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At least 973 records · Page 54Linked to original sources

Retinal angiomatous proliferation with a cilioretinal artery anastomosis: an unusual presentation.

PURPOSE: To report an unusual phenotype of retinal angiomatous proliferation (RAP) in age-related macular degeneration (AMD) and its short-term response to laser photocoagulation. METHODS: Case report. RESULTS: An 85-year-old woman was found to have an unusual RAP with a major feeder vessel originating from a cilioretinal artery and associated with a cilioretinal-retinal anastomosis (C-RRA). Diffuse cystoid macular edema (CME), intraretinal hard exudates in a circinate pattern, and a fibrovascular pigment epithelial detachment (PED) were present. Laser photocoagulation was performed and led to occlusion of the cilioretinal feeder vessel and angiomatous lesion, with less CME. The other (retinal) arm of the C-RRA became more engorged and a new cilioretinal feeder developed, and both were associated with intraretinal hemorrhages. Visual acuity was stable and the PED persisted throughout follow-up. CONCLUSIONS: We report an unusual phenotype of RAP that is associated with a major cilioretinal feeder vessel and comment on the possible effect of such an association on the response to laser treatment.

Aged↗

Retinal angiomatous proliferation treated by intravitreal triamcinolone and photodynamic therapy with verteporfin.

PURPOSE: To examine combined treatment of intravitreal triamcinolone acetonide (IVT) and photodynamic therapy (PDT) for retinal angiomatous proliferation (RAP). METHODS: Ten eyes of eight consecutive patients with RAP underwent a single injection (about 20 mg) of IVT followed 1 month later by PDT. Best-corrected visual acuity (BCVA) was measured by standardized protocol refraction. RESULTS: Median BCVA was 20/160, 20/64, 20/98, 20/89, 20/89, 20/125 at baseline and 1, 3, 6, 9 and 12 months, respectively. Of ten eyes, six (60%) improved BCVA of at least 3 lines at 1, 3, 6 and 9 months. Four (40%) eyes improved BCVA of at least 3 lines at 12 months. Three eyes (30%) lost >3 lines at 12 months. In all patients intraocular pressure was well controlled. No endophthalmitis, retinal detachment or vitreous haemorrhage developed. CONCLUSIONS: Improvement of BCVA suggests that combination treatment with IVT and PDT for RAP merits further investigation.

Angiomatosis↗

Clinicopathological findings of retinal angiomatous proliferation.

BACKGROUND: Neovascular membranes obtained from surgical excision of neovascularization for retinal angiomatous proliferation (RAP) were examined histopathologically in an attempt to elucidate the pathogenic mechanism of RAP. METHODS: Nine eyes of eight patients (mean age, 79 +/- 6 years) who underwent neovascularization excision were studied. Three eyes had stage II with RPE detachment, six had stage III. Immunohistochemical studies were performed to identify von Willebrand factor, vascular endothelial factor (VEGF), CD68 and hypoxia inducible factors (HIF-1 alpha and HIF-2 alpha). RESULTS: Multiple soft drusen were present in the macular area in all patients. In one stage II eye, we observed intraretinal neovascularization as a VEGF-positive mass, CD68-positive macrophage migration and HIF expression. In another stage II eye, neovascularization had extended above the RPE, while VEGF-positive fibroblasts were observed below the RPE. Therefore, in stage II, neither angiographic nor histopathological examinations identified choroidal neovascularization. In one phase III eye, angiography demonstrated choroidal neovascularization and chorioretinal anastomosis. Histopathologically, chorio-retinal communication was observed in the region where the RPE was destroyed, and VEGF-positive neovascularization was also seen below the RPE. CONCLUSIONS: The findings of multiple drusen in elderly patients together with macrophage migration and HIF expression surrounding VEGF-positive retinal neovascularization suggest ischemic and inflammatory factors to be associated with the development and progression of RAP.

