Congenital stationary night blindness: report of an autosomal recessive family and linkage analysis

Congenital stationary night blindness (CSNB) is a group of rare, non-progressive conditions of the retina characterized by abnormal rod function causing impaired night vision. Among them, the Schubert-Bornschein subgroup, itself divided into a complete and an incomplete form, is characterized by a specific electrophysiological pattern. Complete, Schubert-Bornschein CSNB is usually transmitted as a monogenic trait, and most familial cases result from mutations of the NYX gene located on the X chromosome. We report a very rare family with consanguineous, first-cousin parents, where a son and a daughter are affected with this condition, indicating autosomal recessive inheritance. As the family was too small for genome-wide linkage, we considered several candidate loci, including the sidekick SDK1 and SDK2 genes. The latter determine lamina-specific connectivity in the retina, a histological substrate of the ON pathway implicated in complete, Schubert-Bornschein CSNB. Although linkage was excluded in our family, observations like the present one may lead to the identification of a new molecular cause for this condition.     

Enhanced viral clearance in interleukin-18 gene-deficient mice after pulmonary infection with influenza A virus

T helper 1 driven immune responses facilitate host defence during viral infections. Because interleukin-18 (IL-18) mediates T helper 1 driven immune responses, and since mature IL-18 is up-regulated in human macrophages after influenza virus infection in vitro, it has been suggested that IL-18 plays an important role in the immune response to influenza. To determine the role of IL-18 in respiratory tract infection with influenza, IL-18 gene-deficient (IL-18(-/-)) and normal wildtype mice were intranasally inoculated with influenza A virus. Influenza resulted in an increase in constitutively expressed IL-18 in the lungs of wildtype mice. The clearance of influenza A was inhibited by IL-18, as indicated by reduced viral loads on day 8 and day 12 after infection in IL-18(-/-) mice. This enhanced viral clearance correlated with increased CD4(+) T-cell activation in the lungs as reflected by CD69 expression on the cell surface. Surprisingly, interferon-gamma (IFN-gamma) levels were similar in the lungs of IL-18(-/-) mice and wildtype mice. Intracellular IFN-gamma staining revealed similar expression levels in lung-derived natural killer cells, CD4(+) and CD8(+) T cells, indicating that IFN-gamma production is IL-18-independent during influenza virus infection. Tumour necrosis factor-alpha production by CD4(+) T cells was significantly lower in IL-18(-/-) mice than in wildtype mice. Our data indicate that endogenous IL-18 impairs viral clearance during influenza A infection.     

Leaf trajectory verification during dynamic intensity modulated radiotherapy using an amorphous silicon flat panel imager

An independent verification of the leaf trajectories during each treatment fraction improves the safety of IMRT delivery. In order to verify dynamic IMRT with an electronic portal imaging device (EPID), the EPID response should be accurate and fast such that the effect of motion blurring on the detected moving field edge position is limited. In the past, it was shown that the errors in the detected position of a moving field edge determined by a scanning liquid-filled ionization chamber (SLIC) EPID are negligible in clinical practice. Furthermore, a method for leaf trajectory verification during dynamic IMRT was successfully applied using such an EPID. EPIDs based on amorphous silicon (a-Si) arrays are now widely available. Such a-Si flat panel imagers (FPIs) produce portal images with superior image quality compared to other portal imaging systems, but they have not yet been used for leaf trajectory verification during dynamic IMRT. The aim of this study is to quantify the effect of motion distortion and motion blurring on the detection accuracy of a moving field edge for an Elekta iViewGT a-Si FPI and to investigate its applicability for the leaf trajectory verification during dynamic IMRT. We found that the detection error for a moving field edge to be smaller than 0.025 cm at a speed of 0.8 cm/s. Hence, the effect of motion blurring on the detection accuracy of a moving field edge is negligible in clinical practice. Furthermore, the a-Si FPI was successfully applied for the verification of dynamic IMRT. The verification method revealed a delay in the control system of the experimental DMLC that was also found using a SLIC EPID, resulting in leaf positional errors of 0.7 cm at a leaf speed of 0.8 cm/s.     

