Collapsin response mediator proteins (CRMPs) are key for brain development and function. Here, we link CRMP1 to a neurodevelopmental disorder. We report heterozygous de novo variants in the
gene in ...three unrelated individuals with muscular hypotonia, intellectual disability, and/or autism spectrum disorder. Based on in silico analysis these variants are predicted to affect the CRMP1 structure. We further analyzed the effect of the variants on the protein structure/levels and cellular processes. We showed that the human
variants impact the oligomerization of CRMP1 proteins. Moreover, overexpression of the
variants affect neurite outgrowth of murine cortical neurons. While altered CRMP1 levels have been reported in psychiatric diseases, genetic variants in
gene have never been linked to human disease. We report for the first-time variants in the
gene and emphasize its key role in brain development and function by linking directly to a human neurodevelopmental disease.
Background
Neurological complications are associated with poor outcome in patients with infective endocarditis (IE). Although guidelines recommend systematic brain imaging in the evaluation of IE ...patients, the association between early brain imaging findings and outcomes has never been evaluated in critically ill patients. We aimed to assess the association of CT-defined neurological complications with functional outcomes of critically ill IE patients.
Methods
This retrospective cohort study included consecutive patients with severe, left-sided IE hospitalized in the medical ICU of a tertiary care hospital. Patients with no baseline brain CT were excluded. Baseline CT-scans were classified in five mutually exclusive categories (normal, moderate-to-severe ischemic stroke, minor ischemic stroke, intracranial hemorrhage, other abnormal CT). The primary endpoint was 1-year favorable outcome, defined by a modified Rankin Scale score of 0–3.
Results
Between 06/01/2011 and 07/31/2018, 156 patients were included. Among them, 87/156 (56%) had a CT-defined neurological complication, including moderate-to-severe ischemic stroke (
n
= 33/156, 21%), intracranial hemorrhage (
n
= 24/156, 15%), minor ischemic stroke (
n
= 29/156, 19%), other (
n
= 3/156, 2%). At one year, 69 (45%) patients had a favorable outcome. Factors negatively associated with favorable outcome in multivariable analysis were moderate-to-severe ischemic stroke (OR 0.37, 95%CI 0.14 − 0.95) and age (OR 0.94, 95%CI 0.91–0.97). By contrast, the score on the Glasgow Coma Scale was positively associated with favorable outcome (per 1-point increment, OR 1.23, 95%CI 1.08–1.42). Sensitivity analyses conducted in operated patients revealed similar findings. Compared to normal CT, only moderate-to-severe ischemic stroke was associated with more frequent post-operative neurological complications (
n
= 8/23 (35%) vs
n
= 1/46 (2%),
p
< 0.01).
Conclusion
Moderate-to-severe ischemic stroke had an independent negative impact on 1-year functional outcome in critically ill IE patients; whereas other complications, including intracranial hemorrhage, had no such impact.
Pregnancy diagnosis is an important part in reproduction management of wild ruminants involved in free-ranging and captive programs. Pregnancy-associated glycoproteins (PAGs) are placenta-expressed ...proteins released into maternal blood circulation. Tests with high specificity have been developed and validated in domestic species and have been used in some wild ungulate species. One hundred and seventeen serum samples collected from 72 mature female Barbary sheep (Ammotragus lervia) were tested using a commercial enzyme-linked immunosorbent assay (ELISA) test. Pregnancy was determined either postmortem (n = 5) or by visualization of parturition (n = 33). The other sera were controls from known nonpregnant females (n = 71). The following values were obtained: sensitivity = 100.0%, specificity = 95.8%. Using a commercial ELISA for the detection of PAGs appears to be a rapid, inexpensive, and accurate test for pregnancy diagnosis in the endangered Barbary sheep. The number of offspring cannot be determined with this method.
Severe ventriculomegaly is a rare congenital brain defect, usually detected in utero, of poor neurodevelopmental prognosis. This ventricular enlargement can be the consequence of different ...mechanisms: either by a disruption of the cerebrospinal fluid circulation or abnormalities of its production/absorption. The aqueduct stenosis is one of the most frequent causes of obstructive ventriculomegaly, however, fewer than 10 genes have been linked to this condition and molecular bases remain often unknown. We report here 4 fetuses from 2 unrelated families presenting with ventriculomegaly at prenatal ultra-sonography as well as an aqueduct stenosis and skeletal abnormalities as revealed by fetal autopsy. Genome sequencing identified biallelic pathogenic variations in LIG4, a DNA-repair gene responsible for the LIG4 syndrome which associates a wide range of clinical manifestations including developmental delay, microcephaly, short stature, radiation hypersensitivity and immunodeficiency. Thus, not only this report expands the phenotype spectrum of LIG4-related disorders, adding ventriculomegaly due to aqueduct stenosis, but we also provide the first neuropathological description of fetuses carrying LIG4 pathogenic biallelic variations.
Adolescence represents a transition period between childhood and adulthood, and only limited information exists about stroke characteristics in this population. Our aim was to describe the clinical ...and neuroradiologic features, etiologies, initial management, and outcome of ischemic stroke in adolescents.
This retrospective cohort study evaluated all consecutive patients 10 to 18 years with a first-ever ischemic stroke hospitalized between 2007 and 2017 in 10 French academic centers representing a population of ≈10 million. Extracted data from the national database served as validation.
