were observed among younger patients (18-46 y) (adjusted HR=2.56; 95% CI, 1.97-3.31) and among non-tobacco abuse (adjusted HR=2.19; 95% CI, 1.81-2.65), with significant interactions for all comparisons (Pinteraction<0.05. CONCLUSIONS: In this real-world study, RAP was associated with an increased risk of incident DM. Our findings highlight an opportunity for glycemic monitoring and proactive management of patients with RAP to mitigate their risk of developing DM.

AP↗

PubMed2006

A prospective study for the association of Helicobacter pylori infection to a multidimensional measure for recurrent abdominal pain in children.

BACKGROUND: There is a controversial association between Helicobacter pylori infection and recurrent abdominal pain (RAP) in childhood and inconsistent information on specific symptomatology of the infection. AIMS: To examine the prevalence of H. pylori infection among children with RAP compared to asymptomatic children. METHODS: Two prospective studies were conducted. The first study enrolled 223 children diagnosed with RAP from two pediatric gastroenterology clinics in Houston, Texas. Children were qualified if they were identified by their physician as having RAP. A new multidimensional measure for RAP (MM-RAP) consisting of four scales (pain intensity scale, symptoms scale, disability scale, and satisfaction scale) was administered to each child/parent. The second study enrolled 330 asymptomatic children from the same community who did not have any upper gastrointestinal symptoms. Symptomatic and asymptomatic children underwent (13)C-urea breath testing. RESULTS: In the first study, the prevalence of H. pylori in children with RAP was 11% and fell with age from 20% at age < or = 5 years to 7% for children > 10 years (OR = 2.7, 95% CI = 0.7-11.2). There was no association between the mother's educational level and H. pylori prevalence; (12% among children whose mothers completed college versus 11% among those who had elementary school, p = .8). No relationship was found between H. pylori and mean scores of the RAP scales. In the second study, the prevalence of H. pylori in asymptomatic children was 17% and increased with age from 11% for children < or = 5 years to 40% for children > 10 years (OR = 5.4, 95% CI = 2.0-13.8). The mother's educational level was inversely correlated with H. pylori (OR = 3.0, 95% CI = 2.2-6.1, p < .01). CONCLUSIONS: The epidemiologic patterns of H. pylori infection differed significantly between symptomatic and asymptomatic children. Younger children suffering from RAP are more likely to be infected with H. pylori than older children with the same complaint, suggesting that early acquisition may manifest in symptoms that lead to clinic visits.

Abdominal Pain↗

PubMed2002

Dominance of pressure natriuresis in acute depressor responses to increased renal artery pressure in rabbits and rats.

Increasing renal artery pressure (RAP) activates pressure diuresis/natriuresis and inhibits renal renin release. There is also evidence that increasing RAP stimulates release of a putative depressor hormone from the renal medulla, although this hypothesis remains controversial. We examined the relative roles of these antihypertensive mechanisms in the acute depressor responses to increased RAP in anaesthetized rabbits and rats. In rabbits, an extracorporeal circuit was established which allows RAP to be set and controlled without direct effects on systemic haemodynamics. When RAP was maintained at approximately 65 mmHg, cardiac output (CO) and mean arterial pressure (MAP) did not change significantly. In contrast, when RAP was increased to approximately 160 mmHg, CO and MAP fell 20 +/- 5 % and 36 +/- 5 %, respectively, over 30 min. Urine flow also increased more than 28-fold when RAP was increased. When compound sodium lactate was infused intravenously at a rate equal to urine flow, neither CO nor MAP fell significantly in response to increased RAP. In 1 kidney-1 clip hypertensive rats, MAP fell by 54 +/- 10 mmHg over a 2 h period after unclipping. In rats in which isotonic NaCl was administered intravenously at a rate equal to urine flow, MAP did not change significantly after unclipping (-14 +/- 9 mmHg). Our results suggest that the depressor responses to increasing RAP in these experimental models are chiefly attributable to hypovolaemia secondary to pressure diuresis/natruresis. These models therefore appear not to be bioassays for release of a putative renal medullary depressor hormone.

Animals↗

PubMed1997

Assessment of the humoral immune response against Plasmodium falciparum rhoptry-associated proteins 1 and 2.

