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Reed E Pyeritz

Publications and source records attributed to Reed E Pyeritz.

9 recordsLinked to original sources
PubMed2003

Endoplasmic reticulum stress induces hyaluronan deposition and leukocyte adhesion.

There is mounting evidence that perturbations in endoplasmic reticulum (ER) function play a key role in the pathogenesis of a broad range of diseases. We have examined the ability of ER stress to modulate leukocyte binding to colonic and aortic smooth muscle cells. In vitro, control smooth muscle cells bind few leukocytes, but treatment with compounds that induce ER stress, including tunicamycin, A23187, and thapsigargin, promotes leukocyte binding. Likewise, dextran sulfate, another agent capable of inducing ER stress and promoting inflammation in vivo, strongly induces leukocyte adhesion. The bound leukocytes are released by hyaluronidase treatment, indicating a critical role for hyaluronan-containing structures in mediating leukocyte binding. Affinity histochemistry demonstrated that hyaluronan accumulates and is present in cable-like structures in the treated, but not the untreated, cultures and that these structures serve as attachment sites for leukocytes. Hyaluronan-rich regions of both murine and human inflamed colon contain numerous cells that stain intensely for ER-resident chaperones containing the KDEL sequence, demonstrating a relationship between ER stress and hyaluronan deposition in vivo. These results indicate that ER stress may contribute to chronic inflammation by forming a hyaluronan-rich extracellular matrix that is conducive to leukocyte binding.

Animals↗
PubMed2002

Homocysteine binds to human plasma fibronectin and inhibits its interaction with fibrin.

OBJECTIVE: More than 70% of circulating homocysteine is disulfide-bonded to protein, but little is known about the specific proteins that bind homocysteine and their function as a consequence of homocysteine binding. METHODS AND RESULTS: When human plasma was incubated with [(35)S]L-homocysteine, most of the homocysteine bound to albumin. However, additional homocysteine-binding proteins were detected, and 1 of them comigrated with fibronectin. Treatment with 2-mercaptoethanol removed the bound homocysteine, demonstrating the involvement of disulfide bonding. In contrast, [35S]L-cysteine did not bind to fibronectin. Purified fibronectin bound approximately 5 homocysteine molecules per fibronectin dimer. SDS-PAGE of a limited trypsin digestion of homocysteinylated fibronectin showed that several tryptic fragments contained [35S]homocysteine. Sequence analysis demonstrated that the fragments containing bound homocysteine had localized mainly to the C-terminal region, within and adjacent to the fibrin-binding domain. Homocysteinylation of fibronectin significantly inhibited its capacity to bind fibrin by 62% (P<0.005). In contrast, neither the binding of fibronectin to gelatin nor its capacity to serve as an attachment factor for aortic smooth muscle cells was affected. CONCLUSIONS: These results suggest that homocysteine may alter normal thrombosis and delay or interfere with wound healing by impairing the interaction of fibronectin with fibrin.

Arteriosclerosis↗
PubMed2002

Growth and maturation in Marfan syndrome.

Understanding the growth pattern in Marfan syndrome is important for prediction of expected growth, prevention of excessive growth by hormone therapy, timing of surgical epiphysiodesis for cessation of growth, and instituting brace treatment for scoliosis. In this study, we analyze growth patterns and generate growth charts for persons with Marfan syndrome. From the charts of 180 clinically diagnosed Marfan patients, longitudinal height and weight measurements were obtained. From this data, growth charts and growth velocity charts were generated for males and females. Skeletal maturation was studied by determining the Risser signs from the x-rays of 71 males and 56 females. From 22 female patients, age of menarche was available and retrieved either by reviewing the charts or contacting the patients. Mean length at birth was 53 +/- 4.4 cm for males and 52.5 +/- 3.5 cm for females. Mean final height was 191.3 +/- 9 cm for males and 175.4 +/- 8.2 cm for females. Mean birth weight was 3.51 +/- 0.74 kg for males and 3.48 +/- 0.68 kg for females. The puberty-associated peak in growth velocity was 2.4 years earlier than the gender-matched general population for males with Marfan syndrome and 2.2 years earlier for females. Age of menarche was 11.7 +/- 2 years of age, which is also early compared to the general population. This study suggests that the growth spurt and pubertal skeletal maturation occur early in Marfan syndrome. The growth curves generated should help more accurately predict adult stature, as well as monitor progression toward it.

Adolescent↗
PubMed2002

Genetic counseling for congenital heart disease: new approaches for a new decade.

