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Biomedical subjects

A M Schmidt

Publications and source records attributed to A M Schmidt.

At least 91 records · Page 5Linked to original sources
PubMed1996

The receptor for advanced glycation end-products has a central role in mediating the effects of advanced glycation end-products on the development of vascular disease in diabetes mellitus.

Proteins or lipids exposed to aldose sugars undergo initial and ultimately irreversible modification resulting in the formation of so-called advanced glycation end-products (AGEs). AGEs are postulated to be especially important in the setting of diabetes mellitus due to hyperglycaemia characteristic of this disorder. Our work has demonstrated that one of the principal means by which AGEs interact with the vascular wall is by interaction with their cellular receptor, the receptor for advanced glycation end-products (RAGE), which is present on the surface of endothelial cells, smooth muscle cells, mesangial cells, mononuclear phagocytes and certain neurons. AGEs interact with RAGE, resulting in the induction of monocyte chemotaxis as well as oxidant stress. One of the consequences of AGE-RAGE-induced cellular oxidant stress is the enhanced expression of vascular cell adhesion molecule-1 on the endothelial surface, a critical consequence of which is the attraction of mononuclear phagocytes into the vessel wall. In both cases, the pro-inflammatory effects of AGEs may be inhibited in the presence of RAGE blockade, using either anti-RAGE F(ab')2 or soluble RAGE, the extracellular domain of the molecule. These data suggest that inhibition of RAGE may interfere with monocyte chemotaxis and attraction into the vessel wall where AGEs deposit/form, suggesting the potential of this intervention to interfere with a critical step in the development of vascular disease, especially in patients with diabetes.

Animals↗
PubMed1996

Receptors for advance glycation end-products (AGE) - expression by endothelial cells in non-diabetic uraemic patients.

BACKGROUND: Cellular actions of advanced glycation end-products (AGE) are mediated by a receptor for AGE (RAGE), a novel integral membrane protein. Immunohistochemical studies show only low-level RAGE antigen expression in endothelial cells. Design. It was the purposes of the study to compare expression of RAGE antigen by endothelial cells in non-diabetic uraemic patients (n=8) with non-uraemic controls (n=11). Samples of arterial tissue were obtained at the time of renal transplantation (in uraemic patients) and abdominal surgery (in controls). RAGE antigen was visualized using guinea-pig anti-RAGE IgG and PAP technique. RESULTS: Marked staining for RAGE was noted in endothelial cells, both arterial endothelium and endothelium of vasa vasorum of normoglycaemic uraemic patients, but was not demonstrable in endothelial cells of large arteries and only faintly expressed in vasa vasorum of non-uraemic individuals. CONCLUSION: Normal endothelial cells do not constitually express RAGE antigen; in contrast it is expressed by arterial and capillary endothelial cells of uraemic patients. The observation is of note in view of the putative role of AGE of causing atherosclerotic and non-atherosclerotic vascular lesions.

Adult↗
PubMed1996

Advanced glycation endproducts (AGEs) induce oxidant stress in the gingiva: a potential mechanism underlying accelerated periodontal disease associated with diabetes.

We hypothesized that one mechanism underlying advanced periodontal disease in diabetes may involve oxidant stress in the gingiva, induced by the effects of Advanced Glycation Endproducts (AGEs), the irreversible products of non-enzymatic glycation and oxidation of proteins and lipids which accumulate in diabetic plasma and tissue. Infusion of AGE albumin, a prototypic ligand, into mice resulted in increased generation of thiobarbituric acid reactive substances (TBARS) compared with infusion of non-glycated albumin in the gingiva, as well as in the lung, kidney and brain. Pretreatment of the animals with the antioxidants probucol or N-acetylcysteine (NAC) prevented the generation of TBARS in the gingiva. Affinity-purified antibody to AGEs demonstrated increased immunoreactivity for AGEs in the vasculature and connective tissues of the gingiva in streptozotocin-induced diabetic mice compared to non-diabetic controls. Increased immunoreactivity for AGEs was also demonstrated in the gingiva of diabetic humans compared with non-diabetic individuals via immunohistochemistry and ELISA. Consistent with these data, immunohistochemistry for heme oxygenase-1, a marker of enhanced oxidant stress, was increased in the gingival vasculature of diabetic mice and humans compared with non-diabetic controls. These data suggest that AGEs present in diabetic gingiva may be associated with a state of enhanced oxidant stress, a potential mechanism for accelerated tissue injury.