Naturally occurring antibody responses to Plasmodium falciparum rhoptry-associated proteins 1 and 2 (RAP-1 and RAP-2) were measured with recombinant and parasite-derived forms of the antigens. For comparative purposes, responses to multiple forms of three other malarial antigens were also examined. The sera of 100 Papua New Guineans were screened for antibodies. Eighty-six and 82% of individuals over 30 years of age had antibodies that recognized parasite-derived RAP-1 and RAP-2, respectively. Importantly, we found that recombinant and native antigens share linear epitopes seen by the human immune system; thus, the recombinant proteins may be adequate human immunogens. However, antibodies affinity purified on recombinant RAP-1 reacted with other antigens in addition to parasite-derived RAP-1. Thus, the antigenicity of RAP-1 may have been overestimated previously. The recognition of RAP-1 and RAP-2 correlated with age and with the recognition of recombinant forms of the ring-infected erythrocyte surface antigen, merozoite surface protein 1, and merozoite surface antigen 2 (MSA2) antigens. Antibodies to these antigens appear to be generated in response to the total exposure to malaria of the host. Antibodies to conserved regions of MSA2 had stronger correlations with both age and the recognition of other antigens than did the full-length recombinant MSA2 molecule. In contrast to results with the other antigens, there was no significant difference in the ages of individuals with a certain antibody titer to the full-length recombinant or parasite-derived MSA2 molecule, but antibodies to these two antigens did correlate with parasitemia. For all antigens tested, antibody levels after two infections can approach the peak levels of antibodies obtained in immune individuals.

Adolescent↗

PubMed1998

Muscle chemoreflex-induced increases in right atrial pressure.

When oxygen delivery to active muscle is too low for the ongoing rate of metabolism, metabolites accumulate and stimulate sensory nerves within the muscle leading to sympathetic activation (muscle chemoreflex). To date, studies on this reflex have focused primarily on its ability to increase arterial pressure or on the activity of the nerves that mediate this response. Clearly, a rise in cardiac output (CO) constitutes an important adjustment, because it increases the total blood flow available to be distributed among organs competing for flow. However, increments in heart rate and contractility provide limited means of raising CO because of the inverse relationship that exists between CO and right atrial pressure (RAP) in the intact circulation. Our goal was to test whether muscle chemoreflex activation, achieved via graded reductions in hindlimb blood flow by partial vascular occlusion, elicits peripheral vascular adjustments that raise RAP. In four conscious dogs exercising on a treadmill at 3.2 km/h 0% grade, RAP was well maintained during reflex activation despite increases in CO and arterial pressure that are expected to reduce RAP. Thus peripheral vascular adjustments elicited by the reflex successfully defend RAP in a setting where it would otherwise fall. To isolate the effects of the reflex on RAP, CO was maintained constant by ventricular pacing in conjunction with beta1-adrenergic blockade with atenolol. When the reflex was activated by reducing hindlimb blood flow from 0.6 to 0.3 l/min, RAP rose from 5.1 +/- 0.8 to 7.4 +/- 0.4 mmHg (P < 0.05) despite continued large (40 mmHg) increases in arterial pressure. During heavier exercise (6.4 km/h 10% grade) in five dogs with normal ventricular function, the reflex raised RAP from 5.7 +/- 0.9 to 6.6 +/- 0.8 mmHg (P < 0.05) despite increases in CO and arterial pressure. We conclude that the muscle chemoreflex is capable of eliciting substantial increases in RAP.

Animals↗

PubMed1985

Maintenance of renal autoregulation during infusion of aminophylline or adenosine.

Adenosine has been postulated to link control of glomerular filtration rate (GFR) and renal blood flow (RBF) with changes in renal metabolism. In the present study, we examined the role of adenosine in renal autoregulation by comparing the responses of normal anesthetized dogs to step decreases in renal artery pressure (RAP) to the response obtained after receptor blockade of adenosine with aminophylline or by flooding the kidney with exogenous adenosine. In six dogs at normal RAP, intrarenal infusion of aminophylline (10 mumol/min) did not alter renal hemodynamics. GFR and RBF were well autoregulated (greater than 90% of control) at RAP values equal to or greater than 85 mmHg before and after aminophylline. At RAP equal to 75 mmHg, GFR and RBF decreased by 27 +/- 10 and 20 +/- 8%, respectively, before aminophylline and by 25 +/- 7 and 13 +/- 6% after aminophylline. In a different group of six dogs, intrarenal infusion of adenosine (6 mumol/min) significantly increased RBF (32 +/- 9%) and decreased GFR (38 +/- 10%) at normal RAP. However, GFR and RBF were both well autoregulated (greater than 90% of control) at RAP values equal to or greater than 85 mmHg before and after adenosine. At RAP equal to 75 mmHg, GFR and RBF decreased by 10 +/- 5 and 7 +/- 3%, respectively, before adenosine and by 12 +/- 6 and 17 +/- 5% after adenosine. Neither aminophylline nor adenosine attenuated the elevations in plasma renin activity associated with reductions in RAP. These data fail to provide evidence that adenosine is an important factor in autoregulation of GFR and RBF during acute reductions in RAP within the autoregulatory range.

