21 research outputs found
ΠΡΠΈΠΌΠ΅Π½Π΅Π½ΠΈΠ΅ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠ° ΠΏΠ΅Π»ΠΎΠΊΡ-400 (ΠΏΠ΅ΡΠ»ΠΎΠΊΡΠ°ΡΠΈΠ½) Π² Π»Π΅ΡΠ΅Π½ΠΈΠΈ ΠΎΡΡΡΠΎΠ³ΠΎ ΠΏΠΈΠ΅Π»ΠΎΠ½Π΅ΡΡΠΈΡΠ°
ΠΠ°Π½Π° ΠΎΡΠ΅Π½ΠΊΠ° ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ ΠΏΡΠΈΠΌΠ΅Π½Π΅Π½ΠΈΡ Π°Π½ΡΠΈΠ±Π°ΠΊΡΠ΅ΡΠΈΠ°Π»ΡΠ½ΠΎΠ³ΠΎ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠ° ΠΏΠ΅Π»ΠΎΠΊΡβ400 (ΠΏΠ΅ΡΠ»ΠΎΠΊΡΠ°ΡΠΈΠ½) Π² Π»Π΅ΡΠ΅Π½ΠΈΠΈ ΠΎΡΡΡΠΎΠ³ΠΎ ΠΏΠΈΠ΅Π»ΠΎΠ½Π΅ΡΡΠΈΡΠ° ΠΈ ΡΠ΅ΠΊΠΎΠΌΠ΅Π½Π΄ΠΎΠ²Π°Π½ΠΎ Π΅Π³ΠΎ ΠΏΡΠΈΠΌΠ΅Π½Π΅Π½ΠΈΠ΅ Π² ΠΊΠΎΠΌΠΏΠ»Π΅ΠΊΡΠ½ΠΎΠΉ ΡΠ΅ΡΠ°ΠΏΠΈΠΈ.The authors assess the efficacy of antibacterial medication Ρeloxβ400 (pefloxacin) in treatment of acute pyelonephritis. It is recommended to use it in complex therapy
Aicardi-Goutières syndrome harbours abundant systemic and brain-reactive autoantibodies
Generation of three induced Pluripotent Stem Cell lines from individuals with Hypomyelination with Atrophy of Basal Ganglia and Cerebellum caused by a c.745G>A (p.D249N) autosomal dominant mutation in TUBB4A
Mutations in tubulin alpha 4a (TUBB4A) result in a spectrum of leukodystrophies, including Hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC), resulting from a recurring mutation p.Asp249Asn (TUBB4AD249N). H-ABC presents with dystonia, motor and cognitive impairment and pathological features of hypomyelination and loss of cerebellar and striatal neurons. We have generated three induced pluripotent stem cell (iPSC) lines from fibroblast and peripheral blood mononuclear cells (PBMCs) of individuals with TUBB4AD249N mutation. The iPSCs were assessed to confirm a normal karyotype, pluripotency, and trilineage differentiation potential. The iPSCs will allow for disease modeling, understanding mechanisms and testing of therapeutic targets
Neonatal detection of Aicardi Goutières Syndrome by increased C26:0 lysophosphatidylcholine and interferon signature on newborn screening blood spots.
ISR mRNAs as potential blood biomarkers in patients with vanishing white matter
Vanishing white matter (VWM) is a leukodystrophy caused by bi-allelic pathogenic variants in the eukaryotic initiation factor 2B (eIF2B). eIF2B orchestrates the integrated stress response (ISR), a physiological response to cellular stress. In VWM brain, the ISR is deregulated. The degree of ISR deregulation has been shown to correlate positively with disease severity in a representative VWM mouse model. Preclinical studies have shown that the ISR is a viable treatment target for VWM. Suitable biomarkers to assess disease activity and ISR-target engagement in patients are lacking. Therefore, the current study aimed to find potential blood mRNA biomarkers for VWM with nanoString technology. The technology confirmed ISR deregulation in the brains of VWM patients but did not identify a single ISR blood biomarker that can be readily used in clinical setting. A set of three mRNAs that are differentially expressed in blood between VWM patients and controls was detected
Cerebral microangiopathy in leukoencephalopathy with cerebral calcifications and cysts: a\ua0pathological description
Leukoencephalopathy with calcifications and cysts (LCC) is a neurological syndrome recently associated with pathogenic variants in . We report autopsy neuropathological findings from an individual with genetically confirmed LCC. Histologic studies included staining of formalin-fixed paraffin-embedded tissue sections by hematoxylin and eosin, elastic van Gieson, and luxol fast blue. Immunohistochemistry stains against glial fibrillary acidic protein, proteolipid protein, phosphorylated neurofilament, CD31, alpha-interferon, LN3, and inflammatory markers were performed. Gross examination revealed dark tan/gray appearing white matter with widespread calcifications. Microscopy revealed a diffuse destructive process due to a vasculopathy with secondary ischemic lesions and mineralization. The vasculopathy involved clustered small vessels, resembling vascular malformations, and sporadic lymphocytic infiltration of vessel walls. The white matter was also diffusely abnormal, with concurrent loss of myelin and axons, tissue rarefaction with multifocal cystic degeneration, and the presence of foamy macrophages, secondary calcifications, and astrogliosis. The midbrain, pons, and cerebellum were diffusely involved. It is not understood why variants in result in a disorder that predominantly causes neurological disease and significantly disrupts the cerebral vasculature. Clinical and radiological benefit was recently reported in an LCC patient treated with Bevacizumab; it is important that these patients are rapidly diagnosed and trial of this treatment modality is considered in appropriate circumstances
Elevation of proinflammatory cytokines in patients with Aicardi-Goutières syndrome.