Adult↗
PubMed1996

Cross-language identification of consonants. Part 1. Korean perception of English.

Twenty native Korean-speaking subjects heard 22 English word-initial consonants in three vowel contexts produced by three native English talkers. The subjects orthographically labeled each English consonant as the closest Korean consonant. They then judged how similar the English consonant was to the Korean consonant on a scale of 1 to 5. Some English consonants were labeled consistently as a single Korean consonant and judged to be very similar. Other English consonants were labeled consistently as a single Korean consonant but judged to be less similar. Still other English consonants were inconsistently labeled. Korean acoustic cues, vowel context, and token differences appeared to influence labeling choices.

Adult↗
PubMed1996

Age of learning affects rate-dependent processing of stops in a second language.

The aim of this study was to assess the effect of speaking rate changes on the perception of English stop consonants by four groups of subjects: English and Spanish monolinguals, 'early' Spanish/English bilinguals who learned English in childhood, and 'late' bilinguals who learned English in adulthood. Subjects identified, and then later rated for goodness as exemplars of the English /p/ category, the members of two voice onset time (VOT) continua. The English monolinguals identified a well-defined range of VOT stimuli as English /p/, and stimuli with longer VOT values as 'exaggerated' instances of English /p/. Their goodness ratings increased as VOT increased, then showed a systematic decrease as VOT began to exceed values typical for English /p/. The English monolinguals' goodness ratings also varied systematically as a function of speaking rate, which was simulated in the two continua by varying syllable duration. The Spanish monolinguals, on the other hand, failed to consistently identify any of the stimuli as English /p/. Although speaking rate influenced their goodness ratings, the Spanish monolinguals' rate effects differed significantly from the English monolinguals'. The early bilinguals resembled the English monolinguals, and differed from the Spanish monolinguals to a greater extent than did the late Spanish/English bilinguals. This was taken as support for the hypothesis that early bilinguals are more likely than are late bilinguals to establish new phonetic categories for stop consonants in a second language.

Adolescent↗
PubMed1996

Speaking rate effects on stops produced by Spanish and English monolinguals and Spanish/English bilinguals.

Four groups of 10 subjects each (English and Spanish monolinguals, and two groups of Spanish/English bilinguals) produced Spanish or English sentences at speaking rates designated 'normal', 'slow', and 'fast'. Voice onset time (VOT) was measured in word-initial tokens of /p/ and /t/ found in sentence-initial, -medial, and -final words. The four groups produced comparable changes in sentence duration across the three rates. The speaking rate changes exerted less effect on the VOT in stops spoken by the Spanish than the English monolinguals. Moreover, whereas English monolinguals produced /p,t/ (with shorter VOT at a fast than at a normal rate, many Spanish monolinguals showed a trend in the opposite direction. As expected, all 10 early bilinguals produced English stops with VOT values that were similar to the English monolinguals'. They also showed speaking rate effects on VOT that were similar to those observed for the English monolinguals. The late bilinguals, who had begun learning English as adults, showed smaller effects of speaking rate on VOT than did the English monolinguals. Their mean VOT values for English stops spanned a wide range of values. Just 3 of the late bilinguals produced English stops with VOT values that fell within the range of values observed for the English monolinguals.

Adolescent↗
PubMed1996

RAGE: a novel cellular receptor for advanced glycation end products.

Exposure of proteins to reducing sugars results in nonenzymatic glycation with the ultimate formation of advanced glycation end products (AGEs). One means through which AGEs modulate cellular functions is through binding to specific cell surface acceptor molecules. The receptor for AGEs (RAGE) is such a receptor and is a newly identified member of the immunoglobulin superfamily expressed on endothelial cells (ECs), mononuclear phagocytes (MPs), and vascular smooth muscle cells (SMCs) in both vivo and in vitro. Binding of AGEs to RAGE results in induction of cellular oxidant stress, as exemplified by the generation of thiobarbituric acid-reactive substances, expression of heme oxygenase type I, and activation of the transcription factor NF-kB, with consequences for a range of cellular functions. AGEs on the surface of diabetic red cells enhance binding to endothelial RAGE and result in enhanced oxidant stress in the vessel wall. By using reagents to selectively block access to RAGE, the role of this receptor in AGE-mediated perturbation of cellular properties can be dissected in detail.

Animals↗
PubMed1996

Endothelial cell dysfunction secondary to the adhesion of diabetic erythrocytes. Modulation by iloprost.