Adenosine↗

PubMed1985

Mechanisms of angiotensin II natriuresis and antinatriuresis.

The aim of this study was to determine the role of changes in renal arterial pressure (RAP), renal hemodynamics, and tubular reabsorption in mediating the natriuretic and antinatriuretic actions of angiotensin II (ANG II). In seven anesthetized dogs, endogenous ANG II formation was blocked with captopril, and ANG II was infused intravenously at rates of 5-1,215 ng X kg-1 X min-1 while RAP was either servo-controlled at the preinfusion level or permitted to increase. When RAP was servo-controlled, ANG II infusion at all rates from 5-1,215 ng X kg-1 X min-1 decreased urinary sodium excretion (UNaV) and fractional sodium excretion (FENa) while increasing fractional reabsorption of lithium (FRLi) (an index of proximal tubular fractional sodium reabsorption) and causing no change in calculated distal tubule fractional sodium reabsorption (FRDNa). When RAP was permitted to increase, ANG II infusion rates up to 45 ng X kg-1. min-1 also decreased UNaV and FENa while increasing FRLi and causing no change in FRDNa. However, at 135 ng X kg-1 X min-1 and above, UNaV and FENa increased while FRLi and FRDNa decreased when RAP was allowed to rise, even though renal blood flow and filtration fraction were not substantially different from the values observed when RAP was servo-controlled. Filtered sodium load was slightly higher when RAP was permitted to increase during ANG II infusion compared with when RAP was servo-controlled, although the differences were not statistically significant. Thus, even very large doses of ANG II cause antinatriuresis when RAP is prevented from increasing.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1997

Flow versus pressure in the control of renin release in conscious dogs.

In Goldblatt hypertension, renal artery stenosis reduces renal arterial pressure (RAP) and renal blood flow (RBF) and thereby increases plasma renin activity (PRA) levels. Although it is clear that reduction in RAP stimulates renin, the decrease in RBF may contribute to higher PRA as well. However, it has hitherto never been possible to dissociate a decrease in RBF from a concomitant decrease in RAP. To overcome this restriction, we used two protocols. 1) RAP was reduced in a single step to 70 +/- 0.2 mmHg (N = 8). RBF followed the sudden fall in RAP within 15 s but subsequently took on initial levels. In contrast, renal venous PRA increased from 0.95 +/- 0.22 to 5.6 +/- 1.4 ng angiotensin I.ml-1.h-1 (P < 0.05) and remained at higher values even after RBF had regained control conditions. 2) Resonance between RAP and RBF was induced by superimposing slow sinusoidal RAP waves with a period length of 450 s (N = 9), leading to a phase shift of roughly 180 degrees (time delay, 241 +/- 12 s), i.e., RBF was maximal at minimal RAP. Under these conditions, renin release was only dependent on decrements in RAP (delay of only 27 +/- 8 s). In conclusion, RBF played no major role in renin release.

Animals↗

PubMed1996

Relation of mean right atrial pressure to echocardiographic and Doppler parameters of right atrial and right ventricular function.

