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Rapamycin inhibition of interleukin-2-dependent p33cdk2 and p34cdc2 kinase activation in T lymphocytes.

The immunosuppressant rapamycin (RAP) is a potent inhibitor of the entry of interleukin (IL)-2-stimulated T cells into S-phase. Earlier results indicated that RAP treatment arrested the growth of the murine IL-2-dependent T cell line CTLL-2 in late G1-phase. To explore further the interactions of RAP with the cell cycle control machinery in T cells, we examined the effects of RAP treatment on the activation of the cyclin-dependent kinases p34cdc2 and p33cdk2 in G1-phase CTLL-2 cells. Stimulation of factor-deprived cells with IL-2 led to the assembly of high molecular weight complexes containing active p34cdc2 and p33cdk2. The appearance of these complexes was explained, at least in part, by the association of both cyclin-dependent kinases with IL-2-induced cyclin A. RAP treatment profoundly inhibited both cyclin A expression and the appearance of active cyclin A-cyclin-dependent kinase complexes in IL-2-stimulated, late G1-phase CTLL-2 cells. Although p34cdc2 activation was largely dependent on association with cyclin A, a significant proportion of the active p33cdk2 pool was complexed with cyclin E. In contrast to cyclin A, the IL-2-induced accumulation of cyclin E in G1-phase cells was only partially suppressed by RAP, and cyclin E-p33cdk2 complexes were readily detected in drug-treated cells. These cyclin E-cyclin-dependent kinase complexes were nonetheless devoid of histone H1 kinase activity. The inhibitory effects of RAP on the activation of cyclin E- and cyclin A-associated cyclin-dependent kinases suggest that one or both events participate in the regulation of T cell entry into S-phase.

Amino Acid Sequence↗

Rapamycin-induced inhibition of p34cdc2 kinase activation is associated with G1/S-phase growth arrest in T lymphocytes.

The macrolide rapamycin (RAP) is a potent inhibitor of interleukin-2 (IL-2)-induced T-cell proliferation. Current models suggest that RAP, when complexed to its intracellular receptor, FK506-binding protein, interferes with an IL-2 receptor-coupled signaling pathway required for cell-cycle progression from G1- to S-phase. Here we show that RAP treatment inhibits the growth of an IL-2-dependent cytotoxic T-cell line, CTLL-2, in late G1-phase, just prior to entry of the cells into S-phase. In contrast, RAP-treated CTLL-2 cells retained the ability to respond to IL-2 with enhanced cytolytic activity, indicating that RAP was not a general suppressant of cellular responsiveness to IL-2. Subsequent studies revealed that IL-2 stimulation triggered a delayed activation of the p34cdc2 kinase, the timing of which correlated with the G1- to S-phase transition. The IL-2-dependent increase in p34cdc2 kinase activity was blocked by RAP. The RAP sensitivity of the p34cdc2 activation mechanism implicates this signaling pathway in the control of S-phase commitment in IL-2-stimulated T-cells.

Animals↗

Effect of furosemide and subsequent intravenous fluid administration on right atrial pressure of splenectomized horses.

OBJECTIVE: To investigate the effect of i.v. administration of fluids on the furosemide-induced reduction in right atrial pressure (RAP) and relative change in blood volume (BV) of splenectomized mares. ANIMALS: 5 splenectomized mares. PROCEDURE: RAP was measured by use of a micromanometer placed in the right atrium. Jugular venous blood was collected for measurement of hematocrit, plasma total protein concentration, and hemoglobin concentration. Right atrial pressure was recorded and blood samples were collected immediately before furosemide (1 mg/kg of body weight, i.v.) administration, then every 15 minutes for 240 minutes. Beginning 120 minutes after furosemide administration, polyionic fluids (lactated Ringer's solution) were administered (2 L q 15 min) for 120 minutes. RESULTS: Furosemide induced a significant (P < 0.05) decrease in mean RAP (7.6 +/- 1.5 and 3.2 +/- 1.2 mm of Hg before and 15 minutes after furosemide administration, respectively), and BV (8.4 +/- 1.1 % by 15 minutes). Polyionic fluid administration restored RAP and BV. The volume of polyionic fluids administered (32 +/- 2 ml/kg) was not significantly different from the volume of urine produced (38 +/- 7.8 mg/kg). Difference was not apparent in the relation between change in BV and RAP before or after fluid administration. CONCLUSIONS: The effect of furosemide on RAP of horses is mediated in large part by furosemide-induced reduction in BV. However, an effect of furosemide on venous compliance cannot be excluded as contributing to the reduction in RAP.