Keratinocyte growth factor expression by fibroblasts in pulmonary fibrosis: poor response to interleukin-1beta

Keratinocyte growth factor (KGF) is secreted by fibroblasts and protects from pulmonary fibrosis in animal models. Interleukin (IL)-1beta is the most potent inducer of KGF in fibroblasts, acting through the c-Jun pathway. We evaluated in vitro KGF production by human lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF, n = 10) and from control subjects (n = 7) at baseline and after IL-1beta stimulation. Basal KGF secretion by IPF fibroblasts was similar to controls. In fibroblasts from control subjects, IL-1beta increased c-Jun expression, c-Jun activation, and KGF secretion. SP600125, a specific c-Jun N-terminal kinase (JNK) inhibitor, inhibited the effect of IL-1beta. By contrast, in IPF fibroblasts, IL-1beta did not increase c-Jun expression and c-Jun activation, and weakly increased KGF secretion, whereas SP600125 had no effect. IL-1beta similarly increased JunB expression in fibroblasts from patients with IPF and control subjects. Total JNK content was not different in either unstimulated or IL-1beta-stimulated IPF and control fibroblasts. IL-1beta increased phosphorylated JNK in control and IPF fibroblasts, but this increase was weaker and heterogeneous in IPF. Altogether, our results demonstrate a dysregulation of KGF secretion by IPF fibroblasts. The weak response to IL-1beta is associated with a defect of c-Jun expression and activation and a defect of JNK activation.     

Peroxisome proliferator-activated receptor gamma is expressed in airways and inhibits features of airway remodeling in a mouse asthma model

BACKGROUND: Allergic asthma is associated with persistent functional and structural changes in the airways and involves many different cell types. Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, is predominantly expressed in adipose tissue and plays a major role in regulating adipocyte differentiation and glucose metabolism. Recently, PPAR-gamma has been shown to play an important role in the control of inflammatory responses, including within the lung, acting on both immune and nonimmune cells. OBJECTIVE: Our aim was to assess the anti-inflammatory potential of a PPAR-gamma agonist locally delivered by means of nebulization. METHODS: We used a mouse model of asthma induced by sensitization and airway challenge with ovalbumin. Ciglitazone, a PPAR-gamma agonist, was administered by means of nebulization alone at the time of antigen challenge or by means of gavage and nebulization. Treatments with both ciglitazone and GW9662, a specific antagonist, were also performed to verify that ciglitazone's effects were mediated through PPAR-gamma activation. RESULTS: Our results show that PPAR-gamma is mainly expressed in airway epithelium on antigen sensitization. Treatment with ciglitazone reduced PPAR-gamma levels in the lung, whereas combined treatment with GW9662 abrogated this inhibition. Importantly, nebulization with ciglitazone decreased airway hyperresponsiveness, basement membrane thickness, mucus production, collagen deposition, and TGF-beta synthesis. A significant correlation was also found between airway hyperresponsiveness, basement membrane thickness, and TGF-beta levels. CONCLUSION: These results demonstrate that inhaled agonistic ligands of PPAR-gamma might have new therapeutic potential for airway asthmatic inflammation.     

A dual participation of ZAP-70 and scr protein tyrosine kinases is required for TCR-induced tyrosine phosphorylation of Sam68 in Jurkat T cells

Sam68 has been initially described as a substrate of src kinases during mitosis in fibroblasts. Recent evidence suggests that in T lymphocytes Sam68 may act as an adaptor protein and participate in the early biochemical cascade triggered after CD3 stimulation. A direct interaction between Sam68 and the two src kinases involved in T cell activation, p59^fyn and p56^lck, as well as a partnership of Sam68 with various key downstream signaling molecules, like phospholipase Cγ-1 and Grb2, has been shown. In this study we analyze the contribution of p56^lck, as well as the role of ZAP-70, the second class of protein tyrosine kinase involved in T cell activation, in Sam68 tyrosine phosphorylation in the human Jurkat T cell line. Using the src inhibitor PP1 [4-amino-5-(4-methylphenyl)7-(t-butyl) pyrazolo [3,4-d] pyrymidine] and cell variants with defective expression of p56^lck or expressing a dominant negative form of ZAP-70, we demonstrate that, while both p56^lck and ZAP-70 are dispensable for the low constitutive phosphorylation of Sam68 observed in Jurkat cells, a cooperation between the two kinases is required to increase its rapid phosphorylation observed in vivo after CD3 stimulation. We also show that recombinant forms of both p56^lck and ZAP-70 phosphorylate Sam68 in vitro. However, using CD2 stimulated cells, we observe that p56^lck activation by itself does not induce Sam68 tyrosine phosphorylation. We conclude that p59^lck and p56^lck differently participate in regulating the phosphorylation state of Sam68 in T cells and that ZAP-70 may contribute to Sam68 tyrosine phosphorylation and to the specific recruitment of this molecule after CD3 stimulation.     