BACKGROUND: A paucity of data exists as to the relation of mean right atrial pressure (RAP) to Doppler parameters of right atrial and ventricular filling. Furthermore, whether echocardiographic parameters of right atrial and right ventricular function and inferior vena cava improve the relation of Doppler filling dynamics with RAP has not been explored. METHODS AND RESULTS: Doppler and echocardiographic studies were performed simultaneously with measurements of mean RAP in consecutive patients who either had a central venous catheter in the Intensive Care Unit or underwent catheterization of the right side of the heart. The initial population consisted of 35 patients with a mean age (+/-SD) of 60+/-15 years; 34% were on mechanical ventilation. Mean RAP averaged 9+/-5.7 mm Hg (range, 2 to 28 mm Hg). Among tricuspid inflow parameters, the strongest relation with RAP was observed with the ratio of early to late velocity (r=.66). For hepatic venous flow, systolic filling wave indexes had the best relation with atrial pressure, the highest being for systolic filling fraction (r=-.86). Weaker relations were noted with the use of right atrial volumes, right ventricular function, and inferior vena caval diameters. The addition of any of these variables did not improve the relation of systolic filling fraction with RAP. The regression equation (RAP=21.6-24 systolic filling fraction) was tested prospectively in the estimation of atrial pressure 50 patients. The correlation coefficient was .89 in the prospective group and .88 in the total group of 85 patients. The mean difference between predicted and actual pressures in the whole population was -0.2+/-2.6 mm Hg. The sensitivity and specificity for mean RAP>8 mm Hg were 86% and 92%, respectively. CONCLUSIONS: Among echocardiographic and Doppler parameters of right atrial and right ventricular function, hepatic venous flow dynamics relate best to mean atrial pressure and can be used clinically to estimate mean RAP.

Adult↗

PubMed2001

Effects of rapid atrial pacing on the arrhythmogenic activity of single cardiomyocytes from pulmonary veins: implication in initiation of atrial fibrillation.

BACKGROUND: Pulmonary veins (PVs) are important sources of paroxysmal atrial fibrillation. Long-term rapid atrial pacing (RAP) changes atrial electrophysiology and facilitates the maintenance of atrial fibrillation. It is not clear whether RAP alters the arrhythmogenic activity of PVs. The purpose of this study was to isolate single PV cardiomyocytes from control and RAP dogs and evaluate their electrophysiological characteristics. METHODS AND RESULTS: The action potential and ionic currents were investigated in PV cardiomyocytes from control and long-term (6 to 8 weeks) RAP (780 bpm) dogs by use of the whole-cell clamp technique. Dissociation of PVs yielded rod-shaped single cardiomyocytes without (n=91, 60%) or with (n=60, 40%) pacemaker activity. Compared with the control group, the RAP dog PV cardiomyocytes had faster beating rates (0.86+/-0.28 versus 0.45+/-0.07 Hz, P<0.05) and shorter action potential duration. The RAP dog PV cardiomyocytes with pacemaker activity have a higher incidence of delayed (59% versus 7%, P<0.001) or early (24% versus 0%, P<0.005) after depolarization. The RAP dog PV cardiomyocytes with pacemaker activity had smaller slow inward and transient outward but larger transient inward (0.017+/-0.004 versus 0.009+/-0.002 pA/pF, P<0.05) and pacemaker (0.111+/-0.019 versus 0.028+/-0.008 pA/pF, P<0.001) currents. The RAP dog PV cardiomyocytes without pacemaker activity had only smaller slow inward and transient outward and larger pacemaker currents. CONCLUSIONS: PVs contain multiple cardiomyocytes with distinct electrophysiological characteristics. RAP changes the electrophysiological characteristics and arrhythmogenic activity of PVs.

Action Potentials↗

PubMed2005

Effective therapy of human lymphoma xenografts with a novel recombinant ribonuclease/anti-CD74 humanized IgG4 antibody immunotoxin.

Ranpirnase (Rap) is a cytotoxic ribonuclease (RNase) isolated from frog oocytes. Here we describe high antitumor activity of a novel immunotoxin, 2L-Rap-hLL1-gamma4P, composed of 2 Rap molecules, each fused to the N terminus of the light chain of hLL1, an internalizing anti-CD74 humanized antibody. To reduce unwanted side effects, the constant region of hLL1 was changed from gamma1 to gamma4 and further to gamma4P by replacing serine228 to proline to prevent the formation of a half immunoglobulin G (IgG) common for IgG4. In vitro, 2L-Rap-hLL1-gamma4P retained RNase activity, specific binding to CD74, and was significantly more potent against CD74+ cell lines (Daudi, Raji, and MC/CAR) than naked hLL1. In vivo, the pharmacokinetic profile of 2L-Rap-hLL1-gamma4P was similar to that of naked hLL1. The maximum tolerated dose of 2L-Rap-hLL1-gamma4P in severe combined immunodeficient mice (SCID) or BALB/c mice was 50 microg per mouse. In Raji and Daudi Burkitt lymphoma xenograft models, treatment with a single 5 to 50 microg dose of 2L-Rap-hLL1-gamma4P, given as early or delayed treatment, resulted in cures of most animals. Treatment with 2L-Rap-hLL1-gamma4P was significantly better than all controls, including saline, naked hLL1, and nonspecific immunotoxin. In conclusion, 2L-Rap-hLL1-gamma4P demonstrated excellent in vitro and in vivo efficacy and thus merits further consideration as a therapeutic for CD74+ tumors.