Analysis of Variance↗

Coagulation and fibrinolytic parameters in patients with pulmonary hypertension.

BACKGROUND: Vascular endothelium reacts to various pathophysiologic stimuli by releasing several autocoids and cytokines that can be used along with the coagulation and fibrinolytic markers for the diagnosis of hemostatic alterations. Several newer markers for vascular distress, such as tissue plasminogen activator (TPA), tissue plasminogen activator inhibitor-1 (PAI-1), TPA/PAI-1 complex, and the newly reported inhibitor of the coagulation process, namely, tissue factor pathway inhibitor (TFPI), have been implicated in the pathogenesis of pulmonary hypertension. METHODS: To investigate the behavior of endothelial cells at basal and time-dependent venous stasis-induced changes, various markers were measured in patients with primary and secondary pulmonary hypertension and compared with healthy human volunteers (controls) without any family history of thromboembolism or history of hypertensive disorders. The right atrial pressure (RAP) and pulmonary arterial pressure were measured and the hemostatic parameters were correlated to determine the relevance of these parameters with the alterations in the present indices. RESULTS: A fibrinolytic deficit exists in patients with pulmonary hypertension, indicated by the prolongation of the euglobulin clot lysis time at basal conditions and after the venous occlusion test. This defect was mainly due to increased production of PAI-1 by endothelium (patients 59.8 +/- 22.3 AU/ml; controls 30.3 +/- 14.5 AU/ml; p = 0.005). We also report for the first time that a decrease in tissue factor pathway inhibitor antigen was also observed in these patients when RAP was > 9 mmHg [controls 95.6 +/- 61.6 ng/ml; patients with RAP > 9 mmHg 47.2 +/- 19.2 ng/ml (p = 0.044); patients with RAP > 9 mmHg 96.6 +/- 32.4 ng/ml (p = 0.002 compared with patients with RAP > 9 mmHg)], indicating endothelial cell and hemostatic disturbances. CONCLUSIONS: We conclude that the euglobulin clot lysis time was prolonged in patients with pulmonary hypertension compared with controls. The impairment of the fibrinolytic system was due to an elevated concentration of PAI-1. In RAP > 9 mmHg, an additional prothrombotic factor is the decrease in plasma tissue factor pathway inhibitor antigen. It appears from this study that antithrombotic treatment is indicated in these patients.

Adolescent↗

Proteins that bind to RNA polymerase II are required for accurate initiation of transcription at the adenovirus 2 major late promoter.

Extracts prepared from HeLa cell nuclei are inactivated for accurate transcription from the adenovirus 2 major late promoter (Ad2 MLP) by repeated passage over a column containing immobilized calf thymus RNA polymerase II. The capacity for accurate transcription is restored to these extracts by a fraction that is eluted from the RNA polymerase II column with 0.5 M KC1. This fraction contains RNA polymerase II-associating proteins (RAPs). RAPs are not required for the formation of a stable, promoter-associated pre-initiation complex. However, at least one RAP is required for the formation of the first phosphodiester bond at the Ad2 MLP, both when initiation depends only on the TATAAA box, and when initiation is stimulated by the upstream sequence of the promoter. Initiation occurs approximately 1 min after the addition of RAPs to initiation complexes formed in the absence of RAPs. Therefore, the RAP(s) that is an RNA polymerase II initiation factor functions late in the initiation pathway to convert a stable preinitiation complex to an initiation-competent complex.

Adenoviruses, Human↗

Peptidyl-tRNA hydrolase is involved in lambda inhibition of host protein synthesis.

