Clinical biological and genetic heterogeneity of the inborn errors of pulmonary surfactant metabolism

Pulmonary surfactant is a multimolecular complex located at the air-water interface within the alveolus to which a range of physical (surface-active properties) and immune functions has been assigned. This complex consists of a surface-active lipid layer (consisting mainly of phospholipids), and of an aqueous subphase. From discrete surfactant sub-fractions one can isolate strongly hydrophobic surf acta nt proteins B (SP-B) and C (SP-C) as well as collectins SP-A and SP-D, which were shown to have specific structural, metabolic, or immune properties. Inborn or acquired abnormalities of the surfactant, qualitative or quantitative in nature, account for a number of human diseases. Beside hyaline membrane disease of the preterm neonate, a cluster of hereditary or acquired lung diseases has been characterized by periodic acid-Schiff-positive material filling the alveoli. From this heterogeneous nosologic group, at least two discrete entities presently emerge. The first is the SP-B deficiency, in which an essentially proteinaceous material is stored within the alveoli, and which represents an autosomal recessive Mendelian entity linked to the SFTPB gene (MIM 1786640). The disease usually generally entails neonatal respiratory distress with rapid fatal outcome, although partial or transient deficiencies have also been observed. The second is alveolar proteinosis, characterized by the storage of a mixed protein and lipid material, which constitutes a relatively heterogeneous clinical and biological syndrome, especially with regard to age at onset (from the neonate through to adulthood) as well as the severity of associated signs. Murine models, with a targeted mutation of the gene encoding granulocyte macrophage colony-stimulating factor (GM-CSF) (Csfgm) or the beta subunit of its receptor (II3rb1) support the hypothesis of an abnormality of surfactant turnover in which the alveolar macrophage is a key player. Apart from SP-B deficiency, in which a near-consensus diagnostic chart can be designed, the ascertainment of other abnormalities of surfactant metabolism is not straightforward. The disentanglement of this disease cluster is however essential to propose specific therapeutic procedures: repeated broncho-alveolar ravages, GM-CSF replacement, bone marrow grafting or lung transplantation

Infinite square-well, trigonometric P\"oschl-Teller and other potential wells with a moving barrier

Using mainly two techniques, a point transformation and a time dependent supersymmetry, we construct in sequence several quantum infinite potential wells with a moving barrier. We depart from the well known system of a one-dimensional particle in a box. With a point transformation, an infinite square-well potential with a moving barrier is generated. Using time dependent supersymmetry, the latter leads to a trigonometric P\"oschl-Teller potential with a moving barrier. Finally, a confluent time dependent supersymmetry transformation is implemented to generate new infinite potential wells, all of them with a moving barrier. For all systems, solutions of the corresponding time dependent Schr\"odinger equation fulfilling boundary conditions are presented in a closed form

Increased S-nitrosylation and proteasomal degradation of caspase-3 during infection contribute to the persistence of adherent invasive escherichia coli (AIEC) in immune cells

Adherent invasive Escherichia coli (AIEC) have been implicated as a causative agent of Crohn's disease (CD) due to their isolation from the intestines of CD sufferers and their ability to persist in macrophages inducing granulomas. The rapid intracellular multiplication of AIEC sets it apart from other enteric pathogens such as Salmonella Typhimurium which after limited replication induce programmed cell death (PCD). Understanding the response of infected cells to the increased AIEC bacterial load and associated metabolic stress may offer insights into AIEC pathogenesis and its association with CD. Here we show that AIEC persistence within macrophages and dendritic cells is facilitated by increased proteasomal degradation of caspase-3. In addition S-nitrosylation of pro- and active forms of caspase-3, which can inhibit the enzymes activity, is increased in AIEC infected macrophages. This S-nitrosylated caspase-3 was seen to accumulate upon inhibition of the proteasome indicating an additional role for S-nitrosylation in inducing caspase-3 degradation in a manner independent of ubiquitination. In addition to the autophagic genetic defects that are linked to CD, this delay in apoptosis mediated in AIEC infected cells through increased degradation of caspase-3, may be an essential factor in its prolonged persistence in CD patients

Expression profiles of hydrophobic surfactant proteins in children with diffuse chronic lung disease

