Vitamin D3 correlates inversely with systemic dendritic cell numbers and bone erosion in chronic rhinosinusitis with nasal polyps and allergic fungal rhinosinusitis

Vitamin D₃ (VD₃) is a steroid hormone that regulates bone health and numerous aspects of immune function and may play a role in respiratory health. We hypothesized that T helper type 2 (Th2) disorders, chronic rhinosinusitis with nasal polyps (CRSwNP) and allergic fungal rhinosinusitis (AFRS) would have VD₃ deficiencies, resulting in increased mature dendritic cells (DCs) and bone erosion. We conducted a retrospective study examining VD₃ levels in patients with AFRS (n = 14), CRSwNP (n = 9), chronic rhinosinusitis without nasal polyps (CRSsNP) (n = 20) and cerebrospinal fluid leak repair (non‐diseased controls) (n = 14) at time of surgery. Circulating immune cell levels were determined by immunostaining and flow cytometric analysis. Plasma VD₃ and immune regulatory factors (granulocyte–macrophage colony‐stimulating factor and prostaglandin E₂) were measured by enzyme‐linked immunosorbent assay. It was observed that CRSwNP and AFRS demonstrated increased circulating DCs, while chronic rhinosinusitis without nasal polyps displayed increased circulating macrophages. CRSwNP and AFRS were to found to have insufficient levels of VD₃ which correlated inversely with circulating numbers of mature DCs, DC regulatory factors and bone erosion. CRSsNP displayed no change in circulating DC numbers or VD₃ status compared to control, but did display increased numbers of circulating macrophages that was independent of VD₃ status. Lastly, VD₃ deficiency was associated with more severe bone erosion. Taken together, these results suggest support a role for VD₃ as a key player in the immunopathology of CRSwNP and AFRS.     

Prevalence and correlates of sleep paralysis in adults reporting childhood sexual abuse

Sleep paralysis (SP) occurs when rapid eye movement (REM) activity and concomitant paralysis of the skeletal muscles persist as an individual awakens and becomes conscious of his/her surroundings. SP is often accompanied by frightening hallucinations that some researchers suggest may be confounded with memories of childhood sexual abuse (CSA; [McNally, R. J., & Clancy, S. A. (2005). Sleep paralysis in adults reporting repressed, recovered, or continuous memories of childhood sexual abuse. Journal of Anxiety Disorders, 19, 595-602]). The purpose of this study was to evaluate relationships between CSA and SP. Based on self-report, participants (n=263) were categorized into three CSA groups: confirmed, unconfirmed, or no history of CSA. Relative to participants reporting no CSA history, those reporting CSA reported more frequent and more distressing episodes of SP. Post hoc analyses revealed that participants with clinically significant post-traumatic symptoms (irrespective of CSA history) also reported more frequent and more distressing episodes of SP. Significant correlations were found among SP indices and measures of post-traumatic symptoms, depression, dissociation, and absorption. Implications and future research directions are discussed.     

Characterisation of the human GFRalpha-3 locus and investigation of the gene in Hirschsprung disease

BACKGROUND—The GDNF family receptor alpha (GFRα) proteins are extracellular cell surface bound molecules that act as adapters in binding of the GDNF family of soluble neurotrophic factors to the RET receptor. These molecules are essential for development of many neural crest derived cell types and the kidney. Mutations in RET and in two members of the GDNF ligand family are associated with Hirschsprung disease (HSCR), a congenital absence of the enteric ganglia. Members of the GFRα family are also candidates for HSCR mutations. One such gene is GFRα-3, which is expressed in the peripheral nervous system and developing nerves.
OBJECTIVE—We have characterised the structure of the human GFRα-3 locus and investigated the gene for sequence variants in a panel of HSCR patients.
METHODS—Long range PCR or subcloning of PAC clones was used to investigate GFRα-3 intron-exon boundaries. A combination of single strand conformation polymorphism (SSCP) analysis and direct sequencing was used to investigate GFRα-3 sequence variants.
RESULTS—GFRα-3 spans eight coding exons and has a gene structure and organisation similar to that of GFRα-1. We identified three polymorphic variants in GFRα-3 in a normal control population, a subset of which also occurred in HSCR patients. We did not detect any sequence variants within the coding sequence of GFRα-3. We found a base substitution in the 5' UTR of GFRα-3, 15 base pairs upstream of the translation start site. A second substitution was identified in intron 4 (IVS4-30G>A) between the splice branch site and the splice acceptor site. The final variant was a 2 base pair insertion within the splice donor consensus sequence of exon 7 (IVS7+4ins GG).
CONCLUSIONS—We did not detect any correlation between variants of GFRα-3 and the HSCR phenotype. Our data suggest that mutations of this gene are not a cause of HSCR.


Keywords: GFRα-3; Hirschsprung disease; RET     

The substrate-binding protein imposes directionality on an electrochemical sodium gradient-driven TRAP transporter

Substrate-binding protein-dependent secondary transporters are widespread in prokaryotes and are represented most frequently by members of the tripartite ATP-independent periplasmic (TRAP) transporter family. Here, we report the membrane reconstitution of a TRAP transporter, the sialic acid-specific SiaPQM system from Haemophilus influenzae, and elucidate its mechanism of energy coupling. Uptake of sialic acid via membrane-reconstituted SiaQM depends on the presence of the sialic acid-binding protein, SiaP, and is driven by the electrochemical sodium gradient. The interaction between SiaP and SiaQM is specific as transport is not reconstituted using the orthologous sialic acid-binding protein VC1779. Importantly, the binding protein also confers directionality on the transporter, and reversal of sialic acid transport from import to export is only possible in the presence of an excess of unliganded SiaP.     

Effect of transmurally heterogeneous myocyte excitation–contraction coupling on canine left ventricular electromechanics

The excitation–contraction coupling properties of cardiac myocytes isolated from different regions of the mammalian left ventricular wall have been shown to vary considerably, with uncertain effects on ventricular function. We embedded a cell-level excitation–contraction coupling model with region-dependent parameters within a simple finite element model of left ventricular geometry to study effects of electromechanical heterogeneity on local myocardial mechanics and global haemodynamics. This model was compared with one in which heterogeneous myocyte parameters were assigned randomly throughout the mesh while preserving the total amount of each cell subtype. The two models displayed nearly identical transmural patterns of fibre and cross-fibre strains at end-systole, but showed clear differences in fibre strains at earlier points during systole. Haemodynamic function, including peak left ventricular pressure, maximal rate of left ventricular pressure development and stroke volume, were essentially identical in the two models. These results suggest that in the intact ventricle heterogeneously distributed myocyte subtypes primarily impact local deformation of the myocardium, and that these effects are greatest during early systole.