Aged↗

The role of the low-density lipoprotein receptor-related protein (LRP1) in Alzheimer's A beta generation: development of a cell-based model system.

The clearance and degradation of extracellular A beta is critical for regulating beta-amyloid deposition, a major hallmark of brains of patients with A beta in Alzheimer's Disease. The low-density lipoprotein receptor-related protein, LRP1, is a large endocytic receptor that significantly contributes to the balance between degradation and production of A beta. An extracellular portion of the LRP, known as the cluster II region can bind to the secreted form of APP (sAPP-KPI). We show here that a GST fusion protein containing the cluster II region of LRP can be used as a 'mini-receptor' that specifically binds to sAPP-KPI from conditioned cultured medium. The binding between the GST-LRP-cluster II fusion protein and sAPP-KPI can be inhibited with the strong binding ligand of LRP1, called receptor-associated protein (RAP). Furthermore, a cell-based in vitro assay system has been developed to monitor the production of total A beta and A beta(1-42) in the presence and absence of RAP in Chinese hamster ovary (CHO) cell lines both deficient in LRP and expressing LRP. A 3-day treatment of the L2 (CHO cells deficient in LRP and overexpressing APP751) and L3 (CHO cells expressing LRP and overexpressing APP751) cell lines with RAP showed a decrease in total A beta and, interestingly, also a decrease in the ratio of A beta42/A beta(total). This cell-based model system and LRP-cluster II mini-receptor will be very useful for screening novel compounds that can reduce A beta accumulation by inhibiting binding of APP-KPI to LRP1.

Alzheimer Disease↗

Hemodynamic effects of molsidomine vasodilatory therapy in acute myocardial infarction.

The hemodynamic effects and duration of action of 4 mg of intravenous molsidomine (M), a new peripheral vasodilator antianginal agent, were evaluated and compared to those of 10 mg sublingual isosorbide dinitrate (ISDN) in 12 patients with uncomplicated acute myocardial infarction (AMI). Both M and ISDN produced marked decreases in mean right atrial pressure (RAP), mean pulmonary capillary wedge pressure (WP), and mean pulmonary arterial pressure. The maximal decreases in RAP (-56%) and WP (-35%) with intravenous M intended to be more pronounced than with sublingual ISDN (RAP-35% and WP-29%). Physiologic modest declines in systemic vascular resistance, cardiac output, and arterial pressure were similar with the both drugs. The duration of action of M was longer (average 5 hours) than that of ISDN (2 hours). No patient experienced hypotension, tachycardia, or other adverse responses following M, suggesting that M is well isolated by patients with normotensive AMI.

Acute Disease↗

Endotoxin shock in the beagle dog.

The hemodynamic and metabolic responses to endotoxemia were assessed in seven splenectomized, chronically instrumented, conscious but lightly sedated beagle dogs. Measurements included: cardiac output (CO), right and left atrial pressures (RAP, LAP), systemic and pulmonary arterial pressures (SAP, PAP), and heart rate (HR). Arterial blood samples were measured for blood gas tensions, pH, lactate, and pyruvate. After a brief control period, 1 mg/kg endotoxin (Difco 026:B6) was given as an intravenous bolus. Two hours later, each animal was treated with low-molecular weight dextran (LMDX), 2 ml/kg/min for 15 minutes. Endotoxin initially produced a precipitate decline in CO, HR, RAP, LAP, and SAP with concurrent pulmonary hypertension; both pulmonary and systemic vascular resistance increased significantly, then declined to control values as the animal partially recovered. A progressive metabolic acidosis with excess lactate accumulation developed. LMDX produced a significant increase in CO, SAP, PAP, and LAP with a decrease in HR; RAP increased slightly. With hydration, hemodilution was noted along with relief of the metabolic acidosis and the oxygen debt. We conclude (1) neither pulmonary nor systemic vasconstriction persisted in the shocked dog, (2) the response of the pulmonary and systemic vascular beds to endotoxin was qualitatively similar, and (3) oncotic fluid therapy appeared to restore the hemodynamic and metabolic parameters to preshock values.