BACKGROUND: Abnormalities of the intracellular metabolism of the hydrophobic surfactant proteins SP-B and SP-C and their precursors may be causally linked to chronic childhood diffuse lung diseases. The profile of these proteins in the alveolar space is unknown in such subjects. METHODS: We analyzed bronchoalveolar lavage fluid by Western blotting for SP-B, SP-C and their proforms in children with pulmonary alveolar proteinosis (PAP, n = 15), children with no SP-B (n = 6), children with chronic respiratory distress of unknown cause (cRD, n = 7), in comparison to children without lung disease (n = 15) or chronic obstructive bronchitis (n = 19). RESULTS: Pro-SP-B of 25–26 kD was commonly abundant in all groups of subjects, suggesting that their presence is not of diagnostic value for processing defects. In contrast, pro-SP-B peptides cleaved off during intracellular processing of SP-B and smaller than 19–21 kD, were exclusively found in PAP and cRD. In 4 of 6 children with no SP-B, mutations of SFTPB or SPTPC genes were found. Pro-SP-C forms were identified at very low frequency. Their presence was clearly, but not exclusively associated with mutations of the SFTPB and SPTPC genes, impeding their usage as candidates for diagnostic screening. CONCLUSION: Immuno-analysis of the hydrophobic surfactant proteins and their precursor forms in bronchoalveolar lavage is minimally invasive and can give valuable clues for the involvement of processing abnormalities in pediatric pulmonary disorders

Interstitial lung disease in children - genetic background and associated phenotypes

Interstitial lung disease in children represents a group of rare chronic respiratory disorders. There is growing evidence that mutations in the surfactant protein C gene play a role in the pathogenesis of certain forms of pediatric interstitial lung disease. Recently, mutations in the ABCA3 transporter were found as an underlying cause of fatal respiratory failure in neonates without surfactant protein B deficiency. Especially in familiar cases or in children of consanguineous parents, genetic diagnosis provides an useful tool to identify the underlying etiology of interstitial lung disease. The aim of this review is to summarize and to describe in detail the clinical features of hereditary interstitial lung disease in children. The knowledge of gene variants and associated phenotypes is crucial to identify relevant patients in clinical practice

Viscoat versus Visthesia during phacoemulsification cataract surgery: corneal and foveal changes

<p>Abstract</p> <p>Background</p> <p>Ophthalmic viscosurgical devices (OVDs) are widely used in phacoemulsification cataract surgery to maintain adequate intraocular space, stabilize ocular tissue during the operation and decrease the possible damage of the corneal endothelium. Our study has the purpose to compare the corneal and foveal changes of Viscoat and Visthesia in patients undergoing uneventful phacoemulsification cataract surgery.</p> <p>Methods</p> <p>Participants in our study were 77 consecutive patients, who were randomized into two groups based on type of OVD used during phacoemulsification: Viscoat or Visthesia. All patients underwent a complete ophthalmological examination i.e., measurement of best corrected visual acuity (BCVA) by means of Snellen charts, intraocular pressure examination by Goldmann tonometry, slit lamp examination, fundus examination, optical coherence tomography, specular microscopy and ultrasound pachymetry preoperatively and at three time points postoperatively (day 3, 15, 28 postoperatively). The differences in baseline characteristics, as well as in outcomes between the two groups were compared by Mann-Whitney-Wilcoxon test and Student's t-test, as appropriate.</p> <p>Results</p> <p>Intraoperatively, there was no statistically significant difference in the duration of the ultrasound application between the two groups, while Viscoat group needed more time for the operation performance. It is also worthy to mention that Visthesia group exhibited less intense pain than patients in Viscoat group. Postoperatively, there was a statistically significant difference in central corneal thickness, endothelial cell count and macular thickness between the two groups, but BCVA (logMAR) did not differ between the two groups.</p> <p>Conclusions</p> <p>Our study suggests that Viscoat is more safe and protective for the corneal endothelium during uneventful phacoemulsification cataract surgery, while Visthesia is in superior position regarding intraoperative pain. Patients of both groups acquired excellent visual acuity postoperative. Finally, this is the first study comparing OVDs in terms of macular thickness, finding that Visthesia cause a greater increase in macular thickness postoperatively than Viscoat, although it reaches normal ranges in both groups.</p

