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PubMed2003

Hyperoxia induces retinal vascular endothelial cell apoptosis through formation of peroxynitrite.

Hyperoxia exposure induces capillary endothelial cell apoptosis in the developing retina, leading to vaso-obliteration followed by proliferative retinopathy. Previous in vivo studies have shown that endothelial nitric oxide synthase (NOS3) and peroxynitrite are important mediators of the vaso-obliteration. Now we have investigated the relationship between hyperoxia, NOS3, peroxynitrite, and endothelial cell apoptosis by in vitro experiments using bovine retinal endothelial cells (BREC). We found that BREC exposed to 40% oxygen (hyperoxia) for 48 h underwent apoptosis associated with activation of caspase-3 and cleavage of the caspase substrate poly(ADP-ribose) polymerase. Hyperoxia-induced apoptosis was associated with increased formation of nitric oxide, peroxynitrite, and superoxide anion and was blocked by treatment with uric acid, nitro-L-arginine methyl ester, or superoxide dismutase. Analyses of the phosphatidylinositol 3-kinase/Akt kinase survival pathway in cells directly treated with peroxynitrite revealed inhibition of VEGF- and basic FGF-induced activation of Akt kinase. These results suggest that hyperoxia-induced formation of peroxynitrite induces BREC apoptosis by crippling key survival pathways and that blocking peroxynitrite formation prevents apoptosis. These data may have important clinical implications for infants at risk of retinopathy of prematurity.

Animals↗

PubMed2003

High-level activation by a duodenum-specific enhancer requires functional GATA binding sites.

The purine metabolic gene adenosine deaminase (ADA) is expressed at high levels in a well-defined spatiotemporal pattern in the villous epithelium of proximal small intestine. A duodenum-specific enhancer module responsible for this expression pattern has been identified in the second intron of the human ADA gene. It has previously been shown that binding of the factor PDX-1 is essential for function of this enhancer. The studies presented here examine the proposed roles of GATA factors in the enhancer. Site-directed mutagenesis of the enhancer's GATA binding sites crippled enhancer function in 10 lines of transgenic mice, with 9 of the lines demonstrating <1% of normal activity. Detailed studies along the longitudinal axis of mouse small intestine indicate that GATA-4 and GATA-5 mRNA levels display a reciprocal pattern, with low levels of GATA-6 throughout. Interestingly, gel shift studies with duodenal nuclear extracts showed binding only by GATA-4.

Adenosine Deaminase↗

PubMed2004

Regenerative capacity of the dystrophic (mdx) diaphragm after induced injury.

Duchenne muscular dystrophy is characterized by myofiber necrosis, muscle replacement by connective tissue, and crippling weakness. Although the mdx mouse also lacks dystrophin, most muscles show little myofiber loss or functional impairment. An exception is the mdx diaphragm, which is phenotypically similar to the human disease. Here we tested the hypothesis that the mdx diaphragm has a defective regenerative response to necrotic injury, which could account for its severe phenotype. Massive necrosis was induced in mdx and wild-type (C57BL10) mouse diaphragms in vivo by topical application of notexin, which destroys mature myofibers while leaving myogenic precursor satellite cells intact. At 4 h after acute exposure to notexin, >90% of diaphragm myofibers in both wild-type and mdx mice demonstrated pathological sarcolemmal leakiness, and there was a complete loss of isometric force-generating capacity. Both groups of mice showed strong expression of embryonic myosin within the diaphragm at 5 days, which was largely extinguished by 20 days after injury. At 60 days postinjury, wild-type diaphragms exhibited a persistent loss ( approximately 25%) of isometric force-generating capacity, associated with a trend toward increased connective tissue infiltration. In contrast, mdx diaphragms achieved complete functional recovery of force generation to noninjured values, and there was no increase in muscle connective tissue over baseline. These data argue against any loss of intrinsic regenerative capacity within the mdx diaphragm, despite characteristic features of major dystrophic pathology being present. Our findings support the concept that significant latent regenerative capacity resides within dystrophic muscles, which could potentially be exploited for therapeutic purposes.

Animals↗

PubMed2005

Predisposition for venoconstriction in the equine laminar dermis: implications in equine laminitis.

