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author:("amira, Israel")
1.  More Realistic Face Model Surface Improves Relevance of Pediatric In-Vitro Aerosol Studies 
PLoS ONE  2015;10(6):e0128538.
Various hard face models are commonly used to evaluate the efficiency of aerosol face masks. Softer more realistic “face” surface materials, like skin, deform upon mask application and should provide more relevant in-vitro tests. Studies that simultaneously take into consideration many of the factors characteristic of the in vivo face are lacking. These include airways, various application forces, comparison of various devices, comparison with a hard-surface model and use of a more representative model face based on large numbers of actual faces.
To compare mask to “face” seal and aerosol delivery of two pediatric masks using a soft vs. a hard, appropriately representative, pediatric face model under various applied forces.
Two identical face models and upper airways replicas were constructed, the only difference being the suppleness and compressibility of the surface layer of the “face.” Integrity of the seal and aerosol delivery of two different masks [AeroChamber (AC) and SootherMask (SM)] were compared using a breath simulator, filter collection and realistic applied forces.
The soft “face” significantly increased the delivery efficiency and the sealing characteristics of both masks. Aerosol delivery with the soft “face” was significantly greater for the SM compared to the AC (p< 0.01). No statistically significant difference between the two masks was observed with the hard “face.”
The material and pliability of the model “face” surface has a significant influence on both the seal and delivery efficiency of face masks. This finding should be taken into account during in-vitro aerosol studies.
PMCID: PMC4474798  PMID: 26090661
2.  A reach-out system for video microscopy analysis of ciliary motions aiding PCD diagnosis 
BMC Research Notes  2015;8:71.
High-speed Video-Microscopy Analysis (HVMA) is now being used to aid diagnosis of Primary Ciliary Dyskinesia (PCD). Only a few centers however, are equipped with the available resources and equipment to perform these tests. We describe our experience in HVMA reaching-out to many more peripheral and relatively remote areas.
A portable computer with HVMA software, video camera and a microscope were used. Fourteen disperse pediatric centers were reached and a total of 203 subjects were tested within a relatively short time (Clinical Trial Registration: NCT 01070914 (registered February 6, 2010).
With an average time of 20 minutes per patient, the system enabled us to test approximately 10–15 subjects per day. A valid HVMA result was made in 148 subjects and helped in the diagnosis of PCD in many of the patients who were subsequently confirmed to have PCD by electron microscopy and/or immunofluoresence and/or genetics and/or nasal Nitric Oxide testing. The sensitivity of abnormal HVMA to accurately predict PCD was 90.2%.
Discussion and conclusion
This is the first report of an out-reach system to record HVMA for improved diagnosis of PCD in remote regions that are not within reach of PCD centers and experts. It provides immediate preliminary results and instantaneous feedback to the physician, patient and his/her family members in these areas. Future studies to compare this system to conventional desk top systems are warranted.
Trial registration
NCT 01070914 (registered February 6, 2010).
PMCID: PMC4363456  PMID: 25869032
Cilia; Video; Microscopy; Portability
3.  Feasibility of aerosol drug delivery to sleeping infants: a prospective observational study 
BMJ Open  2014;4(3):e004124.
Delivery of inhaled medications to infants is usually very demanding and is often associated with crying and mask rejection. It has been suggested that aerosol administration during sleep may be an attractive alternative. Previous studies in sleeping children were disappointing as most of the children awoke and rejected the treatment. The SootherMask (SM) is a new, gentle and innovative approach for delivering inhaled medication to infants and toddlers. The present pilot study describes the feasibility of administering inhaled medications during sleep using the SM.
Prospective observational study.
Out patients.
13 sleeping infants with recurrent wheezing who regularly used pacifiers and were <12 months old.
Participants inhaled technetium99mDTPA-labelled normal saline aerosol delivered via a Respimat Soft Mist Inhaler (SMI) (Boehringer-Ingelheim, Germany) and SM + InspiraChamber (IC; InspiRx Inc, New Jersey, USA).
The two major outcomes were the acceptability of the treatment and the lung deposition (per cent of emitted dose).
All infants who fulfilled the inclusion criteria successfully received the SM treatment during sleep without difficulty. Mean lung deposition (±SD) averaged 1.6±0.5% in the right lung.
This study demonstrated that the combination of Respimat, IC and SM was able to administer aerosol therapy to all the sleeping infants who were regular pacifier users with good lung deposition. Administration of aerosols during sleep is advantageous since all the sleeping children accepted the mask and ensuing aerosol therapy under these conditions, in contrast to previous studies in which there was frequent mask rejection using currently available devices.