Escherichia coli rap mutants do not support vegetative growth of bacteriophage lambda and die upon transcription of lambda DNA bar sites. Bacteria harbouring a pth(ts) mutation synthesize thermosensitive peptidyl-tRNA hydrolase (Pth) and die at 42 degrees C from a defect in protein synthesis. We present evidence that both rap and pth(ts) mutations affect the same gene: (i) peptidyl-tRNA hydrolase activity was found to be defective in rap mutants; (ii) at a threshold temperature, pth cells, like rap mutants, prevented lambda growth and were killed by transcription of cloned bar sites; (iii) sequencing a 1600 bp DNA fragment comprising both loci revealed an ORF located within the limits set by a complementation analysis and encoding a putative polypeptide of 21 kDa; (iv) cloning and sequencing of rap and pth(ts) mutant DNAs both revealed single nucleotide transitions from the wild type ORF sequence, resulting in Arg134 to His and Gly101 to Asp changes respectively. Analysis of plasmid-directed proteins identified a polypeptide of approximately 21 kDa; the N-terminal sequence, amino acid composition and isoelectric point of this protein match those expected from the ORF nucleotide sequence. We propose that Pth activity, directly or indirectly, is the target for lambda bar RNA leading to rap cell death.

Bacteriophage lambda↗

Rapamycin blocks cell cycle progression of activated T cells prior to events characteristic of the middle to late G1 phase of the cycle.

The effects of rapamycin (RAP) on cell cycle progression of human T cells stimulated with PHA were examined. Cell cycle analysis showed that the RNA content of cells stimulated with PHA in the presence of RAP was similar to that of control T cells stimulated with PHA for 12-24 hr in the absence of the drug. This level was substantially higher than that seen in cells stimulated in the presence of cyclosporin A (CsA), an immunosuppressant known to block cell cycle progression at an early point in the cycle. However, the point in the cell cycle at which RAP acted appeared to be well before the G1/S transition, which occurs about 30-36 hr after stimulation with PHA. In an attempt to further localize the point in the cell cycle where arrest occurred, a set of key regulatory events leading to the G1/S boundary were examined, including p110Rb phosphorylation, which occurred at least 6 hr prior to DNA synthesis, p34cdc2 synthesis, and cyclin A synthesis. In control cultures, p110Rb phosphorylation was detected within 24 hr of PHA stimulation; p34cdc2 and cyclin A synthesis were detected within 30 hr. Addition of RAP to the cultures inhibited each of these events. In contrast, early events, including c-fos, IL-2, and IL-4 mRNAs expression, and IL-2 receptor (p55) expression, were only marginally affected, if at all, in PHA-stimulated T cells. Furthermore, the inhibition of cell proliferation by RAP could not be overcome by addition of exogenous IL-2. These results indicate that RAP blocks cell cycle progression of activated T cells after IL-2/IL-2 receptor interaction but prior to p110Rb phosphorylation and other key regulatory events signaling G1/S transition.

Base Sequence↗

Direct inhibition of human CD8+ lymphocyte activation by cyclosporine A and Rapamune-Sirolimus.

Cyclosporin A (CsA) and Rapamune-Sirolimus (RAP) have been shown to inhibit the in vitro activation of heterogeneous lymphocytes populations, but little is known about their direct actions on isolated CD8+ lymphocytes. In this study the direct effects of RAP and CsA on a highly purified population of CD8+ lymphocytes were examined. Human CD8+ lymphocytes were purified to near homogeneity and stimulated with anti-CD3 antibody, OKT3, or allogeneic cells in the presence of exogenous human recombinant interleukin 2 (IL2). The effects of CsA and RAP on cell proliferation, the entry into the S phase of the cell cycle, the surface expression of Tac antigen, and the release of soluble IL2 receptor and soluble CD8 were analyzed. When CsA and RAP were included in the stimulated CD8+ lymphocyte cultures, these responses were inhibited. OKT3-stimulated CD8+ lymphocytes were sensitive to lower concentrations of the immunosuppressants than those previously reported for peripheral blood mononuclear cells. RAP was effective at a lower dose than CsA and when the agents were applied in combination, cell proliferation was synergistically inhibited. These results demonstrate that CsA and RAP can inhibit the activation and proliferation of purified CD8+ lymphocytes in response to OKT3 or alloantigen in the presence of IL2.