Equine laminitis is a crippling condition associated with a variety of systemic diseases. Although it is apparent that the prodromal stages of laminitis involve microvascular dysfunction, little is known regarding the physiology of this vasculature. The aim of the present study was to determine the relative responses of equine laminar arteries and veins to the vasoconstrictor agonists phenylephrine (1 nM-10 microM), 5-HT (1 nM-10 microM), PGF2alpha (1 nM-100 microM), and endothelin-1 (1 pM-1 microM). We have determined that laminar veins were more sensitive, with respect to the concentration of agonist required to initiate a contractile response and to achieve EC(50), for all agonists tested. EC50 values, for veins and arteries, respectively, were 84+/-7 vs. 688+/-42 nM for phenylephrine, 35+/-6 vs. 224+/-13 nM for 5-HT, 496+/-43 nM vs. 3.0+/-0.6 microM for PGF2alpha, and 467+/-38 pM vs. 70.6+/-6.4 nM for endothelin-1. Moreover, when expressed as a percentage of the response to a depolarizing stimulus (80 mM potassium), the maximal contractile response of laminar veins exceeded that for the laminar arteries for each agonist. These results indicate that there may be a predisposition for venoconstriction within the vasculature of the equine digit. While this physiological predisposition for venoconstriction may be important in the regulation of blood flow during exercise, it also may help to explain why laminitis can result from a variety of pathological systemic conditions.

Animals↗

PubMed2000

Primary atrophic profound linear scleroderma. Report of three cases.

We present 3 unusual cases of deep linear, primary atrophic scleroderma, not preceded by inflammatory reaction and sclerosis, involving the subcutis and deeper tissues. These cases differ in the course and prognosis from typical profound scleroderma since they do not lead to disfiguration and crippling deformities. In contrast to the atrophies left after regression of morphea or linear scleroderma, they do not involve the dermis, which does not show discoloration or changes in texture. Infiltrates in the endomysium, involvement of deeper tissues and the progressive character of the disease argue for atypical primary atrophic profound scleroderma. The coexistence in one case of primary facial hemiatrophy appears to indicate also its relationship with primary linear atrophies of the limbs.

Adult↗

PubMed2004

Power loss for linkage analysis due to the dichotomization of trichotomous phenotypes.

OBJECTIVES: Some traits, while naturally polychotomous, are routinely dichotomized for genetic analysis. Dichotomization, intuitively, leads to a loss of power to detect linkage, as some phenotypic variability is discarded. This paper examines this power loss in the context of a trichotomous trait. METHODS: To examine this power loss, we performed a simulation study where a trichotomous trait was simulated in a sample of 1,000 sib-pairs under various genetic models. The study was replicated 1,000 times. Linkage analysis using a variance components method, as implemented in Mx, was then performed on the trichotomous trait and compared with that on a dichotomized version of the trait. RESULTS: A comparison of the power and false positive rates of the analyses shows that power to detect linkage was increased by up to 22 percentage points simply by examining the trait as a trichotomy instead of a dichotomy. Under all models examined, the trichotomous analysis outperformed the dichotomous version. CONCLUSIONS: Comparable levels of false positive rates under both methods confirm that this power gain comes solely from the information lost upon dichotomization. Thus, dichotomizing tri- or poly-chotomous traits can lead to crippling power loss, especially in the case of many loci of small effect.

Alleles↗

PubMed2005

Early prediction of acute renal injury using urinary proteomics.

AIMS: The lack of early biomarkers for acute renal failure (ARF) has crippled our ability to launch potentially effective therapeutic measures. We tested the hypothesis that urinary proteomics could identify novel early biomarker patterns for ischemic renal injury. METHODS: Sixty patients undergoing cardiopulmonary bypass (CPB) were enrolled. Urine samples obtained at 2 and 6 h post CPB were analyzed by Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS). The primary outcome variable was ARF, defined as a 50% or greater increase in serum creatinine. RESULTS: Fifteen patients (25%) developed ARF 2-3 days after CPB. SELDI-TOF-MS analysis of urine from the ARF group at baseline versus at 2 and 6 h post-CPB consistently showed a marked and statistically significant enhancement of protein biomarkers with m/z of 6.4, 28.5, 43 and 66 kDa. The same biomarkers were enhanced when comparing control versus ARF groups at 2 and 6 h post-CPB. The sensitivity and specificity of the 28.5-, 43- and 66-kDa biomarkers for the prediction of ARF at 2 h following CPB was 100%. The receiver operating characteristic curves revealed an area under the curve of 0.98. CONCLUSION: SELDI-TOF-MS is a novel, non-invasive, sensitive, highly predictive, reproducible, rapid method for the prediction of acute renal injury following CPB.

Acute Kidney Injury↗

PubMed2006

Distal hypospadias repair in adults: the results of 97 cases.