Animals↗

PubMed2004

The failure of retrograde autologous priming of the cardiopulmonary bypass circuit to reduce blood use after cardiac surgical procedures.

UNLABELLED: Hemodilution during cardiopulmonary bypass (CPB) is a primary risk factor for blood transfusion in cardiac surgical patients. Priming of the CPB circuit with the patients' own blood (retrograde autologous priming, RAP) is a technique used to limit hemodilution and reduce transfusion requirements. We designed this study to examine the impact of RAP on perioperative blood product use. Using a retrospective cohort study design, the medical records of all patients undergoing CPB (excluding circulatory arrest cases) by a single surgeon were examined. Data were collected over a 24-mo period when RAP was routinely used as a blood conservation strategy (RAP group, n = 257). This group was compared with a cohort of patients during the 24 mo immediately preceding the introduction of RAP into clinical practice (no RAP group, n = 288). A small, statistically insignificant reduction in the percentage of patients receiving packed red blood cells was observed in the RAP group (44% versus 51% no RAP, P = 0.083). No differences were found between the groups in the number of units of packed red blood cells, platelets, or fresh frozen plasma transfused throughout the perioperative period. These results suggest that overall, RAP does not offer a clinically important benefit as a blood conservation technique. IMPLICATIONS: Priming of the cardiopulmonary bypass circuit with the patients' own blood (retrograde autologous priming) resulted in insignificant reductions in blood use in a large, unselected group of patients undergoing cardiac surgical procedures.

Adult↗

PubMed1995

The expression of megalin (gp330) and LRP diverges during F9 cell differentiation.

The receptor-associated protein, RAP, is a chaperonin-like molecule that binds to two members of the low density lipoprotein receptor (LDLR) superfamily-megalin (gp330) and the LDL receptor-related protein (LRP). In F9 embryonal carcinoma cells, expression of RAP mRNA increases when differentiation is induced with retinoic acid and dibutyryl-cyclic AMP. We have investigated the expression of megalin and LRP and their interaction with RAP in F9 cells using biochemical and immunocytochemical methods. Both receptors are expressed in uninduced F9 cells, but only megalin co-precipitates with RAP. When F9 cells were induced to differentiate into parietal endoderm, the expression of megalin was dramatically increased. The expression of megalin exceeded that of LRP and RAP by an order of magnitude and both receptors co-precipitated with RAP. By immunoelectron microscopy, megalin and LRP were localized to clathrin-coated pits at the cell surface in both undifferentiated and differentiated F9 cells, whereas RAP was found mainly in the ER. A sizeable pool of LRP was also detected in the ER. When F9 cells were grown in suspension in the presence of RA and induced to develop into embryoid bodies, the expression of megalin and LRP segregated into different cell types: megalin was found in the outer epithelial layer and LRP in the stem cells of the inner core. Our results demonstrate that F9 cells induced to differentiate in monolayer culture express megalin, LRP and RAP, and RAP is capable of interacting simultaneously with both receptors. In embryoid bodies the expression of megalin and LRP diverges, and only megalin is expressed in the outer epithelial layer.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1992

The effects of phentolamine and nitroglycerin on right-sided hemodynamics in cardiac patients can be explained by a shift of the systemic venous return curve and right-ventricular output curve.

