Research

TTC7A: Steward of Intestinal Health.

Cell Mol Gastroenterol Hepatol. 2018 Dec 13;:

Authors: Jardine S, Dhingani N, Muise AM

Abstract
The rising incidence of paediatric inflammatory bowel disease (IBD), coupled with the efficiency of whole exome sequencing, has led to the identification of Tetratricopeptide Repeat Domain 7A (TTC7A) as a steward of intestinal health. TTC7A-deficiency is an autosomal recessively inherited disease. In five years since the original description more than 50 patients with >20 distinct disease-causing TTC7A mutations have been identified. Patients exhibit heterogenous intestinal and immunological disease manifestations, including but not limited to multiple intestinal atresias, very early-onset inflammatory bowel disease, loss of intestinal architecture, apoptotic enterocolitis, combined immunodeficiency, and various extraintestinal features related to the skin and/or hair. The focus of this review is to highlight trends in patient phenotypes and to consolidate functional data related to TTC7A’s role in maintaining intestinal homeostasis. TTC7A-deficiency results in fatality in approximately two-thirds of patients, and as more patients continue to be uncovered, elucidating the comprehensive role of TTC7A could reveal druggable targets that may benefit the growing cohort of individuals suffering from IBD.

PMID: 30553809 [PubMed – as supplied by publisher]

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Polymorphisms in the myeloid differentiation primary response 88 pathway do not explain low expression levels in sudden infant death syndrome.

Acta Paediatr. 2018 Dec 14;:

Authors: Bjørnvall CD, Opdal SH, Rognum TO, Ferrante L

Abstract
AIM: The aim of this study was to investigate if a range of known rare and common genetic variants in the Toll-like receptor 4 (TLR4) / myeloid differentiation primary response 88 (MyD88) pathway were present or overrepresented in sudden infant death syndrome (SIDS) compared to controls.
METHODS: Genetic variations in the genes encoding TLR4, MyD88 and Interleukin-1 receptor-associated kinase 4 were analysed. The subjects investigated included 158 SIDS cases with a median age of 15.25 weeks (2-47 weeks), 80 cases of infectious death with a median age of 24.9 weeks (0-285 weeks) and 199 adult controls with a median age of 50 years (11-86 years). The cases were collected in the years 1988 – 2017 and the autopsies were performed at the Department of Forensic Sciences at Oslo University Hospital, Oslo, Norway.
RESULTS: The results showed that none of the genetic variants selected from the MyD88 pathway were associated with neither SIDS nor infectious death. Most of the rare genetic variants were homozygote for the common allele in all groups, while the rest revealed allelic variation.
CONCLUSION: The genetic variations investigated in this study did not appear to be involved in the pathogenesis of SIDS. This article is protected by copyright. All rights reserved.

PMID: 30550627 [PubMed – as supplied by publisher]

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A retrospective study of factors associated with treatment decision for nontuberculous mycobacterial lung disease in adults without altered systemic immunity.

BMC Infect Dis. 2018 Dec 14;18(1):659

Authors: Provoost J, Valour F, Gamondes D, Roux S, Freymond N, Perrot E, Souquet PJ, Kiakouama-Maleka L, Chidiac C, Lina G, Dumitrescu O, Sénéchal A, Ader F

Abstract
BACKGROUND: Nontuberculous mycobacteria (NTM) lung diseases are increasingly recognized as chronic opportunistic infections, occurring in individuals with a wide variety of underlying conditions. In the absence of systemic immunodeficiency, decision of NTM lung disease treatment must relies on a careful risk/benefit assessment, given the requirement of long-term administration of multidrug therapies supported by limited evidence. The primary objective was to identify the factors associated with anti-NTM treatment initiation. Clinical and radiological outcome upon treatment were studied.
METHODS: This retrospective, single center study (2013-2016, 45 months) addressed the criteria supporting treatment decision among adults with NTM lung disease without systemic immunodeficiency at our institution, with the assigned goal to harmonize the practice. All patients matched the current international definitions of NTM lung disease according to the American Thoracic Society criteria. Factors associated with anti-NTM treatment were investigated by conditional logistic regression. Clinical and radiological outcomes of treated and untreated NTM-disease cases were examined. Mortality rate was assessed. An expert radiologist conducted a blinded computed tomography (CT)-scan review of the treated and untreated patients.
RESULTS: Among 51 cases of NTM lung diseases, 25 (49%) received anti-NTM treatment. In univariate analysis, a body mass index (BMI) < 18 kg/m2 (odds ratio (OR), 4.2 [95% confidence interval (CI) 1.2-15.2]; p = 0.042), hemoptysis (OR, 11.8 [95% CI 1.35-12.9]; p = 0.026), excavation(s) (OR, 4.8 [95% CI 1.4-16.4], p = 0.012), prior anti-NTM treatment (OR, 5.65 [95% CI 1.06-29.9]; p = 0.042), Aspergillus spp. co-infection (OR, 6.3 [95% CI 1.8-22.2]; p = 0.004) were associated with treatment initiation. In multivariate analysis, Aspergillus spp. co-infection was the only independent determinant of treatment initiation (OR, 5.3 [95% CI 1.1-25.4]; p = 0.036). Twenty-one (81%) patients received ≥3 anti-NTM drugs. Median treatment duration and follow-up were 36.3 (interquartile range [IQR], 13.1-64.4) weeks and 17.1 (IQR, 8.7-27.1) months, respectively. Regarding radiological outcome, 85 CT-scans were reviewed, showing similar rates of regression or stabilization in treated and untreated patients. Overall mortality rate was not different in treated and untreated patients.
CONCLUSION: The most relevant variable associated with anti-NTM treatment initiation was Aspergillus spp. co-infection. Radiological regression or stabilization of pulmonary lesions was not different between the treated and untreated patients.

