- Compound Heterozygous Variants in the Coiled-Coil Domain Containing 40 Gene in a Chinese Family with Primary Ciliary Dyskinesia Cause Extreme Phenotypic Diversity in Cilia Ultrastructure. [Journal Article]
- FGFront Genet 2018; 9:23
- Purpose: Primary ciliary dyskinesia (PCD) is a rare genetic disorder manifested with recurrent infections of respiratory tract and infertility. Mutations in more than 20 genes inc...
Purpose: Primary ciliary dyskinesia (PCD) is a rare genetic disorder manifested with recurrent infections of respiratory tract and infertility. Mutations in more than 20 genes including the Coiled-Coil Domain Containing 40 (CCDC40) gene are associated with PCD. A Chinese proband with a clinical diagnosis of PCD was analyzed for mutations in these genes to identify the genetic basis of the disease in the family. The proband showed altered mucociliary clearance of the airways, various degree of hyperemia and edema of the mucous membrane, left/right body asymmetry, infertility and ultrastructural abnormality of cilia in both sperm and bronchioles.Methods:The DNA from the proband was analyzed for genetic variation in a subset of genes known to cause PCD using targeted next generation sequencing in order to understand the molecular and genetic basis of the PCD in present family. The result of targeted next generation sequencing has been validated by Sanger sequencing and q-PCR.Results:Targeted next-generation sequencing identified two novel mutations (c.1259delA and EX17_20 deletion) inCCDC40gene that causes abnormalCCDC40mRNA expression. These two novel variants cause disorganization of axoneme filaments, which resulted in reduction of sperm motility and phenotypic diversity in ultrastructure of cilia in the proband.Conclusion:These findings highlight the significance of the mutations inCCDC40as novel candidates for genetic testing in PCD patients as well as the key role of ICSI treatment for the families affected by this ciliary dysmotility. Our findings showed that our work enriched the performance of cilia ultrastructure which were not previously reported in PCD patients.
- Live birth after Laser Assisted Viability Assessment (LAVA) to detect pentoxifylline resistant ejaculated immotile spermatozoa during ICSI in a couple with male Kartagener's syndrome. [Journal Article]
- RBReprod Biol Endocrinol 2018 Feb 05; 16(1):10
- Primary ciliary dyskinesia (PCD) is a rare, autosomal recessive disease with abnormalities in the structure of cilia, causing impairment of muco-ciliary clearance with respiratory tract infections, h...
Primary ciliary dyskinesia (PCD) is a rare, autosomal recessive disease with abnormalities in the structure of cilia, causing impairment of muco-ciliary clearance with respiratory tract infections, heterotaxia and abnormal sperm motility with male infertility. Here, with a comprehensive literature review, we report a couple with an infertility history of 9 years and three unsuccessful IVF treatments, where male partner has Kartagener's Syndrome, a subtype of PCD, displaying recurrent respiratory infections, dextrocardia and total asthenozoospermia. His diagnosis was verified with transmission electron microscopy and genetic mutation screening, revealing total absence of dynein arms in sperm tails and homozygous mutation in the ZMYND10, heterozygous mutations in the ARMC4 and DNAH5 genes. Laser assisted viability assay (LAVA) was performed by shooting the sperm tails during sperm retrieval for microinjection, following detection of pentoxifylline resistant immotile sperm. Live births of healthy triplets, one boy and two monozygotic girls, was achieved after double blastocyst transfer.
- Homozygous missense mutation L673P in adenylate kinase 7 (AK7) leads to primary male infertility and multiple morphological anomalies of the flagella but not to primary ciliary dyskinesia. [Journal Article]
- HMHum Mol Genet 2018 Jan 22
- Motile cilia and sperm flagella share an extremely conserved microtubule-based cytoskeleton, called the axoneme, which sustains beating and motility of both organelles. Ultra-structural and/or functi...
