Organic visual loss measured by kinetic perimetry and retinal electrophysiology in children with functional amblyopia.

Purpose: To demonstrate an organic (retinal) amblyogenic defect in functional amblyopes not responding to treatment.

Methods: Twenty-four children (Mean age: 5.9 ± 1.

Evidences Suggesting that Distinct Immunological and Cellular Responses to Light Damage Distinguishes Juvenile and Adult Rat Retinas.

To unravel the mechanisms behind the higher resistance to light damage of juvenile (JR) versus adult (AR) rats, Sprague Dawley rats were exposed to a bright luminous environment of 10, 000 lux. The light-induced retinopathy (LIR) was assessed with histology, electroretinography and immunohistochemistry (IHC). In JR, 2 days of exposure induced the typical LIR, while >3 days added little LIR.

PPARα-mediated peroxisome induction compensates PPARγ-deficiency in bronchiolar club cells.

Despite the important functions of PPARγ in various cell types of the lung, PPARγ-deficiency in club cells induces only mild emphysema. Peroxisomes are distributed in a similar way as PPARγ in the lung and are mainly enriched in club and AECII cells. To date, the effects of PPARγ-deficiency on the overall peroxisomal compartment and its metabolic alterations in pulmonary club cells are unknown.

Growth charts for individuals with rhizomelic chondrodysplasia punctata.

Rhizomelic chondrodysplasia punctata (RCDP) is a class of peroxisomal disorders characterized by defective plasmalogen biosynthesis. There are multiple recognized types of RCDP, all of which have autosomal recessive inheritance, and their associated genes are known: RCDP type 1 with PEX7, RCDP type 2 with GNPAT, RCDP type 3 with AGPS, RCDP type 4 with FAR1, and RCDP type 5 with PEX5. Among other medical/developmental issues, plasmalogen deficiency has a direct effect on bone growth and results in postnatal growth failure, the severity of which corresponds to the degree of plasmalogen deficiency.

Witnessing the first sign of retinitis pigmentosa onset in the allegedly normal eye of a case of unilateral RP: a 30-year follow-up.

Purpose: A patient initially presented with constricted visual field, attenuated retinal vasculature, pigmentary clumping and reduced ERG in OS only, suggestive of unilateral retinitis pigmentosa (RP). This patient was subsequently seen on eight occasions (over three decades), and, with time, the initially normal eye (OD) gradually showed signs of RP-like degeneration. The purpose of this study was to evaluate which clinical modality (visual field, funduscopy or electroretinography) could have first predicted this fate.

Nuclear bioavailability of the glucocorticoid receptor in a pediatric asthma cohort with variable corticosteroid responsiveness.

Background: Despite the overall effectiveness of glucocorticoids (GCs) in the treatment of asthma, a large proportion of patients do not fully respond to this medication. The objective of the present study was to investigate the potential molecular mechanisms responsible for corticosteroid insensitivity in pediatric asthma.

Methods: Asthmatic children were classified as good (GSR) or poor corticosteroid responders (PSR) based on the changes in pulmonary function following GC treatment.

Estimating ON and OFF contributions to the photopic hill: normative data and clinical applications.

Background: With progressively brighter stimuli, the amplitude of the b-wave of the human photopic electroretinogram (ERG) first increases to a maximal value (Vmax) and then decreases to finally reach a plateau, a phenomenon known as the photopic hill (PH). A mathematical model combining a Gaussian (G) and a logistic (L) growth function was previously proposed to fit this unusual luminance-response curve, where the G and L functions were suggested to represent, respectively, the OFF and ON retinal pathway contributions to the building of the PH.

Method: The PHs of patients presenting stationary diseases affecting specifically the ON (3 CSNB-1) or OFF (4 CPCPA) retinal pathways as well as patients affected with retinitis pigmentosa (14 RP) of different stages or etiology were analyzed using this mathematical model and compared to the PHs of a group of 28 normal subjects.

The mechanism of BH4 -responsive hyperphenylalaninemia--as it occurs in the ENU1/2 genetic mouse model.