PMID: 30547753 [PubMed – in process]

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Imaging of Bronchial Pathology in Antibody Deficiency: Data from the European Chest CT Group.

J Clin Immunol. 2018 Dec 13;:

Authors: Schütz K, Alecsandru D, Grimbacher B, Haddock J, Bruining A, Driessen G, de Vries E, van Hagen PM, Hartmann I, Fraioli F, Milito C, Mitrevski M, Quinti I, Serra G, Kelleher P, Loebinger M, Litzman J, Postranecka V, Thon V, Babar J, Condliffe AM, Exley A, Kumararatne D, Screaton N, Jones A, Bondioni MP, Lougaris V, Plebani A, Soresina A, Sirignano C, Spadaro G, Galal N, Gonzalez-Granado LI, Dettmer S, Stirling R, Chapel H, Lucas M, Patel S, Farber CM, Meyts I, Banerjee AK, Hackett S, Hurst JR, Warnatz K, Gathmann B, Baumann U, Chest CT in Antibody Deficiency Group

Abstract
Studies of chest computed tomography (CT) in patients with primary antibody deficiency syndromes (ADS) suggest a broad range of bronchial pathology. However, there are as yet no multicentre studies to assess the variety of bronchial pathology in this patient group. One of the underlying reasons is the lack of a consensus methodology, a prerequisite to jointly document chest CT findings. We aimed to establish an international platform for the evaluation of bronchial pathology as assessed by chest CT and to describe the range of bronchial pathologies in patients with antibody deficiency. Ffteen immunodeficiency centres from 9 countries evaluated chest CT scans of patients with ADS using a predefined list of potential findings including an extent score for bronchiectasis. Data of 282 patients with ADS were collected. Patients with common variable immunodeficiency disorders (CVID) comprised the largest subgroup (232 patients, 82.3%). Eighty percent of CVID patients had radiological evidence of bronchial pathology including bronchiectasis in 61%, bronchial wall thickening in 44% and mucus plugging in 29%. Bronchiectasis was detected in 44% of CVID patients aged less than 20 years. Cough was a better predictor for bronchiectasis than spirometry values. Delay of diagnosis as well as duration of disease correlated positively with presence of bronchiectasis. The use of consensus diagnostic criteria and a pre-defined list of bronchial pathologies allows for comparison of chest CT data in multicentre studies. Our data suggest a high prevalence of bronchial pathology in CVID due to late diagnosis or duration of disease.

PMID: 30547383 [PubMed – as supplied by publisher]

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The Incidence of Meningitis in Patients with Traumatic Brain Injury Undergoing External Ventricular Drain Placement: A Nationwide Inpatient Sample Analysis.

Neurocrit Care. 2018 Dec 06;:

Authors: Hoffman H, Jalal MS, Chin LS

Abstract
BACKGROUND/OBJECTIVE: Infection is the most common complication of external ventricular drain (EVD) placement. National trends in the annual incidence of meningitis among patients with traumatic brain injury (TBI) who have undergone EVD placement have not been reported.
METHODS: The Nationwide Inpatient Sample was used to select adults with a primary diagnosis of TBI who underwent EVD placement between 2002 and 2011. Annual rates of meningitis among patients who underwent EVD placement were determined. We also calculated mortality rates and length of stay (LOS). Potential factors associated with meningitis were evaluated in a binary logistic regression analysis.
RESULTS: Out of 1,571,927 adult discharges with a primary diagnosis of TBI between 2002 and 2011, 39,029 (2.5%) underwent EVD placement. Of these, 1544 (4.3%) patients developed meningitis. There was no significant trend in the annual incidence of meningitis (p = 0.88), mortality (p = 0.55), or mean LOS (p = 0.13) during the study period. Meningitis and mortality rates remained stable when stratifying patients by hospital volume. In the binary logistic regression, acquired immunodeficiency syndrome, sepsis, and cerebrospinal fluid leak were associated with meningitis.
CONCLUSIONS: The incidence of meningitis in patients who underwent EVD placement remained stable between 2002 and 2011. Further prospective studies are needed to identify approaches for preventing these infections.

