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PubMed1987

The properties of batrachotoxin-modified cardiac Na channels, including state-dependent block by tetrodotoxin.

Batrachotoxin (BTX) modification and tetrodotoxin (TTX) block of BTX-modified Na channels were studied in single cardiac cells of neonatal rats using the whole-cell patch-clamp recording technique. The properties of BTX-modified Na channels in heart are qualitatively similar to those in nerve. However, quantitative differences do exist between the modified channels of these two tissues. In the heart, the shift of the conductance-voltage curve for the modified channel was less pronounced, the maximal activation rate constant, (tau m)max, of modified channels was considerably slower, and the slow inactivation of the BTX-modified cardiac Na channels was only partially abolished. TTX blocked BTX-modified mammalian cardiac Na channels and the block decreased over the potential range of -80 to -40 mV. The apparent dissociation constant of TTX changed from 0.23 microM at -50 mV to 0.69 microM at 0 mV. No further reduction of block was observed at potentials greater than -40 mV. This is the potential range over which gating from closed to open states occurred. These results were explained by assuming that TTX has a higher affinity for closed BTX-modified channels than for open modified channels. Hence, the TTX-binding rate constants are considered to be state dependent rather than voltage dependent. This differs from the voltage dependence of TTX block reported for BTX-modified Na channels from membrane vesicles incorporated into lipid bilayers and from amphibian node of Ranvier.

Animals↗
PubMed1987

Selection, generalized transmission and the evolution of modifier genes. I. The reduction principle.

Modifier gene models are used to explore the evolution of features of organisms, such as the genetic system, that are not directly involved in the determination of fitness. Recent work has shown that a general "reduction principle" holds in models of selectively neutral modifiers of recombination, mutation, and migration. Here we present a framework for models of modifier genes that shows these reduction results to be part of a more general theory, for which recombination and mutation are special cases. The deterministic forces that affect the genetic composition of a population can be partitioned into two categories: selection and transmission. Selection includes differential viabilities, fertilities, and mating success. Imperfect transmission occurs as a result of such phenomena as recombination, mutation and migration, meiosis, gene conversion, and meiotic drive. Selectively neutral modifier genes affect transmission, and a neutral modifier gene can evolve only by generating association with selected genes whose transmission it affects. We show that, in randomly mating populations at equilibrium, imperfect transmission of selected genes allows a variance in their marginal fitnesses to be maintained. This variance in the marginal fitnesses of selected genes is what drives the evolution of neutral modifier genes. Populations with a variance in marginal fitnesses at equilibrium are always subject to invasion by modifier genes that bring about perfect transmission of the selected genes. It is also found, within certain constraints, that for modifier genes producing what we call "linear variation" in the transmission processes, a new modifier allele can invade a population at equilibrium if it reduces the level of imperfect transmission acting on the selected genes, and will be expelled if it increases the level of imperfect transmission. Moreover, the strength of the induced selection on the modifier gene is shown to range up to the order of the departure of the genetic system from perfect transmission.

Biological Evolution↗
PubMed1998

A pilot study on modified endoscopic variceal ligation using endoscopic ultrasonography with color Doppler function.

OBJECTIVE: The purpose of the study was to evaluate feasibility of modified endoscopic variceal ligation (EVL), namely the "intensive ligation" method, using endoscopic ultrasonography with color Doppler function (EUS-CD). METHODS: Forty-five patients with esophageal varices were treated by modified EVL. Variceal hemodynamics in 38 patients were examined using EUS-CD, which showed abdominal hemodynamics in detail under physiological conditions before and after the modified procedure. RESULTS: 1) The median number of treatment sessions was 3.2, and 41 O-rings on average were required per individual patient. 2) The median nonrecurrence period after treatment was 18 months (Kaplan-Meier method). 3) Nine patients with a good response to modified EVL did not have recurrences for 16.9+/-2.8 months, and five with a poor response had recurrences at 5.8+/-2.2 months. Gastric varices were related to the response to modified EVL (p < 0.05, Mann-Whitney's U test). 4) Minor complications in modified EVL as well as standard EVL were experienced; however, we had a patient with the development of meningitis, which was a major septic complication. 5) Before modified EVL, EUS-CD demonstrated that good responders had undeveloped (grade I) gastric varices in five of nine (56%); however, poor responders had developed (grade III) gastric varices in four of five (80%) (p < 0.05, Mann-Whitney's U test]. 6) After modified EVL, EUS-CD revealed that six of nine (67%) good responders and one of five (20%) poor responders showed a decrease in color signals in supplying veins; however, none of the former (0%) and three of the latter (60%) showed an increase (p < 0.05, Mann-Whitney's U test]. CONCLUSION: Modified EVL was safe and effective, at least with regard to intermediate-term outcome, especially when treating patients with undeveloped gastric varices revealed by EUS-CD. Both good and poor responders showed no exacerbation of gastric varices after the modified procedure, ultrasonographically as well as endoscopically.

