87 research outputs found
A reach-out system for video microscopy analysis of ciliary motions aiding PCD diagnosis
Backgrounds
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).
Results
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
Lipid apheresis techniques: current status in Germany
For long-term lipid apheresis therapy, several different technical systems have been developed which enable effective reduction of LDL cholesterol and other atherogenic lipoproteins, such as Lp(a), with sufficient selectivity and good clinical tolerance. Suitable techniques include whole blood adsorption with polyacrylamide and dextran sulfate cellulose, while primary plasma separation is used for cascade filtration, heparin-induced precipitation, immunoadsorption, silicate gel adsorption, and dextran sulfate cellulose (both techniques)
NaV_2O_5 as a quarter-filled ladder compound
A new X-ray diffraction study of the one-dimensional spin-Peierls compound
\alpha-NaV_2O_5 reveals a centrosymmetric (Pmmn) crystal structure with one
type of V site, contrary to the previously postulated non-centrosymmetric
P2_1mn structure with two types of V sites (V^{+4} and V^{+5}). Density
functional calculations indicate that NaV_2O_5 is a quarter-filled ladder
compound with the spins carried by V-O-V molecular orbitals on the rungs of the
ladder. Estimates of the charge-transfer gap and the exchange coupling agree
well with experiment and explain the insulating behavior of NaV_2O_5 and its
magnetic properties.Comment: Final version for PRL, value of U correcte
The microscopic spin-phonon coupling constants in CuGeO_3
Using RPA results, mean field theory, and refined data for the polarization
vectors we determine the coupling constants of the four Peierls-active phonon
modes to the spin chains of CuGeO_3. We then derive the values of the coupling
of the spin system to the linear ionic displacements, the bond lengths and the
angles between bonds. Our values are consistent with microscopic theories and
various experimental results. We discuss the applicability of static approaches
to the spin-phonon coupling. The c-axis anomaly of the thermal expansion is
explained. We give the values of the coupling constants in an effective
one-dimensional Hamiltonian.Comment: 11 pages, two figures, 13 tables, PRB 59 (in press
Molecular-field approach to the spin-Peierls transition in CuGeO_3
We present a theory for the spin-Peierls transition in CuGeO_3. We map the
elementary excitations of the dimerized chain (solitons) on an effective Ising
model. Inter-chain coupling (or phonons) then introduce a linear binding
potential between a pair of soliton and anti-soliton, leading to a finite
transition temperature. We evaluate, as a function of temperature, the order
parameter, the singlet-triplet gap, the specific heat, and the susceptibility
and compare with experimental data on CuGeO_3. We find that CuGeO_3 is close to
a first-order phase transition. We point out, that the famous scaling law
\sim\delta^{2/3} of the triplet gap is a simple consequence of the linear
binding potential between pairs of solitons and anti-solitons in dimerized spin
chains.Comment: 7.1 pages, figures include
Efficacy and safety of azithromycin maintenance therapy in primary ciliary dyskinesia (BESTCILIA): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial.
BACKGROUND
Use of maintenance antibiotic therapy with the macrolide azithromycin is increasing in a number of chronic respiratory disorders including primary ciliary dyskinesia (PCD). However, evidence for its efficacy in PCD is lacking. We aimed to determine the efficacy and safety of azithromycin maintenance therapy for 6 months in patients with PCD.
METHODS
The Better Experimental Screening and Treatment for Primary Ciliary Dyskinesia (BESTCILIA) trial was a multicentre, double-blind, parallel group, randomised, placebo-controlled phase 3 trial done at 6 European PCD clinics (tertiary paediatric care centres and university hospitals in Denmark, Germany, Netherlands, Switzerland, and UK). Patients with a confirmed diagnosis of PCD, aged 7-50 years old, and predicted FEV1 greater than 40% were recruited. Participants were randomly assigned (1:1), stratified by age and study site, via a web-based randomisation system to azithromycin 250 mg or 500 mg as tablets according to bodyweight (</≥ 40 kg) or identical placebo, three times a week for 6 months. The random allocation sequence was a permuted block randomisation, with a block size of four, generated by an external consultancy. Participants, investigators, and care providers were masked to treatment allocation. The primary endpoint was the number of respiratory exacerbations over 6 months. Analysis was by intention to treat. This study is registered in the EU Clinical Trials Register, EudraCT number 2013-004664-58.
FINDINGS
Between June 24, 2014, and Aug 23, 2016, 102 patients were screened, of whom 90 were randomly assigned to either azithromycin (n=49) or placebo (n=41). The study was ended without having included the planned number of participants due to recruitment difficulties. The mean number of respiratory exacerbations over 6 months was 0·75 (SD 1·12) in the azithromycin group compared with 1·62 (1·64) in the placebo group, and participants receiving azithromycin had significantly lower rate of exacerbations during the individual treatment periods (rate ratio 0·45 [95% CI 0·26-0·78]; p=0·004). Four serious adverse events were reported, occurring in one (2%) of 47 participants in the azithromycin group and in three (7%) of 41 participants in the placebo group. Loose stools or diarrhoea were more common in the azithromycin group than in the placebo group (11 [23%] vs two [5%]).