PMID: 30523540 [PubMed – as supplied by publisher]

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Microchimerism in Ghanaian children recipients of whole blood transfusion for severe anaemia.

Vox Sang. 2018 Dec 06;:

Authors: Assennato SM, Owusu-Ofori S, Osei-Akoto A, Lambert NC, Allain JP

Abstract
BACKGROUND AND OBJECTIVES: Transfusion-acquired microchimerism (TA-Mc) has been reported in major trauma but not in young children despite relative immunodeficiency who, in sub-Saharan Africa, often suffer severe anaemia related to haemoglobinopathies or primary malaria infections. We examined the hypothesis that such massive red cell destructions might provide conditions favourable to TA-Mc, particularly when exposed to massive amounts of parasite antigens.
MATERIALS AND METHODS: Twenty-seven female children <5 years transfused with male whole blood for severe anaemia (13 with acute malaria and 14 with other causes) were retrospectively identified, and a blood sample was collected >6 months post-transfusion. Four whole blood samples from paediatric females transfused with blood from female donors and five secondary school female students never pregnant, never transfused were used as negative controls.
RESULTS: Nineteen patients (70%) carried male Mc with four (15%) having high levels of Mc (>100 genome equivalent of male cells/million of host cells) compared to three controls (37·5%). There was no difference in frequency or quantity of male Mc between paediatric patients with severe malaria and paediatric patients with other causes of severe anaemia. TA-Mc was not correlated with patient age, duration of whole blood storage or lymphocyte load transfused. After a median of 7 months post-transfusion, acute malaria did not increase the frequency of TA-Mc. One negative control appeared to carry low-level male cells.
CONCLUSION: Transfusion-acquired microchimerism appears frequent in young children transfused with whole blood for severe anaemia.

PMID: 30523635 [PubMed – as supplied by publisher]

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primary immunodeficiency NOT human immunodeficiency virus

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Chronic granulamatous disease: two decades of experience from a pediatric immunology unit in a country with high rate of consangineous marriages.

Scand J Immunol. 2018 Dec 01;:e12737

Authors: Kutukculer N, Aykut A, Karaca NE, Durmaz A, Aksu G, Genel F, Pariltay E, Cogulu Ö, Azarsız E

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by susceptibility to bacterial and fungal infections resulting from the inadequacy of phagocytic leukocytes to produce reactive oxygen radicals. CGD is a genetically heterogeneous disease with an X-linked recessive (XR-CGD) form caused by mutations in the CYBB (OMIM #300481) gene encoding the gp91(phox) protein, and an autosomal recessive (AR-CGD) form caused by mutations in the CYBA (OMIM #608508), NCF1 (OMIM #608512), NCF2 (OMIM #608515) and NCF4 (OMIM #601488) genes encoding p22(phox), p47(phox), p67(phox), and p40(phox), respectively. The genetic mutation of one of the cytosolic p47phox/p67phox proteins and membrane-bound gp91phox/p22phox proteins, which constitutes the NADPH oxidase enzyme complex, causes the disease. In this study, we evaluated the clinical, laboratory and genetic findings and the prognostic effects of molecular inheritance of our 24 CGD cases (14 XR, 10 autosomal recessive-AR). Consanguinity (3 XR and all AR cases) showed statistically significant relationship with the type of hereditary inheritance (p< .001). 83% patients had an infection since early infancy. The mean age of initiation of symptoms was earlier in XR cases and 78% patients had respiratory tract infections. Bone marrow transplantation was performed in 5 XR cases (2 ex) and 4 AR (1 ex) cases. 3 of 9 XR and 2 of 6 AR cases deceased on medical follow-up. In countries especially with high consanguinity rates, the early diagnosis for appropriate prophylactic treatment of CGD is quitely important to avoid from recurrent severe infections, early death and fatal complications of late transplantation. This article is protected by copyright. All rights reserved.

PMID: 30506560 [PubMed – as supplied by publisher]

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Corrigendum: A Novel Homozygous JAK3 Mutation Leading to T-B+NK- SCID in Two Brazilian Patients.

Front Pediatr. 2018;6:358

Authors: Barreiros LA, Segundo GRS, Grumach AS, Roxo-Júnior P, Torgerson TR, Ochs HD, Condino-Neto A

Abstract
[This corrects the article DOI: 10.3389/fped.2018.00230.].

PMID: 30515370 [PubMed – in process]

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