The present study investigated the effects of phentolamine (PH) and nitroglycerin (NG) on the hemodynamics of the right heart in patients with cardiac disease. The patients were divided into a well-functioning left heart group (W group, n = 15) and a poorly-functioning left heart group (P group, n = 15). Right cardiac hemodynamic parameters and plasma noradrenaline (NA) and adrenaline (A) concentrations were measured before and after administering PH (0.1 mg/kg, i.v.) or NG (0.6 mg, sublingual). In a parallel animal study we obtained a systemic venous return curve by measuring mean circulatory pressure (MCP), mean right atrial pressure (RAP) and cardiac output, before and after administering PH (0.1 mg/kg, i.v.) or NG (12.5 micrograms/kg, i.v.) to anesthetized open-chest dogs (n = 14). We used MCP data (W group: 7.5 mmHg, P group: 10 mmHg) obtained in a separate series of human studies in our laboratory. We constructed the venous return curve by connecting the MCP point on abscissa with the cardiac index (CI)-RAP plot obtained in the clinical study. We also constructed the right ventricular output curve by connecting the point of -2 mmHg on the abscissa with the CI-RAP plot. We obtained the following results: (1) PH shifted the CI-RAP plot to the left and upwards, while NG shifted the CI-RAP plot to the left almost horizontally on the CI-RAP plane, where CI was plotted on ordinate and RAP on abscissa. The length [formula: see text] C = control point, PH = point after PH) of the shift of CI-RAP plot due to PH was greater in the P group than in W group, while there was no difference in the length [formula: see text] C = control point, NG = point after NG) of the shift of CI-RAP plot due to NG between P and W groups. (2) Both PH and NG significantly elevated plasma NA and A concentrations in both the W and P groups. In the P group, PH increased the plasma NA concentration significantly more than did NG, but both drugs increased plasma A concentration to a similar extent. (3) Both PH and NG significantly decreased the mean pulmonary arterial pressure with NG doing so significantly more than PH.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic alpha-Antagonists↗

PubMed2006

[Effect of rapamycin and dexamethasone on differentiation and maturation of murine bone marrow-derived dendritic cells].

AIM: To observe the effect of rapamycin (Rap) and dexamethasone (Dex) on differentiation and development of murine bone marrow-derived dendritic cells (DC) in vitro. METHODS: DC cells generated from C57BL/6 murine bone marrow cells were induced by GM-CSF and IL-4. During the course, Rap or Dex was added to the culture and the cells were then stimulated by LPS. (1)Morphology development of DCs was observed by inverted microscope and scanning electron microscope.(2)The cells were analyzed by flow cytometry (FCM) to determine the proportion of CD11c(+) cells and the change of CD86 and MHC class II molecule.(3)The influence of DCs treated by Rap or Dex on the allogeneic T cell proliferation was studied by one-way MLR. RESULTS: (1)The morphology of DCs maintained in a durable state of immaturity after Rap or Dex pretreatment.(2)The expression of CD11c and MHC-II slightly decreased but CD86 dramatically reduced on Rap-treated DC cells. There was close relationship between the expression of CD11c on Dex-treated cells and the dosage of Dex. The surface expression of CD86 and MHC-II dramatically reduced on Dex-treated DCs. Moreover, DCs treated by Rap or Dex were both able to resist the maturation triggered by LPS.(3)Bone marrow-derived DCs cultured with Dex or Rap had a lower stimulatory effect on allogeneic T cells compared with that of mature DCs. CONCLUSION: Rap and Dex could keep DCs in durable immaturity. Compared with Dex, which inhibited the expression of co-stimulatory molecules, Rap hardly influenced the differentiation of DCs and the expression of MHC class II molecules.

Animals↗

PubMed1997

Mutational analysis of the role of Rap1 in regulating cytoskeletal function in Dictyostelium.

It was shown previously that increased expression of the ras-related rap1 gene in Dictyostelium discoideum altered cell morphology (Rebstein et al., Dev. Genet., 1993, 14, 347-355). Vegetative Rap1 transformants were more flattened and spread than parental Ax2 cells and had increased F-actin near the cell periphery. In addition, Rap1 cells were inhibited in the rapid cell contraction that occurs upon refeeding with nutrient media. In this communication, we show that expression of Rap also markedly reduces the contraction response that occurs upon addition of azide to vegetative cells. The changes in cell morphology, the refeeding contraction response, and the azide contraction response have been used to analyze mutants of Rap1 generated by site-directed mutagenesis. The substitution G12V, predicted to increase the proportion of protein binding GTP, did not alter the effect of Rap on cell morphology or on its ability to inhibit the contraction response to azide, but modestly enhanced the ability of Rap1 to inhibit cell rounding in response to nutrient media. The substitution S17N, predicted to restrict the protein to the GDP-bound state, did not produce the flattened cell morphology and abolished the inhibitory effects of Rap in the two cell contraction assays. These results are consistent with a requirement of GTP binding for the Rap-induced effects. Transformants carrying the Rap-S17N protein had a more polar morphology than the parental Ax2 cells, suggesting the possibility that Rap-S17N interferes with the ability of endogenous Rap to regulate the cytoskeleton. Substitutions at amino acid 38, within the presumptive effector domain, reduced but did not abolish the effects of Rap1 on cell contraction, while the substitution T61Q had no effect on Rap1 activity. Taken together, the results suggest that Rap may have multiple regulatory effects on cytoskeletal function.