Animals↗

Very low density lipoprotein receptor from mammary gland and mammary epithelial cell lines binds and mediates endocytosis of M(r) 40,000 receptor associated protein.

We here report that the M(r) 40,000 receptor associated protein (RAP), previously found to bind to alpha 2-macroglobulin receptor/low density lipoprotein receptor related protein (alpha 2MR/LRP) and glycoprotein 330 (gp330), binds to an M(r) 105,000 membrane protein from bovine mammary gland, human mamma tumors and mammary epithelial cell lines. We have purified this protein from bovine and human sources. N-terminal amino acid sequencing and immunoblotting analyses showed that the protein was identical or closely related to very low density lipoprotein receptor (VLDL-R). Experiments with the human mamma carcinoma cell line MCF-7 showed that this receptor was able to mediate an efficient endocytosis of RAP. These novel findings strongly suggest that RAP functions as a modulator of ligand binding to VLDL-R, similarly to alpha 2MR/LRP and gp330.

Amino Acid Sequence↗

Three matrix metalloproteinases form a non-covalent association with the rhoptry-associated protein-1 of Plasmodium falciparum.

During the characterization of malaria vaccine candidate proteins, three metalloproteinases having a molecular mass of 220, 95 and 70 kDa were found to be co-isolated with the rhoptry-associated protein-1 (RAP-1) complex, but not with RAP-3 or gp195. These enzymes were also found in detergent extracts of saponin-lysed Plasmodium falciparum. Of nine proteinase inhibitors tested, only EDTA was found to abrogate activity. Dose-dependent curves were determined for several metal ions and cobalt was found to synergistically enhance enzyme activity. The gelatinases were immunoprecipitated with monospecific polyclonal antisera to macrophage and fibroblast gelatinase; however, these sera did not react with intracellular parasites by indirect immunofluorescence. These results indicate that the matrix metalloproteinases co-isolated with RAP-1 originate from human serum used to cultivate P. falciparum in vitro.

Animals↗

Generator locations of movement-related potentials with tongue protrusions and vocalizations: subdural recording in human.

Movement-related potentials (MRPs) associated with tongue protrusions and vocalizations were recorded from chronically implanted subdural electrodes over the lower perirolandic area in 7 patients being evaluated for epilepsy surgery. In 3 patients, tongue protrusions elicited a clearly defined, well localized slow negative Bereitschaftspotential (BP) at the motor tongue area, and a positive BP at the sensory tongue area. At the motor tongue area the negative BP was followed by a negative slope (NS') and a motor potential (MP), and at the sensory tongue area the positive BP and a positive reafferent potential (RAP) were seen but no NS' and MP could be identified. In the other 4 patients, tongue protrusions elicited positive BP, NS' and MP at the motor and sensory tongue area, and positive RAP at the sensory area. It was concluded that BPs, NS' and MPs are mainly generated in the motor cortex involving the crown as well as the anterior bank of the central fissure. The sensory cortex (areas 3a and 3b) also participated in the generation of BPs but to a lesser degree. Different degree of involvement of these multiple generators most likely explains the interindividual variability of polarity and distribution of the MRPs. RAPs most likely arise from primary sensory areas 1 and 2. Brain potentials were also recorded at the motor (2 patients) and sensory (2 patients) language areas, but no specific language-related potentials could be identified. Evoked potentials to lip stimulation were investigated in 4 patients. In 3 patients, the responses at the sensory tongue area (P16, N21 and P30) had the same latency but opposite polarity to those at the motor tongue area. In the other patient, the responses (P16, N21 and P30) at the motor and sensory tongue areas were of the same polarity. The MRPs to tongue protrusions in those 4 patients revealed the same polarity relationship between the pre- and postcentral potentials. However, the maximal amplitude of evoked potentials and MRPs was seen at almost the same electrodes, suggesting that the main generators for these MRPs and evoked potentials must be located at contiguous areas in the anterior and posterior bank, respectively, of the central fissure.