CD8-Positive T-Lymphocytes↗

Concept of "true ICP" in monitoring and prognostication in head trauma.

OBJECTIVE: To propose a new coefficient, which contains information about both the absolute ICP and the position of the 'working point' on the pressure-volume curve. METHOD: ICP was monitored continuously in 187 sedated and ventilated patients. The RAP coefficient was calculated as the running (3 minutes) correlation coefficient between slow changes in pulse amplitude and mean ICP. RAP has value 0 on the flat part of the Pressure-Volume Curve and +1 on the ascending exponential part. Then RAP decreases to zero or becomes negative when ICP increases further and affects cerebrovascular pressure-reactivity (which flattens the pressure-volume curve). Variable tICP = ICP* (1 - RAP) has been called 'trueICP'. It magnifies the critical values of ICP when cerebrovascular reactivity is exhausted and dampens those states where absolute ICP is elevated but vascular reactivity is not affected. RESULTS: Both Mean ICP and RAP were independently correlated with outcome (ANOVA:ICP-GOS: F = 22; p < 0.00001, RAP-GOS: F = 9; p < 0.001). 'TrueICP' had stronger association with outcome: F = 28; p < 0.000001. Mortality in those patients having 'trueICP' above the threshold of 19 mm Hg was above 80%, while the mortality in those having cICP below 19 mm Hg was only 20% (F = 80; p < 10(-8)). 'TrueICP' was also suitable for continuous monitoring: sustained rise in tICP above 19 mm Hg was strongly associated with fatal complications. CONCLUSION: The proposed variable is a powerful predictor of fatal outcome following head injury. It is sensitive to both the rising absolute ICP and the critical loss of cerebrovascular regulation.

Adolescent↗

Accuracy of totally implanted ports, tunnelled, single- and multiple-lumen central venous catheters for measurement of central venous pressure.

OBJECTIVE: To verify the accuracy of totally implanted ports, tunnelled central venous catheters (CVC), widely used in cancer patients, and multi-lumen catheters, used in intensive care units (ICUs), in measuring central venous pressure (CVP), using right atrial pressure (RAP) measured in a Swan-Ganz catheter as the reference standard. DESIGN: A prospective study, over a 10-month period. SETTING: A medical-surgical ICU in a comprehensive cancer centre. PATIENTS AND PARTICIPANTS: Patients who had both (1) a Swan-Ganz catheter and (2) either a tunnelled catheter, a single or a multi-lumen catheter, or a totally implanted port. INTERVENTIONS: RAP and CVP were measured simultaneously in each patient. MEASUREMENTS AND RESULTS: Fifty-six pairs of RAP-CVP measurements were performed in 35 patients: 6 tunnelled catheters, 6 non-tunnelled single-lumen catheters, 26 multiple-lumen catheters and 18 totally implanted ports were studied. RAP measured in the Swan-Ganz catheter and CVP measured in the CVC were strongly correlated (r = 0.94, p < 0.01), whatever the type of catheter studied. The mean difference between RAP and CVP was -0.39 +/- 1.73 (SD) mmHg. In 51 cases (91%), the difference was within the limits of agreement (-3.78 to 3.00 mmHg, Bland and Altman method). For the five cases with a difference of 4 mmHg (three totally implanted ports, one double- and one triple-lumen catheter), CVP was greater than RAP. CONCLUSIONS: CVP can be accurately measured in totally implanted ports, tunnelled or non-tunnelled single-lumen and multiple-lumen catheters. When the difference exceeds the limit of agreement, the discrepancy between the two measurements has limited significance in most cases.

Aged↗

Remodeling of the vascular channels in retinal angiomatous proliferations treated with intravitreal triamcinolone acetonide and photodynamic therapy.