We previously showed the correlation between the extent of vascular complications and erythrocyte adherence to endothelium in diabetes mellitus. The accumulation of advanced glycation end products (AGEs) on the erythrocyte surface in diabetes mediates their interaction with endothelial cells through a specific endothelial receptor for AGEs (RAGE). Binding of diabetic erythrocytes to endothelial cells resulted in evidence of oxidant stress responsible for a range of cellular perturbations. In the present study, we have investigated the effect of iloprost, a prostacyclin analog, on several activities modified by diabetic erythrocyte-endothelium interaction: 1) generation of oxidant stress based on production of thiobarbituric acid reactive substances (TBARS: control: 2.37 +/- 0.32 versus iloprost: 1.39 +/- 0.005 mumol/10(11) cells), 2) alteration of the endothelial barrier function as measured by an increase permeability to 125I-albumin (control: 13.31 +/- 0.85 versus iloprost: 9.45 +/- 0.7 10(-7) cm/s) of the endothelial cell monolayer, 3) modification of the endothelial cell function showed by an increase in interleukin-6 release (control: 21.66 +/- 3.11 versus iloprost 15.45 +/- 0.76 ng/10(6) cells). The increase in permeability to albumin as well ass TBARS production and interleukin-6 release were inhibited by iloprost (10(-8)-10(-6) mol/l) treatment in a dose-dependent fashion. These results indicate that erythrocyte associated AGEs might alter endothelial cell function. The perturbations can be limited in vitro by iloprost.

Adult↗
PubMed1995

Calreticulin, an antithrombotic agent which binds to vitamin K-dependent coagulation factors, stimulates endothelial nitric oxide production, and limits thrombosis in canine coronary arteries.

Coagulation Factor IX/IXa has been shown to bind to cellular surfaces, and Factor IXa expresses its procoagulant activity by assembling into the intrinsic Factor X activating complex (Factors IXa/VIIIa/X), which also forms on membrane surfaces. This led us to identify cellular proteins which bind Factor IX/IXa; an approximately 55-kDa polypeptide was purified to homogeneity from bovine lung extracts based on its capacity to bind 125I-Factor IX in a dose-dependent and saturable manner. From protein sequence data of the amino terminus and internal peptides, the approximately 55-kDa polypeptide was identified as calreticulin, a previously identified intracellular calcium-binding protein. Recombinant calreticulin bound vitamin K-dependent coagulation factors, 125I-Factor IX, 125I-Factor X, and 125I-prothrombin (Kd values of approximately 2.7, 3.2, and 8.3 nM, respectively), via interaction with its C-domain, although it did not affect the coagulant properties of these proteins. 125I-Calreticulin also bound to endothelial cells in vitro (Kd approximately 7.4 nM), and mouse infusion studies showed an initial rapid phase of clearance in which calreticulin could be localized on the vascular endothelium. Exposure of endothelial cells to calreticulin led to dose-dependent, immediate, and sustained increase in the production of nitric oxide, as measured using a porphyrinic microsensor. In a canine electrically induced thrombosis model, intracoronary infusion of calreticulin (n = 7) prevented occlusion of the left circumflex coronary artery in a dose-dependent manner compared with vehicle-treated controls (n = 5). These results indicate that calreticulin interacts with the endothelium to stimulate release of nitric oxide and inhibit clot formation.

Animals↗
PubMed1995

Optic nerve fiber count and diameter of the retrobulbar optic nerve in normal and glaucomatous eyes.

BACKGROUND: The caliber of the retrobulbar optic nerve and the count of optic nerve fibers vary considerably in normals. The diameter of the retrobulbar optic nerve also decreases with optic nerve atrophy. This study aimed to determine the relationship between the caliber of the optic nerve and the optic nerve fiber count. METHODS: We counted the optic nerve fibers and measured the diameter of histological cross sections of the optic nerve for 56 normal subjects and 23 patients with absolute glaucoma. RESULTS: The optic nerve fiber count increased significantly (P < 0.0001) by 777,000 fibers for every millimeter increase in retrobulbar optic nerve diameter, starting at a baseline diameter of 1.89 mm. CONCLUSION: Using this linear regression equation, the optic nerve fiber count can be estimated in routine histology by measuring the optic nerve diameter. Taking into account a fixation-induced tissue shrinkage, this method may also give some indication of the optic nerve fiber count intravitally, when, for eyes with opaque optic media, the diameter of the retrobulbar optic nerve has been measured by imaging techniques. Greater retrobulbar optic nerve caliber may indicate greater structural reserve capacity.