Congenital heart disease (CHD), which occurs in about 0.7% of all live-born children, is the leading cause of death from birth defects. Understandably, parents of patients, and increasingly patients themselves, are interested in the risk that further offspring will be affected. Advances in genetics now permit accurate estimation for many forms of CHD, especially the identification of patients and families with recurrence risks of up to 50%. The increased availability of genetic information, combined with the use of noninvasive imaging to look for subtle defects and targeted genetic testing, have demonstrated that the relevant question to ask about an individual's apparently isolated CHD is whether it is syndromic or familial. Syndromes that involve clinically important noncardiac findings may best be managed by, or in consultation with, a clinical geneticist. Other familial syndromes remain entirely within the purview of the cardiologist. The practicing cardiologist needs to continue to stay abreast of genetic discoveries in the field of CHD in order to provide proper management, including genetic counseling, to patients and their families.

Genetic Counseling↗
PubMed2002

Upregulation of smooth muscle cell collagen production by homocysteine-insight into the pathogenesis of homocystinuria.

Patients with untreated homocystinuria have widespread premature atherosclerosis with intimal thickening and collagen-rich, fibrous plaques. We previously demonstrated that homocysteine (Hcy) upregulates collagen synthesis and accumulation by arterial smooth muscle cells (SMCs) [A. Majors, L.A. Ehrhart, E.H. Pezacka, Arterioscler. Thromb. Vasc. Biol. 17 (1997) 2074-2081] but the underlying mechanisms are not known. Since many of the effects of Hcy on intact vessels and vascular cells are thought to involve reactive oxygen species generated from Hcy oxidation, we investigated the role of reactive oxygen species in the upregulation of collagen production by Hcy. Treatment of SMCs with 300 microM l-Hcy increased collagen accumulation 2-3-fold. When added to culture medium containing serum, the exogenous Hcy was rapidly oxidized with a half-life of approximately 1 h but only very low amounts of H(2)O(2) (up to 2 microM) were detected. Three lines of evidence demonstrate that the increased accumulation of collagen was not mediated by reactive oxygen species generated from Hcy oxidation: (1) catalase in the medium did not block the accumulation of collagen in Hcy-treated cultures; (2) the addition of xanthine/xanthine oxidase, a system that generates superoxide and H(2)O(2), did not increase collagen accumulation; and (3) the direct addition of H(2)O(2) did not substantially enhance collagen accumulation. In contrast, heparin, a potent modulator of SMC function, significantly blocked the accumulation of collagen in Hcy-treated cultures. Together, these results demonstrate that the increase in collagen accumulation in Hcy-treated cultures involves alternate mechanisms not involving H(2)O(2).

Animals↗
PubMed2002

Mechanisms and consequences of somatic mosaicism in humans.

Somatic mosaicism -- the presence of genetically distinct populations of somatic cells in a given organism -- is frequently masked, but it can also result in major phenotypic changes and reveal the expression of otherwise lethal genetic mutations. Mosaicism can be caused by DNA mutations, epigenetic alterations of DNA, chromosomal abnormalities and the spontaneous reversion of inherited mutations. In this review, we discuss the human disorders that result from somatic mosaicism, as well as the molecular genetic mechanisms by which they arise. Specifically, we emphasize the role of selection in the phenotypic manifestations of mosaicism.

Cell Lineage↗
PubMedDate not supplied

Leg-length discrepancy and scoliosis in Marfan syndrome.

Leg-length discrepancy (LLD) greater than 2 cm is rare in the general population and is associated with a lumbar postural scoliosis; it has not been studied in the setting of Marfan syndrome. Thirteen LLDs of 2 cm or more were recorded from a group of 250 Marfan patients visiting a medical genetics clinic for complete care. Diagnosis was confirmed by standing anteroposterior pelvic radiograph and/or scanogram. Records and anteroposterior radiographs of the spine were reviewed to obtain Cobb angles for spinal curvatures. A mean discrepancy of 3.2 +/- 1.0 cm and a Cobb angle of 37.0 degrees +/- 28.4 degrees were found. Twelve of 13 curves were convex toward the shorter leg, caudally. Twelve patients had scoliosis greater than 10 degrees. Five curves were severe and progressive, suggesting the need for spinal fusion and prior equalization of leg lengths. LLD correlated weakly with Cobb angle. LLD is more common in individuals with Marfan syndrome than in the general population and is associated with increased structural scoliosis.

Adolescent↗