Adult↗
PubMed2006

Proposal of a modified Cancer of the Liver Italian Program staging system based on the model for end-stage liver disease for patients with hepatocellular carcinoma undergoing loco-regional therapy.

BACKGROUND: The Cancer of Liver Italian Program (CLIP) system was suggested as the primary staging system for hepatocellular carcinoma (HCC). The model for end-stage liver disease (MELD) is a better prognostic predictor for cirrhotic patients compared to Child-Turcotte-Pugh (CTP) system, which is a parameter used in the CLIP model. AIM: To investigate the performance of the modified MELD-based CLIP systems. METHODS: The CTP class in the CLIP model was replaced with MELD score (<10, 10-14, >14; modified CLIP-1), or additional 1 or 2 points were given to patients with MELD score 10-14 or >14, respectively (modified CLIP-2). The modified CLIP systems were compared with the original system in 343 HCC patients undergoing loco-regional therapy. RESULTS: The original CLIP score in all patients was 1.2 +/- 1.1 (range 0-5), compared with 1.4 +/- 1.2 (range 0-5) for modified CLIP-1 and 1.7 +/- 1.4 (range 0-6) for modified CLIP-2 models (p < 0.001). Using mortality as the endpoint, the area under receiver operating characteristic curve for modified CLIP-2 system was 0.858 compared with 0.812 for modified CLIP-1 (p = 0.013) and 0.782 for original CLIP system (p < 0.001) at 12 months; the area was 0.879, 0.830, and 0.762, respectively (p all < 0.001) at 24 months. Survival analysis showed that the modified CLIP systems had a better long-term discriminatory ability for different score groups. CONCLUSIONS: The CLIP model is useful to predict the outcome in HCC patients undergoing loco-regional therapy. The MELD-based modified CLIP systems may have a better predictive ability than the original model for cancer staging.

Aged↗
PubMed1996

Patch testing with allergens from modified rosin (colophony) discloses additional cases of contact allergy.

Most rosin (colophony) used today is chemically modified. Will contact allergy to modified rosin be overlooked when testing is performed with only unmodified rosin in the standard series? 2 components from modified rosins, maleopimaric acid (MPA) and glyceryl I-monoabietate (GMA), earlier identified as contact allergens, were added to the patch test standard series. Some commonly-used modified rosin products were also tested. Positive reactions were observed to the modified components MPA and GMA. Of the patients with positive reactions to MPA and GMA, several did not react to unmodified rosin in the standard series. No reaction was observed to the modified rosin products without a concomitant reaction to unmodified rosin. The positive reactions observed to the modified rosins may be due to residual unmodified material in the product, but a possible contribution from allergenic modified rosin components cannot be disregarded. When a patient's history indicates a rosin allergy, but a negative response to unmodified rosin in the standard series is observed, additional testing with GMA and MPA or, second best, with glycerol-esterified rosin and maleic-anhydride-modified rosin is recommended. Some modified rosin products, which could be used for additional testing, are suggested.

Abietanes↗
PubMed1983

Production of the modified form of human plasminogen in the plasma activated by urokinase.