OBJECTIVE: This study explores a large panel of cytokines in plasma and CSF of patients with Aicardi-GoutiΓ¨res syndrome (AGS) at different ages, in order to establish signatures of cytokines most predictive of AGS. METHODS: Plasma from 22 subjects with known mutations were assayed for cytokines using the Milliplex MAP Immunobead system, and compared to results from 8 age-matched normal controls. CSF of 11 additional patients with mutation-proven AGS was tested in an identical manner and compared to results from age-matched controls. Samples were banked and analysis was carried out retrospectively. RESULTS: Significant elevations were seen in FMS-related tyrosine kinase 3 ligand, IP-10, interleukin (IL)β12p40, IL-15, tumor necrosis factor Ξ±, and soluble IL 2 receptor Ξ± in both AGS patient plasma and CSF relative to controls. Additionally, this cytokine signature was able to correctly cluster 9 of 11 AGS cases based on CSF values. While most cytokines decreased exponentially with age, a subgroup including IP-10 demonstrated persistent elevation beyond early childhood. CONCLUSION: Patients with AGS exhibit plasma and CSF elevations of proinflammatory cytokines. Selected cytokines remain persistently elevated beyond the initial disease phase. This panel of proinflammatory cytokines may be considered for use as diagnostic and therapeutic markers of disease, and may permit improved understanding of disease pathogenesis
TUBB4A mutations result in specific neuronal and oligodendrocytic defects that closely match clinically distinct phenotypes
Hypomyelinating leukodystrophies are heritable disorders defined by lack of development of brain myelin, but the cellular mechanisms of hypomyelination are often poorly understood. Mutations in TUBB4A, encoding the tubulin isoform tubulin beta class IVA (Tubb4a), result in the symptom complex of hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC). Additionally, TUBB4A mutations are known to result in a broad phenotypic spectrum, ranging from primary dystonia (DYT4), isolated hypomyelination with spastic quadriplegia, and an infantile onset encephalopathy, suggesting multiple cell types may be involved. We present a study of the cellular effects of TUBB4A mutations responsible for H-ABC (p.Asp249Asn), DYT4 (p.Arg2Gly), a severe combined phenotype with hypomyelination and encephalopathy (p.Asn414Lys), as well as milder phenotypes causing isolated hypomyelination (p.Val255Ile and p.Arg282Pro). We used a combination of histopathological, biochemical and cellular approaches to determine how these different mutations may have variable cellular effects in neurons and/or oligodendrocytes. Our results demonstrate that specific mutations lead to either purely neuronal, combined neuronal and oligodendrocytic or purely oligodendrocytic defects that closely match their respective clinical phenotypes. Thus, the DYT4 mutation that leads to phenotypes attributable to neuronal dysfunction results in altered neuronal morphology, but with unchanged tubulin quantity and polymerization, with normal oligodendrocyte morphology and myelin gene expression. Conversely, mutations associated with isolated hypomyelination (p.Val255Ile and p.Arg282Pro) and the severe combined phenotype (p.Asn414Lys) resulted in normal neuronal morphology but were associated with altered oligodendrocyte morphology, myelin gene expression, and microtubule dysfunction. The H-ABC mutation (p.Asp249Asn) that exhibits a combined neuronal and myelin phenotype had overlapping cellular defects involving both neuronal and oligodendrocyte cell types in vitro. Only mutations causing hypomyelination phenotypes showed altered microtubule dynamics and acted through a dominant toxic gain of function mechanism. The DYT4 mutation had no impact on microtubule dynamics suggesting a distinct mechanism of action. In summary, the different clinical phenotypes associated with TUBB4A reflect the selective and specific cellular effects of the causative mutations. Cellular specificity of disease pathogenesis is relevant to developing targeted treatments for this disabling condition