An open-label trial of JAK 1/2 blockade in progressive IFIH1 -associated neuroinflammation

IFIH1 gain-of-function causes a spectrum of neuroinflammatory phenotypes associated with enhanced type I interferon production and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway activation.1,2 Patients most often present in infancy, variably exhibiting spasticity, dystonia, seizures, and acquired microcephaly. We report the use of ruxolitinib, a JAK 1/2 blocker, in the treatment of early-onset, progressive neurologic disease due to an IFIH1 mutation

Development and validation of a simple, rapid and sensitive LC-MS/MS method for the measurement of urinary neurotransmitters and their metabolites

Neurotransmitters play crucial roles in physiological functions and their imbalances have demonstrated association in the pathology of several diseases. The measurement of neurotransmitters possesses a great potential as a significant clinical tool. This study presents the development and validation of an LC-MS/MS method for simultaneous quantification of multi-class neurotransmitters associated with dopamine, tryptophan and glutamate-γ-aminobutyric acid pathways. A total of ten neurotransmitters and their metabolites (dopamine, epinephrine, metanephrine, tryptophan, serotonin, kynurenic acid, kynurenine, anthranilic acid, GABA, glutamic acid) were determined based on a simple and rapid \u27dilute and shoot\u27 method using minimal urine volume. The chromatographic separation was achieved using a Poroshell 120 Bonus-RP LC Column in combination with a gradient elution within an 8.5-min time frame. The method exhibited good sensitivity as the limits of quantification ranged between 0.025 and 0.075 μg/mL with acceptable matrix effects ( \u3c ± 14.5%), no carryover and good linearity (r2\u3e 0.98). The accuracy and precision for all analytes were within tolerances, at \u3c ± 9.9% mean relative error (MRE) and \u3c 8.6% relative standard deviation (RSD), respectively. The method was successfully applied in measuring the neurotransmitter concentrations in urine of healthy donors. Furthermore, the undertaken stability experiments indicated that acidified urine specimens allowed the analytes to be stable for prolonged durations in comparison to those untreated. The study also reveals the performance of the method is unaffected by the absence of expensive deuterated reference standards under the experimental conditions employed which further simplifies the analytical procedures and provides a significant cost saving for running the assay

Evaluation of target attainment of oral posaconazole suspension in immunocompromised children

Posaconazole is a broad-spectrum antifungal that is not licensed for use in childre

B cell, Th17, and neutrophil related cerebrospinal fluid cytokine/chemokines are elevated in MOG antibody associated demyelination

Background: Myelin oligodendrocyte glycoprotein antibody (MOG Ab) associated demyelination represents a subgroup of autoimmune demyelination that is separate from multiple sclerosis and aquaporin 4 IgG-positive NMO, and can have a relapsing course. Unlike NMO and MS, there is a paucity of literature on immunopathology and CSF cytokine/chemokines in MOG Ab associated demyelination. Aim: To study the differences in immunopathogenesis based on cytokine/chemokine profile in MOG Ab-positive (POS) and-negative (NEG) groups. Methods: We measured 34 cytokines/chemokines using multiplex immunoassay in CSF collected from paediatric patients with serum MOG Ab POS [acute disseminated encephalomyelitis (ADEM=8), transverse myelitis (TM=2) n=10] and serum MOG Ab NEG (ADEM=5, TM=4, n=9) demyelination. We generated normative data using CSF from 20 non-inflammatory neurological controls. Results: The CSF cytokine and chemokine levels were higher in both MOG Ab POS and MOG Ab NEG demyelination groups compared to controls. The CSF in MOG Ab POS patients showed predominant elevation of B cell related cytokines/chemokines (CXCL13, APRIL, BAFF and CCL19) as well as some of Th17 related cytokines (IL-6 AND G-CSF) compared to MOG Ab NEG group (all p<0.01). In addition, patients with elevated CSF MOG antibodies had higher CSF CXCL13, CXCL12, CCL19, IL-17A and G-CSF than patients without CSF MOG antibodies. Conclusion: Our findings suggest that MOG Ab POS patients have a more pronounced CNS inflammatory response with elevation of predominant humoral associated cytokines/chemokines, as well as some Th 17 and neutrophil related cytokines/chemokines suggesting a differential inflammatory pathogenesis associated with MOG antibody seropositivity. This cytokine/chemokine profiling provides new insight into disease pathogenesis, and improves our ability to monitor inflammation and response to treatment. In addition, some of these molecules may represent potential immunomodulatory targets.16 page(s