Plasminogen, a precursor of proteolytic enzyme plasmin which lyses thrombi in vivo, is postulated to be adsorbed onto fibrin and is converted into a modified form by plasmin. The properties of the modified form examined in vitro support this hypothesis. Nevertheless, it has been postulated that no conversion of native plasminogen into the modified form occurs in plasma, since alpha 2-plasmin inhibitor rapidly inactivates plasmin formed. However, we suggested production of the modified form in the "post-exercise" plasma. The present study was undertaken to examine production of the modified form in a simpler system, urokinase-activated plasma. The amount of the modified form in the plasma was estimated using the previous method with modification, epsilon-aminocaproic acid-containing polyacrylamide gel disc electrophoresis. The amount in the post-exercise plasma was also re-estimated by the present method. The amount of the modified form increased with the increase in urokinase concentration added to plasma. The presence of the modified form in the post-exercise plasma was also confirmed. The modified form could be produced in the plasma where an excess amount of alpha 2-plasmin inhibitor was expected to exist. The present results indicate that conversion of native plasminogen into the modified form may occur in vivo, supporting the hypothesis mentioned above.

Adult↗
PubMed1998

Digestibility and peptide patterns of modified lysozyme after hydrolyzing by protease.

In this study, lysozyme was modified by glucose in the dry state (50 degrees C, RH 75%) and the peptide patterns were investigated using HPLC after hydrolyzing by the pepsin-pancreatin system. Native or modified lysozyme was also administered to rats to clarify digestibility and absorbability in vivo. The digestibility of lysozyme modified by glucose decreased depending on reaction time. In vitro, when lysine residue of lysozyme was modified by glucose at a level of about 50%, the generated peptide patterns with molecular weights (MW) below 3,000 Da were similar to that of native lysozyme, and the yields of peptides from modified lysozyme were lower than those of native lysozyme. However, there are some differences between the hydrolysate patterns of native and modified lysozymes of MW over 10,000 Da, and the yields of these peptides from modified lysozyme are higher than those from native lysozyme. In vivo, the percentage of 30 d-modified lysozyme remaining in rat digestive tracts after 90 min of administration was 11% of the dosage as compared with 0.4% for native lysozyme. However, the digestive peptide patterns of native or modified lysozymes in the rat small intestine were also similar to those of the control. Consequently, it is estimated that modified lysozyme was digested as easily as native lysozyme when the degree of modification of lysine residue by glucose was about 60% even in vivo.

Amino Acids↗
PubMed2000

Transsacral versus modified pelvic landmarks for percutaneous iliosacral screw placement--a computed tomographic analysis and cadaveric study.

The alar roots of the first sacral body are the usual confines for iliosacral screw (IS) placement when stabilizing a sacroiliac joint injury or sacral fracture. The traditional transsacral method of IS placement aligns the screw horizontally through the sacral ala on both the inlet and outlet views of the sacrum. A modified oblique method of IS placement aligns the screw in an oblique fashion, directed inferiorly to superiorly and posteriorly to anteriorly. The purpose of this investigation was to first define the S-1 segment boundaries for both methods of placement by analyzing the 3-dimensional (3-D) composites of 40 pelvic computed tomography (CT) scans, and then to evaluate the actual placement of ISs under fluoroscopy in 10 cadaveric pelves comparing the transsacral with the modified oblique techniques. Critical dimensions of 7.3 mm and 14.6 mm were considered as the diameter sizes of one and two cannulated screws, respectively. From the 3-D CT composites, the mean anterior/posterior (A/P) measurements were 10.9 mm and 18.0 mm, comparing transsacral with modified oblique methods, respectively. Moreover, 9/40 (22.5%) of the transsacral A/P measurements were <7.3 mm, while all of the modified oblique A/P measurements were >7.3 mm. The mean superior/inferior (S/I) measurements were 18.0 mm for transsacral and 26.2 mm for modified oblique placement. Out of 40 transsacral S/I measurements, 4 (10%) were <14.6 mm, while all the modified oblique S/I measurements were >14.6 mm. In the second part of this study, 10 uninjured cadaveric pelves had unilateral percutaneous IS placed under fluoroscopic guidance (inlet, outlet, and lateral projections) by one orthopedic traumatologist. The final position of all 10 screws was confirmed on fluoroscopy by two independent orthopedic trauma surgeons. The first 5 screws were placed by using transsacral pelvic landmarks. Modified landmarks guided the other 5 screws. The accuracy of final screw position was determined by "postoperative" CT scans interpreted by a blinded musculoskeletal radiologist. The screws inserted using transsacral pelvic landmarks were errant in 3 of the 5 cases. Neurovascular complications could be expected from the extraosseous position of all 3 screws. All 5 screws were located within the confines of the S-1 segment by means of the modified oblique technique. Thus, the modified oblique placement technique allowed greater accuracy and reliability over transsacral landmarks in placing percutaneous ISs. The use of the modified oblique pelvic landmarks is warranted during percutaneous iliosacral screw stabilization of the posterior pelvis.