Predominance of Ehrlichia ewingii in Missouri dogs

To investigate the species distribution of Ehrlichia present in Missouri dogs, we tested 78 dogs suspected of having acute ehrlichiosis and 10 healthy dogs. Blood from each dog was screened with a broad-range 16S rRNA gene PCR assay that detects known pathogenic species of Ehrlichia and ANAPLASMA: The species was determined by using species-specific PCR assays and nucleotide sequencing. Ehrlichia antibody testing was performed by using an indirect immunofluorescence assay with Ehrlichia chaffeensis as the antigenic substrate. The broad-range assay detected Ehrlichia or Anaplasma DNA in 20 (26%) of the symptomatic dogs and 2 (20%) of the asymptomatic dogs. E. ewingii accounted for 20 (91%), and E. chaffeensis accounted for 1 (5%) of the positives. Anaplasma phagocytophilum DNA was detected in one dog, and the sequences of regions of the 16S rRNA gene and the groESL operon amplified from the blood of this dog matched the published sequences of this organism. Antibodies reactive with E. chaffeensis were detected in 14 (67%) of the 21 PCR-positive dogs and in 12 (19%) of the 64 PCR-negative dogs. Combining the results of PCR and serology indicated that 33 (39%) of 85 evaluable dogs had evidence of past or current Ehrlichia infection. We conclude that E. ewingii is the predominant etiologic agent of canine ehrlichiosis in the areas of Missouri included in this survey. E. canis, a widely recognized agent of canine ehrlichiosis, was not detected in any animal. The finding of E. ewingii in asymptomatic dogs suggests that dogs could be a reservoir for this Ehrlichia species.     

Trophic action of pharmacological substances with a guanidine group on mouse neuroblastoma cells and chick ganglionic neurons in culture

A series of substances (designated CTQ compounds) with a guanidine group have been synthesized and tested for their ability to promote neuronal survival and neurite outgrowth. Mouse neuroblastoma clonal cell lines grown in serum-containing medium for 10 days as well as primary cultures of embryonic chicken ganglion neurons grown in serum-free defined medium for 1 or 2 days have been used for the experiments. Among the various CTQ compounds (CTQ1–CTQ20) tested, only CTQ8 exerted positive neurotrophic effects on these peripheral neuronal cells. At a concentration of 10⁻⁴ M, CTQ8 enhanced neuritogenesis of neuroblastoma cells. However, the most striking influence of CTQ8 was its promoting effect (6- to 10-fold) on the survival of chicken ciliary and dorsal root ganglionic neurons at concentrations ranging from 10⁻³ M to 5×10⁻⁴ M.     

Effects of 15-hydroperoxyeicosatetraenoic acid on human lymphocyte sheep erythrocyte rosette formation and response to concanavalin A associated with HLA system

The lipoxygenase product hydroperoxyeicosatetraenoic acid (HPETE) has immunosuppressive properties in vitro and in vivo. It was observed that 15-HPETE inhibit the sheep red blood cell rosette formation and the concanavalin A-induced blast transformation of human lymphocytes. This inhibition was HLA-linked. HLA-B12 subjects were less sensitive than non-B12 subjects. It is likely that HPETE acids are macrophage mediators which inhibit some lymphocyte functions.     

Self-management and spina bifida: A systematic review of the literature

BackgroundSelf-management is critical to optimizing the health of individuals with a chronic condition or disability and is, therefore, a central concept in individual and family-centered healthcare delivery. The purpose of this review is to report the state of the science of self-management for individuals with spina bifida (SB) from a lifespan perspective.ObjectiveThis review will summarize the (a) development and use of self-management skills and behaviors across the life span, (b) factors related to self-management behaviors, (c) development of generic or condition-specific measures of self-management used with a spina bifida population, and (d) development and/or outcomes of interventions to improve self-management in SB.MethodsThe search strategy was limited to primary research articles published between 2003 and 2019 and followed PRISMA guidelines. The databases searched included: PubMed, CINAHL, PsycINFO, Web of Science, Cochrane, and Google Scholar. Studies that addressed self-management concepts in individuals throughout the life span and published in English were included.ResultsThe search yielded 108 citations and 56 articles met inclusion/exclusion criteria. A systematic narrative synthesis was reported. The level of evidence identified was primarily Level III articles of good quality. Multiple demographic, environmental, condition and process factors were related to self-management behaviors. SB self-management instruments and intervention development and testing studies were identified.ConclusionsThis review provides a synthesis of the state of the science of self-management including factors related to self-management behaviors, preliminary evidence of instruments for use in SB, factors important to consider in the development and testing of future interventions, and gaps in the literature.