The Pah(enu1/enu2) (ENU1/2) mouse is a heteroallelic orthologous model displaying blood phenylalanine (Phe) concentrations characteristic of mild hyperphenylalaninemia. ENU1/2 mice also have reduced liver phenylalanine hydroxylase (PAH) protein content (∼20% normal) and activity (∼2.5% normal).

Risk of congenital heart defects is influenced by genetic variation in folate metabolism.

Genetic disturbances in folate metabolism may increase risk for congenital heart defects. We examined the association of heart defects with four polymorphisms in folate-related genes (methylenetetrahydrofolate reductase (MTHFR) c.677C.

Evaluation of orally administered PEGylated phenylalanine ammonia lyase in mice for the treatment of Phenylketonuria.

Phenylketonuria (PKU), a Mendelian autosomal recessive phenotype (OMIM 261600), is an inborn error of metabolism causing impaired postnatal cognitive development in the absence of treatment. We used the Pah(enu2/enu2) PKU mouse model to study oral enzyme substitution therapy with various chemically modified formulations of phenylalanine ammonia lyase (Av-p.C503S/p.

T-cell factor/β-catenin activity is suppressed in two different models of autosomal dominant polycystic kidney disease.

During murine kidney development, canonical WNT signaling is highly active in tubules until about embryonic days E16-E18. At this time, β-catenin transcriptional activity is progressively restricted to the nephrogenic zone. The cilial protein genes PKD1 and PKD2 are known to be mutated in autosomal dominant polycystic kidney disease (ADPKD), and previous studies proposed that these mutations could lead to a failure to suppress canonical WNT signaling activity.

Immunohistochemical evidence of synaptic retraction, cytoarchitectural remodeling, and cell death in the inner retina of the rat model of oygen-induced retinopathy (OIR).

Purpose: Postnatal exposure to hyperoxia destroys the plexiform layers of the neonatal rat retina, resulting in significant electroretinographic anomalies. The purpose of this study was to identify the mechanisms at the origin of this loss.

Methods: Sprague-Dawley (SD) and Long Evans (LE) rats were exposed to hyperoxia from birth to postnatal day (P) 6 or P14 and from P6 to P14, after which rats were euthanatized at P6, P14, or P60.

Complete deficiency of methylenetetrahydrofolate reductase in mice is associated with impaired retinal function and variable mortality, hematological profiles, and reproductive outcomes.

Severe deficiency of methylenetetrahydrofolate reductase (MTHFR) with homocystinuria can result in early demise or later-onset neurological impairment, including developmental delay, motor dysfunction, and seizures. We previously characterized BALB/c Mthfr (-/-)mice as a model for this disorder and have recently backcrossed the disrupted allele onto the C57Bl/6 background to examine the variable phenotypes in MTHFR deficiency. Compared with BALB/c Mthfr (-/-)mice, C57Bl/6 Mthfr (-/-)mice have enhanced survival rates (81% vs 26.

Postnatal hyperoxia and the developing rat retina: beyond the obvious vasculopathy.

Although a great deal of emphasis has been placed on the vasculopathy that is associated with oxygen-induced retinopathy (OIR), our studies also revealed significant and irreversible structural (retinal histology) and functional (scotopic and photopic electroretinograms) impairments that were significantly more severe in pigmented Long-Evans rats compared to the more commonly used albino Sprague Dawley rats. In the following pages, we will highlight what we have learned about the retinal pathophysiological processes of OIR taking place in strains of both rats with the hope that this will trigger investigations into new therapeutic strategies to complement those geared at preventing the vasculopathy.

Common variants of the glial cell-derived neurotrophic factor gene do not influence kidney size of the healthy newborn.

Glial cell-derived neurotrophic factor (GDNF) plays an important role in renal development, serving as a trophic factor for outgrowth of the ureteric bud and its continued arborisation. Our previous studies have shown that common variants of the human paired-box 2 (PAX2) gene (a transcriptional activator of GDNF) and rearranged during transfection (RET) gene (encoding the cognate receptor for GDNF) are associated with a subtle reduction in the kidney size of newborns. Since heterozygosity for a mutant GDNF allele causes mild renal hypoplasia and modest hypertension in mice, we considered the possibility that common variants of the GDNF gene might also contribute to renal hypoplasia in humans.