Adolescent↗

An epidemic in the field? Rapid assessment procedures and health research.

This paper reviews the development of various methods designed to generate relevant social information, pertaining to health and disease control, quickly and accurately. In so doing, we examine the use of KAP surveys and the subsequent development of community diagnosis, rapid appraisal methods, rapid epidemiological assessment, and rapid assessment procedures (RAP) for anthropological studies. Our focus is on the development of anthropological RAPs, in response to the lack of professionally trained social scientists to work with disease control programmes and ministries of health, and in light of the demonstrable need for social science input in the development of health policies and programmes. These developments are assessed in terms of scope and method. Issues relating to the representativeness, reliability and validity of RAP studies are discussed, and mechanisms by which to maximise the yield of valid data are presented.

Communicable Disease Control↗

Binding of androgen-receptor complexes to alpha 2u-globulin genes and to the long terminal repeat of mouse mammary tumor virus.

The binding of androgen-receptor complexes to fragments derived from two alpha 2u-globulin genes (RAP 01 and RAO 01) was studied using a DNA-cellulose competition assay. Rat prostate cytosol labelled with [3H]mibolerone was used as a source of the androgen receptor. Two controls were included in these studies: the long terminal repeat (LTR) of mouse mammary tumor virus which has previously been shown to act as an androgen response element and a fragment of the C3 gene of prostatic binding protein which has been demonstrated to bind androgen-receptor complexes. Our experiments indicate that androgen-receptor complexes bind specifically and with comparable affinity to the C3 gene fragment, the LTR and a fragment of RAP 01 located in the 5'-upstream region (bp -642 up to -584). No specific interaction was observed with fragments derived from RAO 01. The region of RAP 01 which binds androgen-receptor complexes has previously been shown to interact with glucocorticoid receptors and contains a 17 bp sequence homologous with the consensus sequence for glucocorticoid-receptor binding. A mutation in this sequence in RAO 01 may be responsible for the loss of glucocorticoid and androgen-receptor binding. It is concluded that at least one member of the alpha 2u-globulin gene family interacts directly with androgen-receptor complexes with an affinity comparable to that observed for other androgen-dependent genes. The binding is observed in a region displaying also affinity for the glucocorticoid receptor.

Alpha-Globulins↗

Screening for alcohol problems in the emergency room: a rapid alcohol problems screen.

This paper compares the sensitivity and specificity of a five-item Rapid Alcohol Problems Screen (RAPS) optimized in this sample with the CAGE, brief MAST, AUDIT, TWEAK, History of Trauma Scale and breathalyzer reading against ICD-10 criteria for alcohol dependence or harmful drinking, by gender, ethnicity and injury status in a probability sample of emergency room patients (n = 1330) from the University of Mississippi Medical Center. The RAPS performed better than all other screening instruments for the total sample of current drinkers who reported ever having had three or more drinks at one time (sensitivity of 90%, specificity of 78%), and performed consistently better across all subgroups than any other single instrument, even at alternate cut points. The Rapid Alcohol Problems Screen may hold promise for use in clinical settings in identifying those who could benefit from a brief intervention or referral for problem drinking, particularly since the instrument is short and patients need not be asked additional questions after screening positive on one of the five items. Further research is necessary to analyze and compare the performance of the RAPS with other screening instruments across demographic subgroups in other emergency room and primary care settings.

Adult↗

The effect of rapamycin on renal function in the rat: a comparative study with cyclosporine.