INTRODUCTION: We reviewed our 9-year experience on 97 men with distal hypospadias who had undergone hypospadias surgeries. SUBJECTS AND METHODS: Patients were divided into two groups: group 1 included 17 men who had one or more unsuccessful surgeries in their childhood, and group 2 included 80 men with no previous hypospadias repairs. Meatal positions were glanular in 6, coronal in 35 and subcoronal in 56 patients. Our 97 hypospadias surgeries involved 42 meatal advancement and glanuloplasty, 41 Mathieu and 14 tubularized incised plate urethroplasty procedures. RESULTS: The overall success rate was 88% (86 of the 97 patients). The success rate was 76.5% for group 1 (13 of the 17 patients) and 91.3% for group 2 (73 of the 80 patients). Better voiding function and good cosmetic appearance was achieved in all patients. Urinary flow rates were significantly higher in all groups postoperatively. The success rates were 91.4 and 85% for the patients with preoperative coronal and subcoronal meatal positions, respectively. The success rate was significantly lower in crippled cases and in cases with longer neourethra. CONCLUSION: Although the same techniques are used for children and adults in hypospadias surgery, the results in adults differ from those in children. The success rate for primary adult cases is quite acceptable, but it is decreased in patients having longer neourethra and having multiple previous interventions.

Adult↗

PubMed2006

Recapitulation of embryological programmes in renal fibrosis--the importance of epithelial cell plasticity and developmental genes.

Chronic fibrosis represents the final common pathway in progressive renal disease. Myofibroblasts deposit the constituents of renal scar, thus crippling renal function. It has recently emerged that an important source of these pivotal effector cells is the injured renal epithelium. This review concentrates on the process of epithelial-mesenchymal transition (EMT) and its regulation. The role of the developmental gene, gremlin, which is reactivated in adult renal disease, is the subject of particular focus. This member of the cysteine knot protein superfamily is critical to the process of nephrogenesis but quiescent in normal adult kidney. There is increasing evidence that gremlin expression reactivates in diabetic nephropathy, and in the diseased fibrotic kidney per se. Known to antagonize members of the bone morphogenic protein (BMP) family, gremlin may also act downstream of TGF-beta in induction of EMT. An increased understanding of the extracellular modulation of EMT and, in particular, of the gremlin-BMP axis may result in strategies that can halt or reverse the devastating progression of chronic renal fibrosis.

Animals↗

PubMed1995

Molecular and cytological evidence of S-adenosyl-L-homocysteine as an innocuous undermethylating agent in vivo.

Undermethylating agents are frequently used in the study of DNA methylation. However, the drugs of choice to induce experimental DNA undermethylation, 5-azacytidine and 5-aza-2'-deoxycytidine, are known to be cytotoxic. We report on S-adenosyl-L-homocysteine (SAH) as an alternative agent for inducing undermethylation of human DNA in vivo. The molecular and cytological evidence presented in this paper clearly suggests that SAH could be even more efficient than the cytidine analogs; in addition, SAH does not exhibit the secondary toxic effects that cripple the usefulness of cytidine analogs.

Base Sequence↗

PubMed1990

Nude mice are not hairless. A morphological study.

In the present study, the morphological aspect of the skin and the hairs of athymic, macroscopically nude mice (NMRI, nu/nu) was investigated by descriptive light- and electron-microscopical methods and compared with the appearance of the skin and the hairs in normally haired mice (NMRI). These morphological studies revealed that athymic, macroscopically nude mice are not at all hairless, but have about the same number of hair bulbs, embedded in the hypodermis, as normally haired animals. However, within the hair follicles of athymic mice, the keratinization processes are obviously deeply impaired, resulting in the formation of short, crippled and bent hair shafts which only seldom emerge from the hair follicles. The cuticles of the inner root sheath and the hair are not built up, the cortex of the hair being composed by abnormal globular aggregates. The epidermis shows similar disturbances of keratinization, which are reflected by the presence of only few and thin bundles of tonofilaments in the basal, spinous and granular layers of the epidermis and, in the stratum corneum, by bizarrely formed and irregularly arranged lamellae of corneocytes, separated from one another. These results demonstrate that athymic, nude mice are not hairless but that the development and differentiation of hairs are severely injured in this mouse mutant. Analogously, the keratinization of the epidermis is also impaired. In view of the previously shown ectodermal defect as primary cause for the dysgenesis of the thymus, it seems to be probable that defects of the ectoderm are actually the common reason for both the thymus dysgenesis and the severe disturbances of hair development in 'athymic, nude' mice.