Aged↗
PubMedDate not supplied

A comparative study of modified starches in direct compression of a water soluble drug-chloroquine phosphate.

Some in vitro properties of chloroquine phosphate tablets formulated with four modified starches were investigated. The drug was formulated as tablets containing 250 mg of chloroquine phosphate and produced by the direct compression technique. The starches were isolated from maize, zea mays, rice, Oryza sativa, cassava, Manihot esculenta and cocoyam, Zanthosoma sagittifolium. They were modified through physicochemical process, Sta-Rx 1500, a directly compressible starch was used as basis for comparison. The hardness of the chloroquine tablets generally decreased to a minimum with all the modified starches at concentration level of 40% and with maximum hardness obtained when their concentrations were increased to 80%. The least hardness values were obtained with modified cocoa yam starch while the highest hardness values were obtained with modified rice starch. Modified rice and cassava starches produced chloroquine tablets that exhibited higher mechanical properties than those of modified maize starch, cocoayam starch and Sta-Rx 1500. On the basis of dissolution profile of chloroquine phosphate tablets, the modified starch samples were ranked in order of increasing dissolution as modified cocoayam maize Sta-Rx 1500 cassava rice starch sample. The release rate of chloroquine was found to be dependent on the physico-chemical properties of the individual modified starch granules such as particle size and degree of gelatinization.

Antimalarials↗
PubMed2006

[Animal trials for mPEG-modified red blood cells].

This study was aimed to investigate the survival rate and difference of transfused modified and unmodified RBC at 24 hours. The modified and unmodified RBC from mice, monkey, pig and human were labeled by using FITC, then these blood RBCs were transfused to homogeneous and heterogeneous animals. The result showed that 24 hour survival rate of unmodified mice RBC transfused to mice was 74%, while survival rate of 2.0 mmol/L mPEG-SPA modified mice RBC transfused to mice was 45%, difference between them was significant. The 24 hour survived rate of unmodified human RBC transfused to mice was 8%, while 24 hours survival rate of 2.0 mmol/L mPEG-SPA modified human RBC transfused to mice was 5% without statistical difference. The 24 hour survived rate of homogeneous transfusion of modified monkey RBC was 90%, while survival rate of modified human and pig RBC was zero on 24 hours after transfusion to monkey. It is concluded that RBC labeling methods and mice species are unrelated to 24 hours survival rate, but mPEG variety and concentration are related to mouse RBC life-span. It is incredible to use mouse RBC homogeneous transfusion result instead of human RBC to evaluate longevity and safety of modified human RBC. But modified human RBC transfused to mice can be a model to evaluate longevity of modified human RBC. It is very difficult to get the result about modified RBC life span by RBC transfusion among great heterogeneous mammal animals. So evaluation in large mammal animal models needs to be further studied.

Animals↗
PubMed1990

Immunotherapy with monomethoxypolyethylene glycol modified allergens.