Acute hemorrhagic leukoencephalopathy: pathological features and cerebrospinal fluid cytokine profiles

Acute hemorrhagic leukoencephalopathy is a rare encephalopathy of unknown etiology, causing fulminant, hemorrhagic central nervous system demyelination with high mortality. It is unclear whether acute hemorrhagic leukoencephalopathy is an entirely distinct entity from acute disseminated encephalomyelitis.We report two patients with rapidly progressive neurological illness resulting in raised intracranial pressure and coma, with biopsy-proven acute hemorrhagic leukoencephalopathy (perivascular hemorrhages and demyelination, predominantly neutrophil infiltrates).Acute cerebrospinal fluid showed pronounced T cell-associated cytokine elevation (interleukins 6, 8, and 17A) and CCL2 or CCL3, higher than in patients with acute disseminated encephalomyelitis, but no B cell-associated cytokine elevation.Improved understanding of the immune process may provide rationale for use of anticytokine biologic agents

Autoantibodies, routine and novel markers of neuroinflammation in people with atypical psychiatric disease

Background: Increasingly, the immune system is recognized as participating in the pathophysiology of psychiatric disease. There is renewed interest in biomarkers identifying immune activation. Methods: We measured serum and cerebral spinal fluid (CSF) autoantibodies with other routine and novel markers of neuroinflammation, including CSF cytokines in patients with atypical psychiatric (AP) disease who were referred by their psychiatrist. Their results were compared with cohorts of non-inflammatory (NI) controls, viral infectious controls and patients with autoimmune encephalitis. Results: Thirty-five AP patients were enrolled (29 females; 6 males), alongside 18 NI controls. Six AP patients had first episode psychosis, 7 had depression, 3 had schizophrenia. Others had a mix of both psychotic and mood disorder features, making their disease difficult to classify. Ten patients had a history of autoimmune disease and 11 a family history of autoimmunity.Low-mid titre (1:80-1:640) anti-nuclear antibodies (ANAs) without associated positive extractable nuclear antigen antibodies were noted in 20 patients. The predominant pattern was speckled (17/20, 85%); other patterns were mitotic spindle apparatus (2) or homogenous and speckled (2). One patient had a high titre 1:2560 speckled ANA associated anti-SSa/Ro60 antibodies and high thyroperoxidase antibodies (900IU/mL; normal 5 monocytes), 5 had raised CSF protein (>0.45g/L), 3 had CSF restricted oligoclonal bands and 13 had raised CSF neopterin (>20nm/L).CSF cytokines: granulocyte-macrophage colony-stimulating factor, and interferon gamma were associated with AP patients. A subset of patients (10) had at least one CSF cytokine beyond 4 standard deviations of the NI cohort.Our data supports more extensive investigation of patients presenting with psychiatric disease across a broad diagnostic spectrum. Further study is needed to validate these results

CSF cytokine/ chemokine concentrations in CSF MOG Ab POS patients and CSF MOG Ab NEG patients.

<p>B cell (CXCL13, CCL19, CXCL12,) and Th17 (G-CSF, IL-17A) cytokines/chemokines were elevated in CSF MOG Ab POS patients when compared to CSF MOG Ab NEG patients (P<0.05). Dotted lines represent medians. The statistical analysis was performed using Man Whitney’s test.</p

CSF cytokine/ chemokine concentrations in serum MOG Ab POS, serum MOG Ab NEG demyelination groups and controls according to T and B cell subsets.

<p>Th17 (IL-6 & G-CSF), B cell related (CXCL13, CCL19, APRIL & BAFF) and other cytokines and chemokines (TNF-α, IL1ra and IL-10) were elevated in serum MOG Ab POS patients compared to serum MOG Ab NEG group (p<0.05). Dotted lines represent medians. The statistical analysis was performed using Kruskal Wallis test.</p

Clinical and laboratory investigations in MOG Ab POS and NEG demyelination syndromes.

<p>Clinical and laboratory investigations in MOG Ab POS and NEG demyelination syndromes.</p