Animals↗

PubMed1992

Studies on avian spinal cord chimeras. I. Neurological and histological manifestations.

Spinal cord chimeras were produced by replacing a small fragment of neural tube of a 2-day-old White Leghorn chicken embryo with a similar fragment from a Japanese quail embryo. The embryo mortality was 61%, and 72% of hatched birds were 'cripples' and had to be sacrificed within 5 days after hatching. Forty-nine chimeras, 10.9% of the total number of operated embryos, were alive for more than 3 weeks. For at least 17 days after hatching, all birds behaved like normal chicks, and the grey quail-like feathers were the only manifestations of their chimerism. Initial neurological symptoms of unsteady walking and drooping of the wings were noted in all birds except for 1 that died an accidental death before it became sick. Advanced symptoms characterized by paralysis of the legs forcing the bird to lie on its side were noted in 40 birds. The chimeras could be divided into two groups, each consisting of 24 birds. The short-survival (SS) chimeras of the first group became terminally ill and had to be sacrificed within 3 months. The long-survival (LS) chimeras of the second group showed more protracted disease, in that only 16 of them showed symptoms of the advanced disease, and the majority showed partial or complete recovery. Ten of the LS birds were kept alive for more than 8 months. Furthermore, many LS chimeras lost their grey feathers. The hallmarks of neurohistological manifestations were mononuclear cell infiltrates, demyelinization with preservation of axons and scar formation. These lesions were restricted to the quail fragment of the spinal cord except for 2 birds in which distant cellular infiltrates were observed. Direct immunofluorescence tests for chicken IgG were positive in spinal cords of most SS chimeras but only of some LS chimeras.

Animals↗

PubMed1995

Superantigens: the paradox of T-cell activation versus inactivation.

Superantigens are interesting for several reasons. They exhibit unusual T-cell activation characteristics, they allow to follow in vivo ligand-reactive T cells, they cause T-cell-mediated shock symptoms and they may be causally involved in certain human diseases. This review focuses on the paradox of T-cell activation versus T-cell inactivation as caused by bacterial superantigens in vivo. T-cell activation leads to the acute release of toxic concentrations of lymphokines including tumor necrosis factor alpha/beta, gamma-interferon, interleukin (IL)-2, IL-4 and IL-10. T-cell inactivation mirrors induction of anergy, T-cell receptor downregulation, and that of CD2, CD4 and CD8 cell surface molecules, as well as of apoptosis. Two waves of apoptosis cripple the T-cell repertoire of superantigen-reactive T cells, an immediate one being induced within 24 h and a late one occurring at days 3-4. In between, clonal expansion of anergic ligand-reactive T cells takes place.

Down-Regulation↗

PubMed1987

Congenital diaphragmatic hernia: current controversies in prenatal and postnatal management.

A prenatal diagnosis of congenital diaphragmatic hernia (CDH) is associated with a poor prognosis, especially if diagnosed early in gestation and associated with polyhydramnios. Although uncommon, it is important to rule out associated anomalies, so that elective termination can be considered. If CDH is an isolated anomaly, the outcome is related to the degree of pulmonary hypoplasia caused by viscera displacing the lung in utero. Unfortunately, our ability to assess lung size, and thus prognosis, is limited. Most babies with CDH either die shortly after birth or survive to lead normal lives, so that continuation of the pregnancy is extremely unlikely to produce a chronically ill pulmonary cripple. The fetus should be followed with periodic ultrasounds and delivered at a perinatal center with appropriate neonatal and surgical expertise. There is no evidence that altering the timing or mode of delivery affects outcome. The only way to alter outcome and save the severely affected fetus is to remove the viscera from the chest and allow the fetal lung to develop before birth. Despite the fact that fetal repair of CDH makes sense physiologically, however, it remains a highly experimental technique. Postnatal management of CDH involves resuscitation, paralysis, and positive pressure ventilation. The practice of emergency repair is not supported by pathophysiology, and operation should be delayed until the patient has been stabilized. Mortality is often due to pulmonary hypoplasia, but in some cases, there is a period of deterioration due to pulmonary hypertension resulting in right-to-left shunting (persistent fetal circulation). Pharmacological agents are often used to decrease pulmonary vascular resistance and increase cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)

Female↗

PubMed1987

A new technique for skin closure in hypospadias: ipsilateral penoscrotal approximation for closure.