BACKGROUND: The objective was to describe the remodeling of the vascular channels in stage II retinal angiomatous proliferation (RAP) treated by intravitreal injections of triamcinolone acetonide (TA) and subsequent photodynamic therapy (PDT). METHODS: Stage II RAP secondary to age-related macular degeneration was documented by dynamic digital fluorescein and indocyanine green angiography in 3 consecutive patients (3 eyes). All eyes were treated with intravitreal injection of TA (4 mg, 0.1 ml) followed by PDT 5-10 days later. RESULTS: Indocyanine green angiography (ICGA) revealed a complete remodeling of the vascular structure of the three RAPs after treatment. The feeding retinal artery, which shunted a major part of the blood flow from the original arteriole toward the intraretinal neovascular complex before treatment, regained a normal appearance after treatment. With RAP closure, the blood flow was again directed through the original retinal arteriole, and the connection to the RAP was no longer visible. CONCLUSIONS: Stage II RAPs are difficult lesions to treat. A real remodeling of the vascular lesion is achieved with the combined use of intravitreal TA and PDT. This finding corroborates the need for randomized clinical trials currently under way to evaluate this combination treatment in wet, age-related macular degeneration.

Aged↗

Irritable bowel syndrome: the commonest cause of recurrent abdominal pain in children.

UNLABELLED: Apley, working in Bristol, UK, defined recurrent abdominal pain (RAP) in 1958. After extensive investigations, he found that 8% of children presenting to his clinic with RAP had an organic pathology. The aims of this study were to identify (1) causes of RAP using modern methodology, (2) factors associated with organic RAP and (3) children with non-organic RAP who fulfill the diagnostic criteria for irritable bowel syndrome (IBS). Children, aged over 3 years, presenting with RAP were prospectively recruited to this study. They had a detailed questionnaire completed, a full examination with screening tests (blood for coeliac screen, Helicobacter pylori antibody titre, inflammatory markers, serum amylase, liver function tests, and full blood count, urine and stool analyses and abdominal ultrasonography). Endoscopy and oesophageal pH monitoring were performed if clinically indicated. IBS was diagnosed if the child had no organic pathology and fulfilled the Rome II criteria. Out of 103 children (median age of 10 years, mean 10.04, SD +/-3.44), 31 children (30%) had organic pathologies. Factors associated with organic pain were nocturnal symptoms (P<0.01) and abdominal tenderness (P<0.005) and with non-organic pain were periumbilical locality (P<0.002), pain alleviation on defaecation (P<0.04) and low fibre diet (P<0.005). Of children with non-organic pain, 37/52 (51%) fulfilled the criteria for IBS (36% of the total). CONCLUSION: Of children presenting with recurrent abdominal pain in a hospital setting, 30% have a diagnosable organic aetiology compared to 8% in Apley's time. Irritable bowel syndrome, however, may be the commonest cause of recurrent abdominal pain and should be considered.

Abdominal Pain↗

Fingerprinting of DNA and RNA by arbitrarily primed polymerase chain reaction: applications in cancer research.

RNA fingerprinting by RAP-PCR is a powerful tool for the temporal and spatial analysis of differential gene expression. Many biological situations exist where differential gene expression results in distinguishable phenotypes, including, for example, tissue and cell types, responses to hormones, growth factors, stress, and the heterologous expression of certain genes. There are several methods for detecting differential gene expression and cloning differentially expressed genes that do not rely on a biological assay of phenotype. Most of these methods fall into two general categories: subtractive hybridization and differential screening. RAP-PCR offers numerous advantages over these methods, including its simplicity and its ability to compare the fluctuations in gene expression between multiple samples simultaneously using minute amounts of RNA. In addition, RAP-PCR can yield information on the overall patterns of gene expression between different cell types or between different physiological conditions of the same cell type. Comparison of the RAP-PCR fingerprints from these different experimental groups permits one to draw inferences regarding the overall cellular states of gene expression and the interrelation between gene transcripts belonging to the same or different regulatory pathways. Hypotheses regarding signal transduction pathways can be obtained using this information. RAP-PCR offers applications in cancer research in the detection of tumor-specific alterations in gene expression, providing a bountiful source of tumor markers. The pleiotropic impact of oncogene activation, tumor suppressor gene inactivation, and mutator mutations, in gene regulation, can be readily assessed by RAP-PCR in model systems both in vitro and in vivo.