Methylenetetrahydrofolate reductase deficiency and low dietary folate reduce tumorigenesis in Apc min/+ mice.

Background: Clinical studies suggest that mild methylenetetrahydrofolate reductase (MTHFR) deficiency and high dietary folate may reduce the risk for colorectal cancer. There is concern, however, that high folate intake (a consequence of food fortification) may enhance tumour growth in individuals with pre-existing tumours or genetic predisposition to tumorigenesis.

Aim: To determine if Mthfr deficiency and low dietary folate influence tumorigenesis in mice genetically predisposed to form numerous intestinal adenomas (Apc(min/+)).

Pharmacological demarcation of the growth hormone, gut motility and feeding effects of ghrelin using a novel ghrelin receptor agonist.

The peptide hormone ghrelin exerts a wide spectrum of activities including the stimulation of GH release, feeding, and gastrointestinal motility, purportedly via the activation of a common receptor, GH secretagogue receptor (since renamed the GRLN-R) The aim of the present study was to determine whether these effects can be separated pharmacologically. Tranzyme Pharma (TZP)-101 is a small-molecule agonist with potent binding affinity (inhibitory constant = 16 nm) and full agonist activity (EC50 = 29 nm, maximum response = 111%) at the human recombinant GRLN-R. Pharmacokinetic profiling of TZP-101 in rat determined a plasma elimination half-life of 99 min and low blood-brain barrier permeability (0.

The effect of oxygen and light on the structure and function of the neonatal rat retina.

The neonatal rat is born with its eyes closed and an immature visual system, that some say is equivalent to that of a human fetus at 26 weeks of gestation. From birth, the visual system of the newborn rat will gradually mature, the first manifestation of that being the opening of the eye which usually take place at postnatal day 14. Complete maturation of the retina and visual pathways is normally reached at the end of the first month of life.

Mefolinate (5-methyltetrahydrofolate), but not folic acid, decreases mortality in an animal model of severe methylenetetrahydrofolate reductase deficiency.

Severe deficiency of methylenetetrahydrofolate reductase (MTHFR) results in homocystinuria, with a variety of neurological and vascular complications, and sometimes death in the first year of life. MTHFR (EC 1.5.

Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice.

Low dietary folate and polymorphisms in genes of folate metabolism can influence risk for pregnancy complications and birth defects. Methionine synthase reductase (MTRR) is required for activation of methionine synthase, a folate- and vitamin B(12)-dependent enzyme. A polymorphism in MTRR (p.

Profound phenotypic variation among mice deficient in the maintenance of genomic imprints.

Background: An alteration in the mechanism that maintains the monoallelic, imprinted expression of genes can result in their biallelic expression and lead to disruptions in fetal development. Here, we examined the consequences of a loss of maintenance methylation at one specific stage of preimplantation, induced by a deficiency of the oocyte-derived Dnmt1o protein and known to produce biallelic expression of imprinted genes.

Methods: Phenotypes of mid-gestation Dnmt1o-deficient mouse embryos were assessed by a scoring system based on the developmental stage of 17 anatomical features and by magnetic resonance microscopy.

Early manifestations of postnatal hyperoxia on the retinal structure and function of the neonatal rat.

Purpose: Postnatal hyperoxia in rats causes an arrest in growth of retinal blood vessels, along with severe changes in retinal ultrastructure and function. Previous studies focused on consequences of postnatal hyperoxia at time points substantially removed from the hyperoxic insult. In this study, the earliest manifestations of this retinopathy were examined.

Structural and functional maturation of the retina of the albino Hartley guinea pig.

Purpose: Altricial animals, such as rats and mice, are born with their eyes closed, compared to precocial animals, such as guinea pigs and humans, which have their eyes opened at birth. The purpose of this study was to investigate if the retina of guinea pigs (precocial animal) is subjected to a postnatal maturation process similar to that previously reported for rodents.

Methods: Photopic and scotopic electroretinograms (ERG) and retinal histology were obtained from albino guinea pigs aged P1 to P75.