On the basis of the results of experiments in naive mice, i.e., in mice which had not been presensitized, it was anticipated that mPEG-modified allergens would suppress the specific IgE response in allergic humans. However, only minor or no suppression of IgE antibodies was induced on administration of mPEG conjugates in allergic patients with a longstanding IgE response. This observation was later confirmed in pre-sensitized animals. The mPEG-modified allergens can be synthesized in a reproducible manner. This makes mPEG-modified allergens suitable for production and quality control. There is indirect evidence, i.e., identification of IgE and IgG antibody stimulation against all identified allergens, that the relevant determinants are available for processing by the immune system. By contrast, the polymerization of allergens by formaldehyde or glutaraldehyde leads to ill-defined, cross-linked high molecular weight materials. As in the case of other modified allergens, mPEG-modified allergens have been developed primarily because of their lower allergenicity than the original allergen preparations. However, they also retain clinical efficacy of the same magnitude as that induced by unmodified allergen preparations, which is a prerequisite for clinical use. IT with mPEG-modified pollen allergen preparations has been proven to be as effective as IT with unmodified allergens, when these preparations are given in similar doses. Furthermore, a more pronounced beneficial effect can be obtained with higher doses of mPEG-modified allergen, without the risk of side effects which are often precipitated by unmodified allergens. Therefore, it seems reasonable to suggest that children and young adults with developing sensitivity to perennial allergens, and without chronic changes of the bronchial mucosa, are the most suitable candidates for IT with mPEG-modified allergen preparations. Mite asthma, which always includes bronchial inflammation and nonspecific hyperresponsiveness, represents a more complicated model. In mite asthmatics mPEG-modified mite allergen preparations were safer than the corresponding unmodified preparation. Although bronchial sensitivity to allergen and histamine did not change significantly in mite asthmatics during the observation time, it appears that IT with mPEG-modified mite allergen led to a decrease in the releasability of histamine from skin mast cells, as measured by SPT, to a similar degree as observed in pollinosis patients. Therefore, it may be inferred that the allergic component of asthma might be influenced by IT with mPEG allergens. As a consequence, before the start of IT, the degree of reversibility of pathophysiological changes in the bronchial wall should be considered.(ABSTRACT TRUNCATED AT 400 WORDS)

Allergens↗
PubMed1981

Immunochemical studies of DNA modified by cis-dichlorodiammineplatinum(II) in vivo and in vitro.

Two rabbits were immunized with native DNA modified in vitro by cis-dichlorodiammineplatinum(II) (cis-Pt). The interactions between the antiserum and several natural and synthetic nucleic acids were studied primarily by radioimmunoassays. Native DNA's modified by platinum compounds with labile groups in the cis position are recognized by the antiserum. No cross-reaction is found with native DNA's substituted by other platinum compounds [trans-dichlorodiammineplatinum(II), cis-diamminotetrachloroplatinum(IV), and chlorodiethylenetriamminoplatinum(II)] and with natural and synthetic modified polyribonucleotides. cis-Pt-modified oligodeoxyribonucleotides and enzymatically hydrolyzed cis-Pt-modified native DNA do not bind to the antiserum. cis-Pt-modified double-stranded synthetic polydeoxyribonucleotides are either hardly recognized or not recognized at all. The antiserum recognized a modified double-stranded helix in DNA which is not formed in several modified synthetic DNA's and RNA's. At least two different antigenic determinants are present in cis-Pt-modified DNA at a ratio of cis-Pt to bases equal to 0.05. Finally, the antiserum does not react with in vivo cis-Pt-modified DNA.

Animals↗
PubMed1999

Catalytic activity and conformation of chemically modified subtilisin Carlsberg in organic media.

Subtilisin Carlsberg, an alkaline protease from Bacillus licheniformis, was modified with polyoxyethylene (PEG) or aerosol-OT (AOT), and the solubility, conformation, and catalytic activity of the modified subtilisins in some organic media were compared under the same conditions. The solubility of modified subtilisins depended on the solubility of the modifier. On the other hand, the conformational changes depended on the solubility, rather than the property, of the modifier. When the modified subtilisin was dissolved in water-miscible polar solvents such as dimethylsulfoxide, acetonitrile, and tetrahydrofuran, significant conformational changes occurred. When modified subtilisin was dissolved in water-immiscible organic solvents, such as isooctane and benzene, the solvent did not induce significant conformational changes. The catalytic activity in the transesterification reaction of the N-acetyl-L-phenylalanine ethylester of the modified subtilisin in organic solvents was higher than that of native subtilisin. The high activity of modified subtilisin was thought to be due to a homogeneous reaction by the dissolved enzymes.

Bacillus↗
PubMed1993

An immunohistochemical analysis for cancer of the esophagus using monoclonal antibodies specific for modified nucleosides.