Male adult Sprague-Dawley rats were treated for 14 days with either rapamycin (RAP, 1.5 mg/kg/d i.p.) in carboxymethylcellulose (RAP/CMC) or polyethyleneglycol (RAP/PEG), cyclosporine (CsA, 15 mg/kg/d by gavage) or with the appropriate drug vehicles. Biochemical indices of renal function and integrity were determined throughout the experimental period, at the end of which the rats were killed and kidneys examined histologically. All animals gained weight at a similar rate to untreated animals except those treated with RAP; RAP/PEG animals were lighter on day 14 compared with day 0 values, whilst RAP/CMC animals were lighter only in comparison with CMC-only controls on day 14. Significant increases in urinary flow rate (UFR) were found in each drug treatment group. RAP/CMC, RAP/PEG and CsA caused mild renal functional impairment, but only with CsA was there a significant reduction in 51Cr-EDTA clearance. Significant enzymuria, resulting from drug but not vehicle administration, was observed only in the CsA-treatment group. Increased plasma and urinary glucose levels, elevated in all drug-treatment groups, were related to increased UFR. Kidneys of RAP-treated rats appeared normal, whereas mild, focal, acute tubular necrosis was evident in all CsA-tested animals. Pancreases of all drug-treated animals were histologically normal.

Acetylglucosaminidase↗

A role for monomeric G-proteins in synaptic plasticity in the rat dentate gyrus in vitro.

Recent studies have implicated Ras signalling in synaptic plasticity. In this study we have investigated a role for the low molecular weight G proteins Ras, Rap, Ra1 and Rac in long-term potentiation and depression using Clostridium Sordelli Lethal Toxin-82 (LT-82), which inactivates Ras, Rap, Ra1 and Rac, and manumycin A, a Ras inhibitor. Perfusion of hippocampal slices with LT-82 (200 ng/ml) attenuated LTP (83+/-10%, n=5, P<0.01, compared with controls of 160+/-11% at 60 min post HFS, n=5). LT-82 had no effect on LTD (63+/-1% at 100 ng/ml, n=5 and 66+/-1% at 200 ng/ml, n=4, compared to controls of 56+/-6%, n=6). Manumycin A (2 microM) had no effect on LTP (162+/-2%, n=5, compared to controls of 167+/-13%, n=5), but significantly attenuated LTD (88+/-6%, n=5, P<0.01, compared to controls of 63+/-9%, n=7). LT-82 (200 ng/ml) significantly increased the amplitude of the isolated NMDA-EPSP at 60 min post-drug application (240+/-40%, n=5, P<0.01, compared with controls of 100+/-4%, n=5). However, manumycin A, had no significant effect on NMDAR-EPSP amplitude (92+/-2%, n=5, compared with controls). These results demonstrate an important role for Ras in LTD and a role for Rap, Ra1 and Rac in LTP.

Animals↗

Recognizing and defining true Ras binding domains I: biochemical analysis.

Common domain databases contain sequence motifs which belong to the ubiquitin fold family and are called Ras binding (RB) and Ras association (RalGDS/AF6 Ras associating) (RA) domains. The name implies that they bind to Ras (or Ras-like) GTP-binding proteins, and a few of them have been documented to qualify as true Ras effectors, defined as binding only to the activated GTP-bound form of Ras. Here we have expressed a large number of these domains and investigated their interaction with Ras, Rap and M-Ras. While their (albeit weak) sequence homology suggest that the domains adopt a common fold, not all of them bind to Ras proteins, irrespective of whether they are called RB or RA domains. We used fluorescence spectroscopy and isothermal titration calorimetry to show that the binding affinities vary over a large range, and are usually specific for either Ras or Rap. Moreover, the specificity is dictated by a set of key residues in the interface. Stopped-flow kinetic analysis showed that the association rate constants determine the different affinities of effector binding, while the dissociation rate constants are in a similar range. Manual sequence analysis allowed us to define positively charged sequence epitopes in certain secondary structure elements of the ubiquitin fold (beta1, beta2 and alpha1) which are located at similar positions and comprise the hot spots of the binding interface. These residues are important to qualify an RA/RB domain as a true candidate Ras or Rap effector.