Clinical Trial Registry
PMCID: PMC3975762  PMID: 24670428
4.  CCDC65 Mutation Causes Primary Ciliary Dyskinesia with Normal Ultrastructure and Hyperkinetic Cilia 
PLoS ONE  2013;8(8):e72299.
Primary ciliary dyskinesia (PCD) is a genetic disorder characterized by impaired ciliary function, leading to chronic sinopulmonary disease. The genetic causes of PCD are still evolving, while the diagnosis is often dependent on finding a ciliary ultrastructural abnormality and immotile cilia. Here we report a novel gene associated with PCD but without ciliary ultrastructural abnormalities evident by transmission electron microscopy, but with dyskinetic cilia beating.
Genetic linkage analysis was performed in a family with a PCD subject. Gene expression was studied in Chlamydomonas reinhardtii and human airway epithelial cells, using RNA assays and immunostaining. The phenotypic effects of candidate gene mutations were determined in primary culture human tracheobronchial epithelial cells transduced with gene targeted shRNA sequences. Video-microscopy was used to evaluate cilia motion.
A single novel mutation in CCDC65, which created a termination codon at position 293, was identified in a subject with typical clinical features of PCD. CCDC65, an orthologue of the Chlamydomonas nexin-dynein regulatory complex protein DRC2, was localized to the cilia of normal nasal epithelial cells but was absent in those from the proband. CCDC65 expression was up-regulated during ciliogenesis in cultured airway epithelial cells, as was DRC2 in C. reinhardtii following deflagellation. Nasal epithelial cells from the affected individual and CCDC65-specific shRNA transduced normal airway epithelial cells had stiff and dyskinetic cilia beating patterns compared to control cells. Moreover, Gas8, a nexin-dynein regulatory complex component previously identified to associate with CCDC65, was absent in airway cells from the PCD subject and CCDC65-silenced cells.
Mutation in CCDC65, a nexin-dynein regulatory complex member, resulted in a frameshift mutation and PCD. The affected individual had altered cilia beating patterns, and no detectable ultrastructural defects of the ciliary axoneme, emphasizing the role of the nexin-dynein regulatory complex and the limitations of certain methods for PCD diagnosis.
PMCID: PMC3753302  PMID: 23991085
5.  LRRC6 Mutation Causes Primary Ciliary Dyskinesia with Dynein Arm Defects 
PLoS ONE  2013;8(3):e59436.
Despite recent progress in defining the ciliome, the genetic basis for many cases of primary ciliary dyskinesia (PCD) remains elusive. We evaluated five children from two unrelated, consanguineous Palestinian families who had PCD with typical clinical features, reduced nasal nitric oxide concentrations, and absent dynein arms. Linkage analyses revealed a single common homozygous region on chromosome 8 and one candidate was conserved in organisms with motile cilia. Sequencing revealed a single novel mutation in LRRC6 (Leucine-rich repeat containing protein 6) that fit the model of autosomal recessive genetic transmission, leading to a change of a highly conserved amino acid from aspartic acid to histidine (Asp146His). LRRC6 was localized to the cytoplasm and was up-regulated during ciliogenesis in human airway epithelial cells in a Foxj1-dependent fashion. Nasal epithelial cells isolated from affected individuals and shRNA-mediated silencing in human airway epithelial cells, showed reduced LRRC6 expression, absent dynein arms, and slowed cilia beat frequency. Dynein arm proteins were either absent or mislocalized to the cytoplasm in airway epithelial cells from a primary ciliary dyskinesia subject. These findings suggest that LRRC6 plays a role in dynein arm assembly or trafficking and when mutated leads to primary ciliary dyskinesia with laterality defects.
PMCID: PMC3602302  PMID: 23527195
6.  CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs 
Nature genetics  2010;43(1):72-78.
Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by recurrent infections of the upper and lower respiratory tract, reduced fertility in males and situs inversus in about 50% of affected individuals (Kartagener syndrome). It is caused by motility defects in the respiratory cilia that are responsible for airway clearance, the flagella that propel sperm cells and the nodal monocilia that determine left-right asymmetry1. Recessive mutations that cause PCD have been identified in genes encoding components of the outer dynein arms, radial spokes and cytoplasmic pre-assembly factors of axonemal dyneins, but these mutations account for only about 50% of cases of PCD. We exploited the unique properties of dog populations to positionally clone a new PCD gene, CCDC39. We found that loss-of-function mutations in the human ortholog underlie a substantial fraction of PCD cases with axonemal disorganization and abnormal ciliary beating. Functional analyses indicated that CCDC39 localizes to ciliary axonemes and is essential for assembly of inner dynein arms and the dynein regulatory complex.
PMCID: PMC3509786  PMID: 21131972

Results 1-6 (6)