Adult↗
PubMed1995

Traditional and phonological treatment for teaching English fricatives and affricates to Koreans.

Non-native speakers of English are being seen for accent reduction in speech-language pathology clinics although there is little evidence that treatment is effective. Two types of treatment were evaluated. Traditional articulation-based treatment was successful for 2 native Korean speakers in improving English fricatives and affricate production. A second treatment using phonologically based contrasts was also successful for the same sounds with 2 other Korean speakers. Some issues in foreign accent reduction are discussed.

Humans↗
PubMed1995

Effects of speaking rate changes on native and nonnative speech production.

Twenty monolingual English speakers and 40 native Spanish speakers, who were either relatively proficient or nonproficient in English, produced English /p/ at self-selected normal and fast speaking rates. The native English (NE) subjects showed much the same rate effect on voice onset time (VOT) seen in earlier studies. Native Spanish (NS) subjects who were relatively proficient in pronouncing English used fewer short-lag stops and showed an English-like rate effect on VOT. NS subjects who were relatively nonproficient in English, on the other hand, used more short-lag stops and did not show a significant speaking rate effect on VOT, although they did demonstrate speaking rate effects on vowel duration and phrase duration. Among the NS subjects were 21 whose VOT values closely matched those of the NE subjects at both speaking rates, and who showed a rate effect similar to that found for the NE subjects. Their ability to modify VOT across speaking rates suggested that these NS subjects may have established a phonetic category for English /p/.

Adult↗
PubMed1995

Native speakers of Spanish show rate-dependent processing of English stop consonants.

English monolinguals and native Spanish speakers of English used a 9-point scale to rate syllable-initial stops for goodness as realizations of the English /p/ category. Voice onset time (VOT) was varied in a set of short-duration ('fast-rate') consonant-vowel (CV) stimuli, and in a set of longer-duration ('slow-rate') CV stimuli. The VOT values ranged from values typical for English /b/ to values which exceeded those typical for English /p/. Results for the native English (NE) subjects replicated those obtained previously using the same two continua. Goodness ratings systematically increased, then decreased as VOT values extended beyond the range typical for English /p/. The NE subjects gave their highest ratings to stimuli with VOT values of about 50 ms. For stops with longer VOT values, their ratings were higher for stimuli in the slow-rate than fast-rate continuum. The native Spanish (NS) subjects were assigned to two subgroups based on degree of foreign accent in their pronunciation of English sentences. Both proficient and nonproficient NS subjects gave their highest ratings to stimuli with much the same VOT values as the NE subjects, even though /p/ is realized with short-lag VOT in Spanish. The nonproficient, but not the proficient NS subjects showed significantly smaller rate effects on goodness ratings than did the NE subjects. However, the subjects in both NS groups gave significantly higher ratings to stimuli with short-lag VOT values than did the NE subjects. The results are discussed in terms of the hypothesis that adult learners of a second language may establish new perceptual phonetic categories for phonetic segments not found in the native language.

Adult↗
PubMed1995

Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes.

Vascular cell adhesion molecule-1 (VCAM-1), an inducible cell-cell recognition protein on the endothelial cell surface (EC), has been associated with early stages of atherosclerosis. In view of the accelerated vascular disease observed in patients with diabetes, and the enhanced expression of VCAM-1 in diabetic rabbits, we examined whether irreversible advanced glycation endproducts (AGEs), could mediate VCAM-1 expression by interacting with their endothelial cell receptor (receptor for AGE, RAGE). Exposure of cultured human ECs to AGEs induced expression of VCAM-1, increased adhesivity of the monolayer for Molt-4 cells, and was associated with increased levels of VCAM-1 transcripts. The inhibitory effect of anti-RAGE IgG, a truncated form of the receptor (soluble RAGE) or N-acetylcysteine on VCAM-1 expression indicated that AGE-RAGE-induced oxidant stress was central to VCAM-1 induction. Electrophoretic mobility shift assays on nuclear extracts from AGE-treated ECs showed induction of specific DNA binding activity for NF-kB in the VCAM-1 promoter, which was blocked by anti-RAGE IgG or N-acetylcysteine. Soluble VCAM-1 antigen was elevated in human diabetic plasma. These data are consistent with the hypothesis that AGE-RAGE interaction induces expression of VCAM-1 which can prime diabetic vasculature for enhanced interaction with circulating monocytes.

Animals↗
PubMed1995

Expression of receptors for advanced glycosylated end-products in renal disease.