Base Sequence↗

Atrial natriuretic factor stimulates luteal guanylate cyclase.

Effect of a synthetic atrial natriuretic peptide, rat atriopeptin II (rAP-II) on the formation of cyclic nucleotides and progesterone production in Percoll-purified rat luteal cells was investigated. Incubation of luteal cells with varying concentrations of rAP-II resulted in a dose-related stimulation of intracellular cyclic GMP content; maximum stimulation being achieved with 10 nM rAP-II. The increase in cyclic GMP formation was extremely rapid and a 12-fold increase in the cyclic GMP content over basal level was attained within 5 min of incubation of the cells with 10 nM rAP-II. In the presence of phosphodiesterase inhibitor, 3-isobutyl-1-methyl-xanthine, both basal and rAP-II-stimulated levels of cyclic GMP were increased approximately 10 times, but the magnitude of stimulation remained similar in the presence or absence of the inhibitor. The atrial peptide at the concentration of 1-100 nM, however, had no effect on either basal or gonadotropin-stimulated progesterone production and cyclic AMP formation by the luteal cells. Furthermore, the increase in the level of cellular cyclic GMP content of rAP-II was demonstrated to result from a selective activation of particulate guanylate cyclase.

1-Methyl-3-isobutylxanthine↗

Effect of a tumour-promoting phorbol ester on atrial peptide-induced testosterone production and cyclic GMP accumulation by isolated mouse Leydig cells.

The objective of this study was to investigate the effects of 4 beta-phorbol 12-myristate 13-acetate (4 beta-PMA)--a potent activator of protein kinase C--on the responsiveness of mouse Leydig cells to stimulation with rat atriopeptin II (rAP-II). We report that, in these cells, the stimulation of testosterone production by rAP-II could be inhibited in a dose-dependent manner by 4 beta-PMA (1-200 nM). In contrast, the basal steroidogenesis was stimulated 2-fold by 4 beta-PMA. There was no inhibition of testosterone production when the cells were stimulated with 8-bromo cyclic GMP (8Br-cGMP) in the presence of 4 beta-PMA. Furthermore, addition of 4 beta-PMA resulted in a marked reduction in the amount of cGMP accumulated in response to rAP-II stimulation. 4 alpha-Phorbol 12-myristate 13-acetate (4 alpha-PMA) was found to have no effect at all. The inhibitory effect of 4 beta-PMA on steroidogenesis could be completely reversed by the addition of 0.25 mM 3-isobutyl 1-methylxanthine (IBMX), a phosphodiesterase inhibitor. Also, the 4 beta-PMA-induced lowering of cGMP content could be partially reversed by IBMX. Membrane fractions from cells treated with 4 beta-PMA or 4 alpha-PMA did not differ in their contents of either basal or rAP-II-stimulated guanylate cyclase activities. We conclude that the 4 beta-PMA-mediated inhibition of testosterone production by Leydig cells stimulated with rAP-II results from an activation of a phosphodiesterase enzyme, hypothetically through an activated protein kinase C. This leads to a reduction in the cellular cGMP content through an increased metabolic removal of cGMP formed in response to rAP-II stimulation.

Animals↗

Responsiveness of the rehabilitation activities profile and the Barthel index.