BACKGROUND: Modified nucleosides such as 1-methyl-adenosine and pseudouridine exist as minute components of transfer ribonucleic acid (tRNA) and are excreted in the urine in large amounts in the presence of malignancy. Although use of these modified nucleosides as tumor markers has long been studied and many reports have detailed their relationship with malignant tumors and the urinary excretion of various modified nucleosides, there have been no reports on modified nucleosides in esophageal carcinoma. METHODS: Monoclonal antibody patterns against 1-methyladenosine and pseudouridine were studied in esophageal carcinoma, freshly resected esophageal carcinoma tissue specimens fixed in 10% neutral formaldehyde solution, embedded in paraffin, and sectioned for immunohistochemical study. Inhibition enzyme-linked immunosorbent assay (ELISA) was used to examine urinary excretion of these modified nucleosides in patients with esophageal carcinoma. RESULTS: Although rare in normal esophageal epithelium, these modified nucleosides were strongly stained in esophageal carcinoma cells. Most carcinoma cells exhibited a cytoplasmic pattern, although some cells at the infiltrating edge displayed a nuclear pattern. These modified nucleosides were intensely imaged in 11 of 12 cultured esophageal cell lines, the exception being one line that had a much longer doubling time. Using ELISA, urinary excretion of these modified nucleosides was found to be significantly higher in patients with esophageal carcinoma than in healthy subjects; such excretion correlated with carcinoma size and stage and tended to decrease after treatment. CONCLUSIONS: These findings indicate that the modified nucleosides 1-methyladenosine and pseudouridine may be useful as tumor markers for esophageal carcinoma.

Adenosine↗
PubMed2002

Modified scar grade: a prognostic indicator in small peripheral lung adenocarcinoma.

BACKGROUND: Several studies have shown the prognostic value of desmoplasia for lung adenocarcinomas. The authors evaluated the density and extent of desmoplasia by modifying the scar grade, as well as the prognostic impact on patient survival. METHODS: Modified scar grade was defined as follows: Grade 1, no desmoplasia; Grade 2, sparse desmoplastic reaction; Grade 3, dense desmoplastic reaction with diameter of 10 mm or less; Grade 4, dense desmoplastic reaction with diameter exceeding 10 mm. In addition, the prognostic impact of conventional histologic factors and modified scar grade was analyzed in 239 cases of small peripheral lung adenocarcinoma (maximum dimension, </= 30 mm) for which long-term follow-up data were available. RESULTS: The 5 and 10-year survival rates according to the modified scar grade were 100% and 100% for Grade 1 lung adenocarcinoma (n = 29); 91.7% and 83.7% for Grade 2 (n = 61); 67.6% and 52.7% for Grade 3 (n = 78); and 50.0% and 37.5% for Grade 4 (n = 71), respectively. A significant difference in patient survival was found between Grade 1 or 2 versus Grade 3 or 4 (P < 0.0001, by log rank test). Multivariate analysis showed that modified scar grade was an independent prognostic factor (P = 0.0176), as were pathologic stage (P = 0.0293), lymph node metastasis (P = 0.0191), lymphatic permeation (P = 0.0022), and pleural involvement (P = 0.0452). Modified scar grade also had a significant impact on survival in various subsets of patients, including those with pathologic Stage IA disease, patients with tumors of diameter 20 mm or less, or patients with mixed subtype tumors with a bronchioloalveolar component. CONCLUSIONS: Modified scar grade is a useful prognostic factor in patients with small lung adenocarcinomas. Tumors with a sparse fibroblastic reaction (modified scar Grade 2) may represent early invasive cancers or invasive cancers with low malignant potential, which should be distinguished from frankly invasive cancers (modified scar Grade 3 or 4).

Adenocarcinoma↗
PubMedDate not supplied

Modified radical neck dissection in cancer of the mouth, pharynx, and larynx.

A retrospective analysis of 390 determinate radical neck dissections (RND) performed for cancers of the mouth, pharynx, and larynx was carried out. There were 75 patients (19%) who had a modified RND. These were separately analyzed and the outcome was compared to those who had a standard total RND. Our goal was to assess the effectiveness of modified RND in controlling disease in the neck, and to identify its impact on survival and quality of life. Overall neck recurrence rate in the entire modified RND group was 28%, 35% in the partial RND, and 25% in the comprehensive modified RND. Neck recurrence rate was no worse in the comprehensive modified RND for N0 and N1 cases, but increased significantly (as compared to the group of patients with standard RND) in the N2 and N3 cases (52% vs. 33%). Treatment of neck recurrences following modified RND was primarily by surgery, with a 48% 3-year disease-free survival. Overall survival was the same for modified RND (68%) and for standard total RND (63%). This was true for all N stages individually. The morbidity of standard total RND is discussed and the goals of modified RND are analyzed. Definitions and a standardized nomenclature for the various types of modified RND are suggested for uniformity of reporting.