Sixteen patients, between 2 and 45 years old, with hypospadias underwent repair with our new skin closure procedure called ipsilateral penoscrotal approximation for closure (IPSAC). Complete functional success was obtained in all 6 patients with distal hypospadias and in 7 of 10 patients with proximal hypospadias. Meatal regression and urethrocutaneous fistula were complications in one-stage repair. Another urethrocutaneous fistula resulted from fifth-stage repair in the case of an adult hypospadias cripple. Cosmetically, there were two cases with unsightly thickening of the base of the penis in this early series. It was found that this IPSAC procedure had two major advantages: it provided (1) a tension-relieving skin closure, and (2) correction of scrotal deformity, especially in one-stage repair with the parameatal flap and in multi-staged repair with absolute penile skin deficiency.

Adolescent↗

PubMed1980

Economics of surgery and medical treatment in coronary artery disease.

Coronary disease is a major cause of increase in health-care costs. The disease is widespread, crippling, affects the money-making age groups and is expensive to treat whether medically or surgically. As benefits of surgery become more clearly realized, and receive a stronger statistical backing, it may be found that an expensive operation is more cost-beneficial than a series of less expensive hospital admissions. Whatever the cost-benefit or cost-effective ratios prove to be, it is likely that most patients faced with a choice between painful or pain-free life will choose the pain-free option, especially if 'the insurance will pay for it'.

Cardiac Care Facilities↗

PubMed1997

Dilated cardiomyopathy associated with deficiency of the cytoskeletal protein metavinculin.

BACKGROUND: The cytoskeleton plays an important role in maintaining cell structure and integrity. Defects in cytoskeletal proteins can cripple cell strength and may cause cardiomyopathy. We analyzed heart tissues from subjects with dilated cardiomyopathy for abnormalities in the cardiac cytoskeleton. Metavinculin, a cardiac isoform of the cytoskeletal protein vinculin, connects actin microfilaments to the intercalated disk and membrane costameres of the heart. METHODS AND RESULTS: Metavinculin and vinculin transcripts and protein were analyzed by polymerase chain reaction (PCR) and Western blotting. Thirty-three human heart specimens were studied, including 5 normal controls, 4 subjects with ischemic cardiomyopathy, 1 with X-linked cardiomyopathy, and 23 with idiopathic dilated cardiomyopathy (IDC). PCR of cardiac cDNA detected absence of the metavinculin transcript in cardiac tissue from a subject with IDC. PCR of genomic DNA showed that the metavinculin exon was present but not utilized in the cardiac transcript. Western blot analysis demonstrated absence of metavinculin protein in the heart from this subject. Immunostaining of cardiac vinculin in this heart showed disorganized intercalated disk structures. Metavinculin deficiency was associated with normal cardiac expression of the cytoskeletal proteins vinculin, alpha-actinin, and dystrophin. Normal metavinculin expression in the other heart specimens suggests that the defect is specific in the IDC subject identified. CONCLUSIONS: These results demonstrate an association between metavinculin deficiency and dilated cardiomyopathy due to a defect in alternative mRNA splicing.

Blotting, Western↗

PubMed1998

DNA computation: theory, practice, and prospects.

L. M. Adleman launched the field of DNA computing with a demonstration in 1994 that strands of DNA could be used to solve the Hamiltonian path problem for a simple graph. He also identified three broad categories of open questions for the field. First, is DNA capable of universal computation? Second, what kinds of algorithms can DNA implement? Third, can the error rates in the manipulations of the DNA be controlled enough to allow for useful computation? In the two years that have followed, theoretical work has shown that DNA is in fact capable of universal computation. Furthermore, algorithms for solving interesting questions, like breaking the Data Encryption Standard, have been described using currently available technology and methods. Finally, a few algorithms have been proposed to handle some of the apparently crippling error rates in a few of the common processes used to manipulate DNA. It is thus unlikely that DNA computation is doomed to be only a passing curiosity. However, much work remains to be done on the containment and correction of errors. It is far from clear if the problems in the error rates can be solved sufficiently to ever allow for general-purpose computation that will challenge the more popular substrates for computation. Unfortunately, biological demonstrations of the theoretical results have been sadly lacking. To date, only the simplest of computations have been carried out in DNA. To make significant progress, the field will require both the assessment of the practicality of the different manipulations of DNA and the implementation of algorithms for realistic problems. Theoreticians, in collaboration with experimentalists, can contribute to this research program by settling on a small set of practical and efficient models for DNA computation.

Algorithms↗