Animals↗

PubMed1991

Heterogeneous amino acids in Ras and Rap1A specifying sensitivity to GAP proteins.

Guanosine triphosphatase (GTPase) activity of Ras is increased by interaction with Ras-GAP (GTPase-activating protein) or with the GAP-related domain of the type 1 neurofibromatosis protein (NF1-GRD), but Ras is not affected by interaction with cytoplasmic and membrane forms of Rap-GAP; Rap1A, whose effector function can suppress transformation by Ras, is sensitive to both forms of Rap-GAP and resistant to Ras-GAP and NF1-GRD. A series of chimeric proteins composed of portions of Ras and Rap were constructed; some were sensitive to Ras-GAP but resistant to NF1-GRD, and others were sensitive to cytoplasmic Rap-GAP but resistant to membrane Rap-GAP. Sensitivity of chimeras to Ras-GAP and cytoplasmic Rap-GAP was mediated by amino acids that are carboxyl-terminal to the effector region. Residues 61 to 65 of Ras conferred Ras-GAP sensitivity, but a larger number of Rap1A residues were required for sensitivity to cytoplasmic Rap-GAP. Chimeras carrying the Ras effector region that were sensitive only to Ras-GAP or only to cytoplasmic Rap-GAP transformed NIH 3T3 cells poorly. Thus, distinct amino acids of Ras and Rap1A mediate sensitivity to each of the proteins with GAP activity, and transforming potential of Ras and sensitivity of Ras to Ras-GAP are at least partially independent properties.

Cell Membrane↗

PubMed2005

Treatment of retinal angiomatous proliferation in age-related macular degeneration: a series of 104 cases of retinal angiomatous proliferation.

OBJECTIVE: To report the management of retinal angiomatous proliferation (RAP), a recently described intraretinal neovascular lesion occurring in age-related macular degeneration. METHODS: This was a retrospective review of consecutive patients with age-related macular degeneration who underwent treatment of RAP from January 1, 2000, through January 31, 2003. Inclusion criteria were age 55 years or older, signs of age-related macular degeneration, and diagnosis of RAP based on dynamic indocyanine green angiography. Baseline angiograms were reviewed and RAP was classified into the following 3 stages: stage 1, intraretinal neovascularization, early stage; stage 2, subretinal neovascularization, middle stage; and stage 3, choroidal neovascularization, late stage. Treatment and concomitant treatment results were assessed separately for each RAP stage. The clinical data were statistically analyzed (chi2 test and analysis of variance) for 2 main outcome measures--complete obliteration of the lesion and final visual acuity. RESULTS: Eighty-one patients (99 eyes) with 104 RAPs were identified. Forty-two lesions were at stage 1, 42 at stage 2, and 20 at stage 3. The following 5 treatments were performed: direct laser photocoagulation of the vascular lesion, laser photocoagulation of the feeder retinal arteriole, scatter "gridlike" laser photocoagulation, photodynamic therapy, and transpupillary thermotherapy. Complete obliteration of RAP was achieved in about 24 (57.1%) of the stage 1 lesions (direct laser photocoagulation of the vascular lesion, 73% success rate; photodynamic therapy, 45%), 11 (26.2%) of the stage 2 lesions (scatter gridlike laser photocoagulation, 38% success rate; direct laser photocoagulation of the vascular lesion, 17%), and only 3 (15.0%) of stage 3 lesions (P = .001). Predictive factors with a significant effect on final visual acuity were initial visual acuity (P = .003) and early lesion stage (P = .04). Best final visual acuity was 0.41 (mean, direct laser photocoagulation of the vascular lesion in stage 1) and 0.39 (mean, photodynamic therapy in stage 1), with a mean decrease of 2.5 and 3 lines from baseline, respectively. CONCLUSIONS: Treatment of RAP remains difficult. Early detection of the lesion and subsequent direct conventional laser photocoagulation seems to be associated with better anatomical and functional outcome. Once the vascular complex is well established, anatomical closure is rarely achieved. Further study is warranted to assess the long-term efficacy and the need for re-treatment.

Aged↗