Motile cilia and sperm flagella share an extremely conserved microtubule-based cytoskeleton, called the axoneme, which sustains beating and motility of both organelles. Ultra-structural and/or functional defects of this axoneme are well-known to cause primary ciliary dyskinesia (PCD), a disorder characterized by recurrent respiratory tract infections, chronic otitis media, situs inversus, male infertility and in most severe cases, hydrocephalus. Only recently, mutations in genes encoding axonemal proteins with preferential expression in the testis were identified in isolated male infertility; in those cases, individuals displayed severe asthenozoospermia due to Multiple Morphological Abnormalities of the sperm Flagella (MMAF) but not PCD features. In this study, we performed genetic investigation of two siblings presenting MMAF without any respiratory PCD features, and we report the identification of the c.2018T > G (p.Leu673Pro) transversion in AK7, encoding an adenylate kinase, expressed in ciliated tissues and testis. By performing transcript and protein analyses of biological samples from individual carrying the transversion, we demonstrate that this mutation leads to the loss of AK7 protein in sperm cells but not in respiratory ciliated cells, although both cell types carry the mutated transcript and no tissue-specific isoforms were detected. This work therefore, supports the notion that proteins shared by both cilia and sperm flagella may have specific properties and/or function in each organelle, in line with the differences in their mode of assembly and organization. Overall, this work identifies a novel genetic cause of asthenozoospermia due to MMAF and suggests that in humans, more deleterious mutations of AK7 might induce PCD.
- IgM Augments Complement Bactericidal Activity with Serum from a Patient with a Novel CD79a Mutation. [Journal Article]
- JCJ Clin Immunol 2018 Jan 15
- Antibody replacement therapy for patients with antibody deficiencies contains only IgG. As a result, concurrent IgM and IgA deficiency present in a large proportion of antibody deficient patients per...
Antibody replacement therapy for patients with antibody deficiencies contains only IgG. As a result, concurrent IgM and IgA deficiency present in a large proportion of antibody deficient patients persists. Especially patients with IgM deficiency remain at risk for recurrent infections of the gastrointestinal and respiratory tract. The lack of IgM in the current IgG replacement therapy is likely to contribute to the persistence of these mucosal infections because this antibody class is especially important for complement activation on the mucosal surface. We evaluated whether supplementation with IgM increased serum bactericidal capacity in vitro. Serum was collected from a patient with agammaglobulinemia and supplemented with purified serum IgM to normal levels. Antibody and complement deposition on the bacterial surface was determined by multi-color flow cytometry. Bacterial survival in serum was determined by colony-forming unit counts. We present a patient previously diagnosed with agammaglobulinemia due to CD79A (Igα) deficiency revealing a novel pathogenic insertion variant in the CD79a gene (NM_001783.3:c.353_354insT). Despite IgG replacement therapy and antibiotic prophylaxis, this patient developed a Campylobacter jejuni spondylodiscitis of lumbar vertebrae L4-L5. We found that serum IgM significantly contributes to complement activation on the bacterial surface of C. jejuni. Furthermore, supplementation of serum IgM augmented serum bactericidal activity significantly. In conclusion, supplementation of intravenous IgG replacement therapy with IgM may potentially offer greater protection against bacterial infections, also in the context of increasing antibiotic resistance.
- Long-term nutritional and gastrointestinal aspects in patients with ataxia telangiectasia. [Journal Article]
- NNutrition 2018; 46:48-52
- CONCLUSIONS: There is a progressive growth failure and low nutritional intake with age in patients with A-T, starting in early childhood in males, and more prominent in patients with cough and choking during meals. A proactive approach and insertion of a percutaneous gastrostomy tube as soon as the BMI-Z starts to decrease should be considered.
- Intra cranial granulomatous disease in common variable immunodeficiency: Case series and review of the literature. [Review]
- SASemin Arthritis Rheum 2017 Oct 20
- CONCLUSIONS: CNS disease is a rare challenging complication of CVID. Patients with brain involvement are generally female, Caucasian, and likely have lung involvement. Although immunoglobulin and steroids remain the first line of treatment, other immunosuppressive agents have shown some promise with regards to recurrent relapsing presentations.
- An atypical presentation of pulmonary sequestration. [Journal Article]
- JRJ Res Med Sci 2017; 22:127
- Pulmonary sequestration (PS) is a rare congenital malformation of the lower respiratory tract and is commonly complicated by recurrent infections and presents with respiratory failure. We report an a...
Pulmonary sequestration (PS) is a rare congenital malformation of the lower respiratory tract and is commonly complicated by recurrent infections and presents with respiratory failure. We report an atypical clinical presentation of postprandial abdominal pain and cramps in a patient with intralobar PS.
- Forecasting influenza-like illness dynamics for military populations using neural networks and social media. [Journal Article]
- PlosPLoS One 2017; 12(12):e0188941
- This work is the first to take advantage of recurrent neural networks to predict influenza-like illness (ILI) dynamics from various linguistic signals extracted from social media data. Unlike other a...