Animals↗

RNA fingerprinting--a new method to screen for differences in plant litter degrading microbial communities.

Microbial activities are essential for the nutrient turnover processes in soil and play an important role in the degradation of complex organic material, for example, plant leaf litter. However, very little is known about the microorganisms and their genes involved during the course of leaf litter decomposition. In the present study, we describe the non-radioactive application of RNA arbitrarily primed-PCR (RAP-PCR) protocol in combination with the classic litter bag technique to investigate the metabolic profiles of microbial community involved in leaf litter degradation after 2 and 8 weeks of degradation in four different soil sites, without using selective primer systems for PCR. Due to the significantly reduced target sites for PCR primers, compared to the published papers about RAP fingerprinting of more complex microbial communities based on DNA analysis (only transcripts from microbes on the litter material were analysed), the patterns of parallel samples were highly reproducible (>95%). Shifts in microbial community structure and function were observed during the course of degradation. Each litter sample had its unique metabolic profile and both soil effects and litter quality effects were evident. RAP-PCR products were also cloned to generate libraries. Clone libraries were screened by restriction fragment length polymorphism (RFLP) and representative samples sequenced to identify the inserts. Both mRNA and rRNA transcripts were obtained confirming the presence of mRNA in total RNA preparations. Hence, the described protocol is a good screening method to find similarities or differences in the structure and function of microbial communities involved in litter degradation, which may be the basis for more detailed studies by cloning and sequencing approaches.

Electrophoresis, Polyacrylamide Gel↗

The infant as a prelinguistic model for language learning impairments: predicting from event-related potentials to behavior.

Associations between efficient processing of brief, rapidly presented, successive stimuli and language learning impairments (LLI) in older children and adults have been well documented. In this paper we examine the role that impaired rapid auditory processing (RAP) might play during early language acquisition. Using behavioral measures we have demonstrated that RAP abilities in infancy are critically linked to later language abilities for both non-speech and speech stimuli. Variance in infant RAP thresholds reliably predict language outcome at 3 years-of-age for infants at risk for LLI and control infants. We present data here describing patterns of electrocortical (EEG/ERP) activation at 6 month-of-age to the same non-verbal stimuli used in our behavioral studies. Well-defined differences were seen between infants from families with a history of LLI (FH+) and FH- controls in the amplitude of the mismatch response (MMR) as well as the latency of the N250 component in the 70 ms ISI condition only. Smaller mismatch responses and delayed onsets of the N250 component were seen in the FH+ group. The latency differences in the N250 component, but not the MMR amplitude variation, were significantly related to 24-month language outcome. Such converging tasks provide the opportunity to examine early precursors of LLI and allow the opportunity for earlier identification and intervention.

Brain Mapping↗

A novel peptide isolated from phage library to substitute a complex system for a vaccine against staphylococci infection.

Staphylococcus aureus is a major human pathogen and many of the strains are resistant to conventional antibacterial treatment. The bacteria cause disease largely due to the production of multiple toxins, whose synthesis is controlled by an RNA molecule termed RNAIII. The production of RNAIII is induced by quorum sensing systems, one of them containing the protein RNAIII activating protein (RAP). Here we show that we partially purified supernatant of S. aureus, used this fraction to vaccinate mice, and selected antibody-binding peptides by phage display. Mice were vaccinated with the various peptides and challenged with S. aureus. One of the binding peptide termed R13 induced a protective immune response. Western blot analysis showed that the anti-R13 antibodies specifically bind to native or recombinant RAP. Mice vaccinated with R13 were protected and protection was sustained for the duration of the 6-month study period. Our results show that R13 could be used as a long-term effective protective-peptide-vaccine to prevent S. aureus infections and once again show that targeting the RAP quorum sensing system is an effective approach to preventing staphylococcal infections. In addition our studies show that selection of specific protective peptides by phage display using sera induced by complex antigens is a rapid and effective way to identify the protective antigen and select for a peptide vaccine.

Animals↗