The Multifunctional Host Defense Peptide SPLUNC1 Is Critical for Homeostasis of the Mammalian Upper Airway

Otitis media (OM) is a highly prevalent pediatric disease caused by normal flora of the nasopharynx that ascend the Eustachian tube and enter the middle ear. As OM is a disease of opportunity, it is critical to gain an increased understanding of immune system components that are operational in the upper airway and aid in prevention of this disease. SPLUNC1 is an antimicrobial host defense peptide that is hypothesized to contribute to the health of the airway both through bactericidal and non-bactericidal mechanisms. We used small interfering RNA (siRNA) technology to knock down expression of the chinchilla ortholog of human SPLUNC1 (cSPLUNC1) to begin to determine the role that this protein played in prevention of OM. We showed that knock down of cSPLUNC1 expression did not impact survival of nontypeable Haemophilus influenzae, a predominant causative agent of OM, in the chinchilla middle ear under the conditions tested. In contrast, expression of cSPLUNC1 was essential for maintenance of middle ear pressure and efficient mucociliary clearance, key defense mechanisms of the tubotympanum. Collectively, our data have provided the first in vivo evidence that cSPLUNC1 functions to maintain homeostasis of the upper airway and, thereby, is critical for protection of the middle ear

Topographical and Biological Evidence Revealed FTY720-Mediated Anergy-Polarization of Mouse Bone Marrow-Derived Dendritic Cells In Vitro

Abnormal inflammations are central therapeutic targets in numerous infectious and autoimmune diseases. Dendritic cells (DCs) are involved in these inflammations, serving as both antigen presenters and proinflammatory cytokine providers. As an immuno-suppressor applied to the therapies of multiple sclerosis and allograft transplantation, fingolimod (FTY720) was shown to affect DC migration and its crosstalk with T cells. We posit FTY720 can induce an anergy-polarized phenotype switch on DCs in vitro, especially upon endotoxic activation. A lipopolysaccharide (LPS)-induced mouse bone marrow-derived dendritic cell (BMDC) activation model was employed to test FTY720-induced phenotypic changes on immature and mature DCs. Specifically, methods for morphology, nanostructure, cytokine production, phagocytosis, endocytosis and specific antigen presentation studies were used. FTY720 induced significant alterations of surface markers, as well as decline of shape indices, cell volume, surface roughness in LPS-activated mature BMDCs. These phenotypic, morphological and topographical changes were accompanied by FTY720-mediated down-regulation of proinflammatory cytokines, including IL-6, TNF-α, IL-12 and MCP-1. Together with suppressed nitric oxide (NO) production and CCR7 transcription in FTY720-treated BMDCs with or without LPS activation, an inhibitory mechanism of NO and cytokine reciprocal activation was suggested. This implication was supported by the impaired phagocytotic, endocytotic and specific antigen presentation abilities observed in the FTY720-treated BMDCs. In conclusion, we demonstrated FTY720 can induce anergy-polarization in both immature and LPS-activated mature BMDCs. A possible mechanism is FTY720-mediated reciprocal suppression on the intrinsic activation pathway and cytokine production with endpoint exhibitions on phagocytosis, endocytosis, antigen presentation as well as cellular morphology and topography

Neuroanatomical Variability of Religiosity

We hypothesized that religiosity, a set of traits variably expressed in the population, is modulated by neuroanatomical variability. We tested this idea by determining whether aspects of religiosity were predicted by variability in regional cortical volume. We performed structural magnetic resonance imaging of the brain in 40 healthy adult participants who reported different degrees and patterns of religiosity on a survey. We identified four Principal Components of religiosity by Factor Analysis of the survey items and associated them with regional cortical volumes measured by voxel-based morphometry. Experiencing an intimate relationship with God and engaging in religious behavior was associated with increased volume of R middle temporal cortex, BA 21. Experiencing fear of God was associated with decreased volume of L precuneus and L orbitofrontal cortex BA 11. A cluster of traits related with pragmatism and doubting God's existence was associated with increased volume of the R precuneus. Variability in religiosity of upbringing was not associated with variability in cortical volume of any region. Therefore, key aspects of religiosity are associated with cortical volume differences. This conclusion complements our prior functional neuroimaging findings in elucidating the proximate causes of religion in the brain