The goal of this study was to compare the responsiveness for clinically meaningful change over time of a newly designed functional status scale, the Rehabilitation Activities Profile (RAP), with more frequently used Barthel Index (BI). Four techniques for the quantification of responsiveness were utilized: effect sizes, p-values, t-statistics and ROC curves. The patient's return home was chosen as external criterion. An inception cohort of stroke patients was followed during 26 weeks. All patients still hospitalized on the 14th day after the stroke were included. The functional assessments took place at 2, 3, 4, 8, 12, and 26 weeks after stroke. The patients were visited at the hospital, home, nursing home, or rehabilitation center. Of the 125 patients included in the study, 18 patients died during the observation period, 2 patients were lost to follow-up, and 1 patient refused to cooperate after 12 weeks. After 26 weeks, 104 patients remained for analysis. Three time periods were discerned: 2 to 12 weeks (early response), 12 to 26 weeks (late response), and 2 to 26 weeks after stroke (overall response). The effect sizes of the RAP were consistently higher on all three time periods than those of the BI. The p-value of the overall response mean change score of the RAP appeared to discriminate between patients returning home and those not returning home, whereas the BI failed on this point (p = 0.004 vs. 0.496). Using t-statistics, the RAP showed a higher efficiency in expressing change on all time periods (relative efficiency = 1.42, 1.77, and 1.43, respectively). The receiver operating characteristic surface area of the RAP score was higher than the area of the BI score (0.74 and 0.59, respectively for the early response period). In conclusion, all results seemed to indicate that the RAP is more responsive than the BI when returning home is chosen as an external criterion.

Activities of Daily Living↗

Photodynamic therapy for retinal angiomatous proliferations and pigment epithelium detachment.

PURPOSE: To evaluate results of photodynamic therapy (PDT) with verteporfin for subfoveal neovascular age-related macular degeneration (ARMD) with retinal angiomatous proliferation (RAP) and pigment epithelial detachment (PED). DESIGN: Interventional case series. METHODS: Thirteen eyes (11 stage 2 and 2 stage 3 RAP) underwent PDT. Best-corrected visual acuity (BCVA), fluorescein and indocyanine-green angiography were performed to evaluate the outcome. RESULTS: After 13.5 +/- 2.5 months and 1.7 +/- 0.4 treatments, mean BCVA decreased from 20/73 to 20/174 (P = .04). Occlusion of RAP and flattening of PED was observed in three eyes, and persistence of PED in six. Two eyes deteriorated to disciform lesions, one developed hemorrhagic PED, and one evolved toward stage 3 RAP. Three eyes, with PED exceeding 50% of the entire lesion, developed retinal pigment epithelium tear. CONCLUSIONS: PDT might prove effective for neovascular ARMD with RAP and small PED, whereas it might cause acute retinal pigment epithelium tear for RAP with PED exceeding 50% of the lesion.

Aged↗

Is biliary microlithiasis a significant cause of idiopathic recurrent acute pancreatitis? A long-term follow-up study.

BACKGROUND & AIMS: The cause of recurrent acute pancreatitis (RAP) is not known in 10%-30% of patients. The aim of the present study was to determine the cause of idiopathic RAP in a long-term follow-up study. METHODS: All consecutive patients with idiopathic RAP underwent detailed evaluations and investigations to find out the cause. The pancreatitis was considered to be idiopathic when no cause could be found after standard investigations that included serum biochemistry, transabdominal ultrasonography, and computerized tomography scan of the abdomen. The detailed work-up included repeat serum biochemistry and transabdominal ultrasonography, an endoscopic retrograde cholangiopancreatography, duodenal bile microscopy to diagnose biliary microlithiasis, and endoscopic ultrasonography. RESULTS: Seventy-five patients were studied from June 1995 to May 2003. Their mean age was 31.9 years and 80% were male. The mean number of attacks of acute pancreatitis was 4.82 (range, 2-10). The cause of RAP was attributed to biliary microlithiasis in only 10 (13%) of 75 patients. Two additional patients developed gallstones during the follow-up period. Thirty-five (47%) patients developed chronic pancreatitis during the follow-up period. Ten of these 35 patients with chronic pancreatitis had biliary microlithiasis; 8 of these 10 patients had undergone cholecystectomy/endoscopic sphincterotomy yet continued to have recurrent pancreatitis and developed chronic pancreatitis. Miscellaneous causes were found in 10 (13%) patients. No cause was found in the remaining 18 (24%) patients. CONCLUSIONS: Microlithiasis was not a significant cause of idiopathic RAP in our patients. About one half of the patients with RAP developed chronic pancreatitis during the follow-up period.

Acute Disease↗