Aminoacyl-tRNA synthetase deficiencies in search of common themes.

PURPOSE: Pathogenic variations in genes encoding aminoacyl-tRNA synthetases (ARSs) are increasingly associated with human disease. Clinical features of autosomal recessive ARS deficiencies appear very diverse and without apparent logic. We searched for common clinical patterns to improve disease recognition, insight into pathophysiology, and clinical care. METHODS: Symptoms were analyzed in all patients with recessive ARS deficiencies reported in literature, supplemented with unreported patients evaluated in our hospital. RESULTS: In literature, we identified 107 patients with AARS, DARS, GARS, HARS, IARS, KARS, LARS, MARS, RARS, SARS, VARS, YARS, and QARS deficiencies. Common symptoms (defined as present in ≥4/13 ARS deficiencies) included abnormalities of the central nervous system and/or senses (13/13), failure to thrive, gastrointestinal symptoms, dysmaturity, liver disease, and facial dysmorphisms. Deep phenotyping of 5 additional patients with unreported compound heterozygous pathogenic variations in IARS, LARS, KARS, and QARS extended the common phenotype with lung disease, hypoalbuminemia, anemia, and renal tubulopathy. CONCLUSION: We propose a common clinical phenotype for recessive ARS deficiencies, resulting from insufficient aminoacylation activity to meet translational demand in specific organs or periods of life. Assuming residual ARS activity, adequate protein/amino acid supply seems essential instead of the traditional replacement of protein by glucose in patients with metabolic diseases.

A virtual asthma clinic for children: fewer routine outpatient visits, same asthma control.

eHealth is an appealing medium to improve healthcare and its value (in addition to standard care) has been assessed in previous studies. We aimed to assess whether an eHealth intervention could improve asthma control while reducing 50% of routine outpatient visits.In a multicentre, randomised controlled trial with a 16-month follow-up, asthmatic children (6-16 years) treated in eight Dutch hospitals were randomised to usual care (4-monthly outpatient visits) and online care using a virtual asthma clinic (VAC) (8-monthly outpatient visits with monthly web-based monitoring). Outcome measures were the number of symptom-free days in the last 4 weeks of the study, asthma control, forced expiratory volume in 1 s, exhaled nitric oxide fraction, asthma exacerbations, unscheduled outpatient visits, hospital admissions, daily dose of inhaled corticosteroids and courses of systemic corticosteroids.We included 210 children. After follow-up, symptom-free days differed statistically between the usual care and VAC groups (difference of 1.23 days, 95% CI 0.42-2.04; p=0.003) in favour of the VAC. In terms of asthma control, the Childhood Asthma Control Test improved more in the VAC group (difference of 1.17 points, 95% CI 0.09-2.25; p=0.03). No differences were found for other outcome measures.Routine outpatient visits can partly be replaced by monitoring asthmatic children via eHealth.

Episodic viral wheeze and multiple-trigger wheeze in preschool children are neither distinct nor constant patterns. A prospective multicenter cohort study in secondary care.

OBJECTIVES: To evaluate whether episodic viral wheeze (EVW) and multiple-trigger wheeze (MTW) are clinically distinguishable and stable preschool wheezing phenotypes. METHODS: Children of age 1 to 4 year with recurrent, pediatrician-confirmed wheeze were recruited from secondary care; 189 were included. Respiratory and viral upper respiratory tract infection (URTI) symptoms were recorded weekly by parents in an electronic diary during 12 months. Every 3 months, diary-based symptoms were classified as EVW or MTW and compared to phenotypes assigned by pediatricians based on clinical history. We collected nasal samples for respiratory virus PCR during URTI, respiratory symptoms and in absence of symptoms. RESULTS: Of 660 3-month periods, the diary-based phenotype was EVW in 11%, MTW in 54% and 35% were free from respiratory episodes. Pediatrician-based classification showed 59% EVW and 26% MTW. The Kappa measure of agreement between diary-based and pediatrician-assigned phenotypes was very low (0.12, 95%CI, 0.07-0.17). Phenotypic instability was observed in 32% of cases. PCR was positive in 71% during URTI symptoms, 66% during respiratory symptoms and 38% in the absence of symptoms. CONCLUSION: This study shows that EVW and MTW are variable over time within patients. Pediatrician classification of these phenotypes based on clinical history does not correspond to prospectively recorded symptom patterns. The applicability of these phenotypes as a basis for therapeutic decisions and prognosis should be questioned.

Design of a multispecies probiotic mixture to prevent infectious complications in critically ill patients.

BACKGROUND & AIMS: Although the potential for probiotics is investigated in an increasing variety of diseases, there is little or no consensus regarding the desired probiotic properties for a particular disease in question, nor about the final design of the probiotic. Specific strain selection procedures were undertaken to design a disease-specific multispecies probiotic. METHODS: From a strain collection of 69 different lactic acid bacteria a primary selection was made of 14 strains belonging to different species showing superior survival in a simulated gastrointestinal environment. Functional tests like antimicrobial activity against a range of clinical isolates and cytokine inducing capacity in cultured human peripheral blood mononuclear cells were used to further identify potential strains. RESULTS: Specific strains inhibited growth of clinical isolates whereas others superiorly induced the anti-inflammatory cytokine IL-10. Based on functional tests and general criteria regarding probiotic design and safety, a selection of the following six strains was made (Ecologic 641); Bifidobacterium bifidum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus salivarius and Lactococcus lactis. Combination of these strains resulted in a wider antimicrobial spectrum, superior induction of IL-10 and silencing of pro-inflammatory cytokines as compared to the individual components. CONCLUSIONS: Application of strict criteria during the design of a disease-specific probiotic prior to implementation in clinical trials may provide a rational basis for use of probiotics.

Absence of Neisseria meningitidis serogroup C-specific antibodies during the first year of life in the Netherlands: an age group at risk?

In The Netherlands, a single meningococcal serogroup C conjugate (MenCC) vaccination is administered to children at the age of 14 months. Here, we report the levels of MenC polysaccharide-specific antibodies in children at birth and at 3, 11, and 12 months of age and the presence of functional antibodies at 11 months of age, before infants receive their MenCC immunization. We observed a rapid decline in polysaccharide-specific antibodies after birth and no induction of naturally elicited polysaccharide-specific antibodies. Furthermore, at 11 months of age, no bactericidal antibodies are observed. These data indicate that these infants may be at risk in the period prior to MenCC immunization, if Neisseria meningitidis serogroup C starts to (re)circulate.