BACKGROUND: Advanced glycation endproducts (AGEs) are believed to mediate long-term complications in diabetes mellitus. In this context we studied the expression of the receptor for AGEs (RAGE) in the kidney of patients with a variety of different renal diseases. METHODS: RAGE was detected by immunocytochemistry in renal biopsies. We compared the staining for RAGE in nine patients with diabetic nephropathy, 20 with inflammatory and/or immune complex and 10 with non-inflammatory renal diseases. Normal renal tissue from seven patients with tumour nephrectomies served as controls. RESULTS: In controls the only cells expressing RAGE constitutively were interstitial cells and vascular smooth muscle cells (6/7), while distal tubular cells were rarely positive (1/7). Endothelial cells of arteries/arterioles, glomerular endothelial cells, podocytes, and capsular epithelial cells were consistently negative. In diabetic nephropathy, inflammatory and/or immune complex, and non-inflammatory renal diseases, all cell types mentioned above became positive for RAGE. Whilst the distribution of RAGE in the tissue was quite similar, staining intensity in inflammatory and/or immune complex diseases was higher than in diabetic nephropathy. CONCLUSION: RAGE induction in the kidney is not specific for diabetic nephropathy and occurs in other types of renal diseases as well.

Adolescent↗
PubMed1994

Receptor for advanced glycation end products (AGEs) has a central role in vessel wall interactions and gene activation in response to circulating AGE proteins.

The extended interaction of aldoses with proteins or lipids results in nonenzymatic glycation and oxidation, ultimately forming AGEs, the presence of which in the plasma and vessel wall is associated with diabetic vascular complications. We show here that AGE albumin in the intravascular space interacts with the vessel wall via binding to an integral membrane protein, receptor for AGE (RAGE), a member of the immunoglobulin superfamily, resulting in clearance from the plasma and induction of interleukin 6 mRNA. Intravenously infused 125I-AGE albumin showed a rapid phase of plasma clearance with deposition in several organs. Rapid removal of 125I-AGE albumin from the plasma was prevented by administration of a soluble, truncated form of RAGE, which blocked binding of 125I-labeled AGE albumin to cultured endothelial cells and mononuclear phagocytes, as well as by pretreatment with anti-RAGE IgG. Ultrastructural studies with AGE albumin-colloidal gold conjugates perfused in situ showed that in murine coronary vasculature this probe was taken up by endothelial plasmalemmal vesicles followed by transport either to the abluminal surface or by accumulation in intracellular vesicular structures reminiscent of endosomes and lysosomes. Consequences of AGE-RAGE interaction included induction of interleukin 6 mRNA expression in mice. These data indicate that RAGE mediates the interaction of AGEs with the vessel wall, both for removal of these glycated proteins from the plasma and for changes in gene expression.

Animals↗
PubMed1994

Advanced glycation end products (AGEs) on the surface of diabetic erythrocytes bind to the vessel wall via a specific receptor inducing oxidant stress in the vasculature: a link between surface-associated AGEs and diabetic complications.

Vascular complications are an important cause of morbidity and mortality in patients with diabetes. The extent of vascular complications has been linked statistically to enhanced adherence of diabetic erythrocytes to endothelial cells (ECs) and to the accumulation of a class of glycated proteins termed advanced glycation end products (AGEs). We hypothesized that formation of AGEs on the surface of diabetic erythrocytes could mediate their interaction with ECs leading to binding and induction of vascular dysfunction. Enhanced binding of diabetic erythrocytes to ECs was blocked by preincubation of erythrocytes with anti-AGE IgG or preincubation of ECs with antibodies to the receptor for AGE (RAGE). Immunoblotting of cultured human ECs and immunostaining of normal/diabetic human tissue confirmed the presence of RAGE in the vessel wall. Binding of diabetic erythrocytes to endothelium generated an oxidant stress, as measured by production of thiobarbituric acid-reactive substances (TBARS) and activation of the transcription factor NF-kappa B, both of which were blocked by probucol or anti-RAGE IgG. Erythrocytes from diabetic rats infused into normal rats had an accelerated, early phase of clearance that was prevented, in part, by antibody to RAGE. Liver tissue from rats infused with diabetic erythrocytes showed elevated levels of TBARS, which was prevented by pretreatment with anti-RAGE IgG or probucol. Thus, erythrocyte surface AGEs can function as ligands that interact with RAGE on endothelium. The extensive contact of diabetic erythrocytes bearing surface-associated AGEs with vessel wall RAGE could be important in the development of vascular complications.

Animals↗