Carcinoma, Squamous Cell↗
PubMed2004

Substrates modified by advanced glycation end-products cause dysfunction and death in retinal pericytes by reducing survival signals mediated by platelet-derived growth factor.

AIMS/HYPOTHESIS: Premature death of retinal pericytes is a pathophysiological hallmark of diabetic retinopathy. Among the mechanisms proposed for pericyte death is exposure to AGE, which accumulate during diabetes. The current study used an in vitro model, whereby retinal pericytes were exposed to AGE-modified substrate and the mechanisms underlying pericyte death explored. METHODS: Pericytes were isolated from bovine retinal capillaries and propagated on AGE-modified basement membrane (BM) extract or non-modified native BM. The extent of AGE modification was analysed. Proliferative responses of retinal pericytes propagated on AGE-modified BM were investigated using a 5-bromo-2-deoxy-uridine-based assay. The effect of extrinsically added platelet-derived growth factor (PDGF) isoforms on these proliferative responses was also analysed alongside mRNA expression of the PDGF receptors. Apoptotic death of retinal pericytes grown on AGE-modified BM was investigated using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling labelling, mitochondrial membrane depolarisation and by morphological assessment. We also measured both the ability of PDGF to reverse Akt dephosphorylation that was mediated by AGE-modified BM, and increased pericyte apoptosis. RESULTS: Retinal pericytes exposed to AGE-modified BM showed reduced proliferative responses in comparison to controls (p<0.05-0.01), although this effect was reversed at low-AGE modifications. PDGF mRNA levels were differentially altered by exposure to low and high AGE levels, and AGE-modified BM caused significantly increased apoptosis in retinal pericytes. Pre-treatment of AGE-modified BM with PDGF-AA and -BB reversed the apoptosis (p<0.05-0.001) and restored Akt phosphorylation in retinal pericytes. CONCLUSIONS/INTERPRETATION: Evidence suggests that substrate-derived AGE such as those that occur during diabetes could have a major influence on retinal pericyte survival. During diabetic retinopathy, AGE modification of vascular BM may reduce bioavailability of pro-survival factors for retinal pericytes.

Animals↗
PubMed1999

Opaque2 modifiers alter transcription of the 27-kDa gamma-zein genes in maize.

Opaque2 modifier genes cause a two- to three-fold increase in the amount of gamma-zein RNA and protein in maize kernels, and can convert the soft, starchy endosperm of an opaque2 mutant to a hard, vitreous phenotype. We analyzed several aspects of transcriptional and post-transcriptional regulation of gamma-zein gene expression in wild-type, opaque2 and modified opaque2 genotypes to investigate the molecular mechanisms by which opaque2 modifiers influence the expression of gamma-zein genes. We found that the poly(A) tails of the gamma-zein RNAs A and B were of similar length in normal, opaque2 and modified opaque2 genotypes. Multiple poly(A) addition sites were detected for the gamma-zein A and B RNAs, but no evidence was obtained that o2 modifiers influence the selection of these sites. Nucleotide sequence analysis of gamma-zein A and B cDNAs derived from 18-DAP endosperm from normal, opaque2, and modified opaque2 kernels confirmed the use of eight different poly(A) addition sites for gamma-zein A transcripts and six different sites for the gamma-zein B transcripts. It also revealed that the A/B gamma-zein RNA ratio in modified opaque2 was at least 40:1, compared to 1:1 in wild type and 3:1 in opaque2. Nuclear run-on transcription assays showed a dramatic shift in the transcription rate of the gamma-zein A gene relative to the B gene in the modified opaque2 genotype. These results are consistent with a model in which the two opaque2 modifier loci influence gamma-zein gene expression through different mechanisms: one affects transcription of the gamma-zein locus and the other influences the steady state level of gamma-zein RNA.

3' Untranslated Regions↗