INTERPRETATION
This first multinational randomised controlled trial on pharmacotherapy in PCD showed that azithromycin maintenance therapy for 6 months was well tolerated and halved the rate of respiratory exacerbations. Azithromycin maintenance therapy is an option for patients with PCD with frequent exacerbations potentially leading to reduced need for additional antibiotic treatments and preventing irreversible lung damage.
FUNDING
European Commission Seventh Framework Programme and Children's Lung Foundation (Denmark)
Derivation and Validation of a Chronic Total Coronary Occlusion Intervention Procedural Success Score From the 20,000-Patient EuroCTO Registry: The EuroCTO (CASTLE) Score.
OBJECTIVES: The aim was to establish a contemporary scoring system to predict the outcome of chronic total occlusion coronary angioplasty. BACKGROUND: Interventional treatment of chronic total coronary occlusions (CTOs) is a developing subspecialty. Predictors of technical success or failure have been derived from datasets of modest size. A robust scoring tool could facilitate case selection and inform decision making. METHODS: The study analyzed data from the EuroCTO registry. This prospective database was set up in 2008 and includes >20,000 cases submitted by CTO expert operators (>50 cases/year). Derivation (n = 14,882) and validation (n = 5,745) datasets were created to develop a risk score for predicting technical failure. RESULTS: There were 14,882 patients in the derivation dataset (with 2,356 [15.5%] failures) and 5,745 in the validation dataset (with 703 [12.2%] failures). A total of 20.2% of cases were done retrogradely, and dissection re-entry was performed in 9.3% of cases. We identified 6 predictors of technical failure, collectively forming the CASTLE score (Coronary artery bypass graft history, Age (≥70 years), Stump anatomy [blunt or invisible], Tortuosity degree [severe or unseen], Length of occlusion [≥20 mm], and Extent of calcification [severe]). When each parameter was assigned a value of 1, technical failure was seen to increase from 8% with a CASTLE score of 0 to 1, to 35% with a score ≥4. The area under the curve (AUC) was similar in both the derivation (AUC: 0.66) and validation (AUC: 0.68) datasets. CONCLUSIONS: The EuroCTO (CASTLE) score is derived from the largest database of CTO cases to date and offers a useful tool for predicting procedural outcome
European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia
The diagnosis of primary ciliary dyskinesia is often confirmed with standard, albeit complex and expensive, tests. In many cases, however, the diagnosis remains difficult despite the array of sophisticated diagnostic tests. There is no "gold standard" reference test. Hence, a Task Force supported by the European Respiratory Society has developed this guideline to provide evidence-based recommendations on diagnostic testing, especially in light of new developments in such tests, and the need for robust diagnoses of patients who might enter randomised controlled trials of treatments. The guideline is based on pre-defined questions relevant for clinical care, a systematic review of the literature, and assessment of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. It focuses on clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence. It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of primary ciliary dyskinesia; and to provide advice when the diagnosis was not conclusive. Finally, this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for primary ciliary dyskinesia
Recessive <i>HYDIN</i> mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous
recessive disorder characterized by defective cilia and flagella
motility. Chronic destructive-airway disease is caused by
abnormal respiratory-tract mucociliary clearance. Abnormal
propulsion of sperm flagella contributes to male infertility.
Genetic defects in most individuals affected by PCD cause
randomization of left-right body asymmetry; approximately half
show situs inversus or situs ambiguous. Almost 70 years after
the hy3 mouse possessing Hydin mutations was described as a
recessive hydrocephalus model, we report HYDIN mutations in PCD-
affected persons without hydrocephalus. By homozygosity mapping,
we identified a PCD-associated locus, chromosomal region 16q21-
q23, which contains HYDIN. However, a nearly identical 360 kb
paralogous segment (HYDIN2) in chromosomal region 1q21.1
complicated mutational analysis. In three affected German
siblings linked to HYDIN, we identified homozygous c.3985G>T
mutations that affect an evolutionary conserved splice acceptor
site and that subsequently cause aberrantly spliced transcripts
predicting premature protein termination in respiratory cells.
Parallel whole-exome sequencing identified a homozygous nonsense
HYDIN mutation, c.922A>T (p.Lys307( *)), in six individuals from
three Faroe Island PCD-affected families that all carried an 8.8
Mb shared haplotype across HYDIN, indicating an ancestral
founder mutation in this isolated population. We demonstrate by
electron microscopy tomography that, consistent with the effects
of loss-of-function mutations, HYDIN mutant respiratory cilia
lack the C2b projection of the central pair (CP) apparatus;
similar findings were reported in Hydin-deficient Chlamydomonas
and mice. High-speed videomicroscopy demonstrated markedly
reduced beating amplitudes of respiratory cilia and stiff sperm
flagella. Like the hy3 mouse model, all nine PCD-affected
persons had normal body composition because nodal cilia function
is apparently not dependent on the function of the CP
apparatus
ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6
Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function
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