This work is the first to take advantage of recurrent neural networks to predict influenza-like illness (ILI) dynamics from various linguistic signals extracted from social media data. Unlike other approaches that rely on timeseries analysis of historical ILI data and the state-of-the-art machine learning models, we build and evaluate the predictive power of neural network architectures based on Long Short Term Memory (LSTMs) units capable of nowcasting (predicting in "real-time") and forecasting (predicting the future) ILI dynamics in the 2011 - 2014 influenza seasons. To build our models we integrate information people post in social media e.g., topics, embeddings, word ngrams, stylistic patterns, and communication behavior using hashtags and mentions. We then quantitatively evaluate the predictive power of different social media signals and contrast the performance of the-state-of-the-art regression models with neural networks using a diverse set of evaluation metrics. Finally, we combine ILI and social media signals to build a joint neural network model for ILI dynamics prediction. Unlike the majority of the existing work, we specifically focus on developing models for local rather than national ILI surveillance, specifically for military rather than general populations in 26 U.S. and six international locations., and analyze how model performance depends on the amount of social media data available per location. Our approach demonstrates several advantages: (a) Neural network architectures that rely on LSTM units trained on social media data yield the best performance compared to previously used regression models. (b) Previously under-explored language and communication behavior features are more predictive of ILI dynamics than stylistic and topic signals expressed in social media. (c) Neural network models learned exclusively from social media signals yield comparable or better performance to the models learned from ILI historical data, thus, signals from social media can be potentially used to accurately forecast ILI dynamics for the regions where ILI historical data is not available. (d) Neural network models learned from combined ILI and social media signals significantly outperform models that rely solely on ILI historical data, which adds to a great potential of alternative public sources for ILI dynamics prediction. (e) Location-specific models outperform previously used location-independent models e.g., U.S. only. (f) Prediction results significantly vary across geolocations depending on the amount of social media data available and ILI activity patterns. (g) Model performance improves with more tweets available per geo-location e.g., the error gets lower and the Pearson score gets higher for locations with more tweets.
- Effect of once-daily, modified-release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency (DREAM): a single-blind, randomised controlled trial. [Journal Article]
- LDLancet Diabetes Endocrinol 2017 Dec 08
- CONCLUSIONS: Patients with adrenal insufficiency on conventional glucocorticoid replacement therapy multiple times a day exhibit a pro-inflammatory state and weakened immune defence. Restoration of a more physiological circadian glucocorticoid rhythm by switching to a once-daily, modified-release regimen reduces bodyweight, normalises the immune cell profile, reduces recurrent infections, and improves the quality of life of patients with adrenal insufficiency.
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- Acute bronchiolitis: Influence of viral co-infection in infants hospitalized over 12 consecutive epidemic seasons. [Journal Article]
- JMJ Med Virol 2018; 90(4):631-638
- Bronchiolitis is the first lower respiratory tract viral infection manifesting in infants younger than 12 months of age. Our aim was to evaluate clinical and serological differences in infants with b...
Bronchiolitis is the first lower respiratory tract viral infection manifesting in infants younger than 12 months of age. Our aim was to evaluate clinical and serological differences in infants with bronchiolitis from a single or from multiple viruses. Our secondary aim was to investigate differences in recurrent wheezing episodes after 12-24-36 months of follow-up. We reviewed the clinical records for 486 full-term infants hospitalized for bronchiolitis with at least one virus detected in the nasopharyngeal aspirate. In 431 (88.7%) patients one virus was detected and in 55 (11.3%) infants more than one virus was found. No differences were observed in the length of hospitalization, clinical severity score, O2supplementation or admission to the intensive care unit. Single virus was associated with higher serum C-reactive protein (C-RP) than infants with multiple viruses and higher blood neutrophil counts. Respiratory syncytial virus (RSV) was the most frequently detected virus. RSV alone was associated with higher C-RP (P = 0.007), compared to RSV coinfection. Infants with human rhinovirus (hRV) alone had higher white blood cell counts, higher blood neutrophils, and higher serum C-RP levels than hRV co-infection (P = 0.029, P = 0.008, P = 0.008). RSV + hRV, the most frequent co-infection, was associated with lower neutrophil count and lower C-RP levels (P = 0.008, P = 0.016) and less fever (P = 0.012), when comparing RSV versus hRV versus RSV + hRV. No differences were found in the frequency of recurrent wheezing between single versus multiple viruses after bronchiolitis. Our findings suggest that in infants with bronchiolitis multiple viral co-infections can occur, without influence in the clinical severity of the disease. Infants with co-infection seems to mount a lower inflammatory response.