A total of 60 patients were included (53% male, median age 15.2 years). Diagnosis at first medical contact was misevaluated in 36%, more frequently in posterior than anterior circulation strokes (55% vs 20% respectively, odds ratio 4.8, 95% confidence interval 1.41-16.40,
= 0.01). Recanalization treatment rate was high (n = 19, 32%): IV thrombolysis (17%), endovascular therapy (11.7%), or both IV and intra-arterial thrombolysis (3.3%); safety was good (only 1 asymptomatic hemorrhagic transformation). Despite thorough etiologic workup, 50% of strokes remained cryptogenic. The most common determined etiologies were cardioembolism (15%), vasculitis and autoimmune disorders (12%, occurring exclusively in female patients), and arterial dissections (10%, exclusively in male patients). Recurrent ischemic cerebrovascular events occurred in 12% (median follow-up 19 months). Recurrence rate was 50% in patients with identified vasculopathy but 0% after cryptogenic stroke. Functional outcome was favorable (Rankin Scale score 0-2 at day 90) in 80% of cases.
Ischemic strokes in adolescents harbor both pediatric and adult features, emphasizing the need for multidisciplinary collaboration in their management. Recanalization treatments appear feasible and safe.
This study evaluated an ELISA on bulk tank milk (BTM) samples and a qPCR on a single composite fecal sample to detect paratuberculosis seropositive cattle dairy herds. Individual serum (
= 15 372), ...BTM and composite fecal samples were obtained from 192 herds. The within-herd apparent seroprevalence was categorized and compared with BTM ELISA and fecal qPCR results. The BTM ELISA had poor overall sensitivity (16%) to detect seropositive herds but higher sensitivity (53%) in the higher apparent seroprevalence group of > 9%. Using an optimized cut-off point (5.0% S/P), sensitivities overall and in the high apparent seroprevalence group were 53% and 88%, respectively. The BTM ELISA gave 5% positive results in seronegative herds and 25% using the optimized cut-off. Fecal qPCR had 72% sensitivity to detect seropositive herds and 88% in the higher apparent seroprevalence group, but gave 25% positive results in fully seronegative herds. The combination of BTM ELISA and composite fecal qPCR improved the sensitivity to detect seropositive herds.
In the human genome, about 750 genes contain one intron excised by the minor spliceosome. This spliceosome comprises its own set of snRNAs, among which U4atac. Its noncoding gene,
, has been found ...mutated in Taybi-Linder (TALS/microcephalic osteodysplastic primordial dwarfism type 1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes. These rare developmental disorders, whose physiopathological mechanisms remain unsolved, associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy, and immunodeficiency. Here, we report bi-allelic
mutations in five patients presenting with traits suggestive of the Joubert syndrome (JBTS), a well-characterized ciliopathy. These patients also present with traits typical of TALS/RFMN/LWS, thus widening the clinical spectrum of
-associated disorders and indicating ciliary dysfunction as a mechanism downstream of minor splicing defects. Intriguingly, all five patients carry the n.16G>A mutation, in the Stem II domain, either at the homozygous or compound heterozygous state. A gene ontology term enrichment analysis on minor intron-containing genes reveals that the cilium assembly process is over-represented, with no less than 86 cilium-related genes containing at least one minor intron, among which there are 23 ciliopathy-related genes. The link between
mutations and ciliopathy traits is supported by alterations of primary cilium function in TALS and JBTS-like patient fibroblasts, as well as by
zebrafish model, which exhibits ciliopathy-related phenotypes and ciliary defects. These phenotypes could be rescued by WT but not by pathogenic variants-carrying human U4atac. Altogether, our data indicate that alteration of cilium biogenesis is part of the physiopathological mechanisms of TALS/RFMN/LWS, secondarily to defects of minor intron splicing.
Purpose
The effect of renal replacement therapy (RRT) in comatose patients with acute kidney injury (AKI) remains unclear. We compared two RRT initiation strategies on the probability of awakening in ...comatose patients with severe AKI.
Methods
We conducted a post hoc analysis of a trial comparing two delayed RRT initiation strategies in patients with severe AKI. Patients were monitored until they had oliguria for more than 72 h and/or blood urea nitrogen higher than 112 mg/dL and then randomized to a delayed strategy (RRT initiated after randomization) or a more-delayed one (RRT initiated if complication occurred or when blood urea nitrogen exceeded 140 mg/dL). We included only comatose patients (Richmond Agitation-Sedation scale RASS < − 3), irrespective of sedation, at randomization. A multi-state model was built, defining five mutually exclusive states: death, coma (RASS < − 3), incomplete awakening (RASS − 3; − 2), awakening (RASS − 1; + 1 two consecutive days), and agitation (RASS > + 1). Primary outcome was the transition from coma to awakening during 28 days after randomization.
Results
A total of 168 comatose patients (90 delayed and 78 more-delayed) underwent randomization. The transition intensity from coma to awakening was lower in the more-delayed group (hazard ratio HR = 0.36 0.17–0.78;
p
= 0.010). Time spent awake was 10.11 days 8.11–12.15 and 7.63 days 5.57–9.64 in the delayed and the more-delayed groups, respectively. Two sensitivity analyses were performed based on sedation status and sedation practices across centers, yielding comparable results.
Conclusion
In comatose patients with severe AKI, a more-delayed RRT initiation strategy resulted in a lower chance of transitioning from coma to awakening.
