scholarly journals Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Sandra Kleinecke ◽  
Sarah Richert ◽  
Livia de Hoz ◽  
Britta Brügger ◽  
Theresa Kungl ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Schwann Cell ◽  
Disease Onset ◽  
Lysosomal Storage ◽  
Disease Mechanism ◽  
Axonal Membrane ◽  
Secondary Failure ◽  
Peripheral Nerve Function ◽  
One Year ◽  
Myelin Sheath Thickness

Impairment of peripheral nerve function is frequent in neurometabolic diseases, but mechanistically not well understood. Here, we report a novel disease mechanism and the finding that glial lipid metabolism is critical for axon function, independent of myelin itself. Surprisingly, nerves of Schwann cell-specific Pex5 mutant mice were unaltered regarding axon numbers, axonal calibers, and myelin sheath thickness by electron microscopy. In search for a molecular mechanism, we revealed enhanced abundance and internodal expression of axonal membrane proteins normally restricted to juxtaparanodal lipid-rafts. Gangliosides were altered and enriched within an expanded lysosomal compartment of paranodal loops. We revealed the same pathological features in a mouse model of human Adrenomyeloneuropathy, preceding disease-onset by one year. Thus, peroxisomal dysfunction causes secondary failure of local lysosomes, thereby impairing the turnover of gangliosides in myelin. This reveals a new aspect of axon-glia interactions, with Schwann cell lipid metabolism regulating the anchorage of juxtaparanodal Kv1-channels.

scholarly journals FRI0493 THE INTERLEUKIN-1B INHIBITOR CANAKINUMAB FOR REFRACTORY STILL’S DISEASE: LONG-TERM EXPERIENCE IN 50 CONSECUTIVE PATIENTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 845.1-845
Author(s):  
K. Laskari ◽  
P. Athanassiou ◽  
A. Georgiadis ◽  
C. Gerodimos ◽  
G. Gkoni ◽  
...  
Keyword(s):  
Complete Remission ◽  
Median Time ◽  
Disease Onset ◽  
Adult Patients ◽  
Sustained Remission ◽  
Concomitant Treatment ◽  
Still’S Disease ◽  
Research Support ◽  
Still's Disease ◽  
Secondary Failure

Background:Interleukin-1 (IL-1) is a major mediator of the inflammatory cascade in Still’s disease and an established therapeutic target.Objectives:To assess the efficacy and safety of the IL-1b inhibitor canakinumab in adolescent and adult patients with refractory Still’s disease.Methods:We conducted a retrospective longitudinal outcome study of 50 consecutive patients aged 39 years (median, range 14-72), fulfilling the Yamaguchi disease classification criteria, with active disease despite treatment with corticosteroids (CS) (n=11) and/or methotrexate (n=9) and/or biologics (n=30) [tumor necrosis factor inhibitors (n=13), IL-6 blockade (n=7), abatacept (n=2), anakinra (n=24); ≥1 biologics (n=13)]. Canakinumab 150-300 mg was administered sc, starting every 4 (n=48) or 8 weeks (n=2), for a median of 24 months (range 3-84). Concomitant treatment included CS (n=41), methotrexate (n=12) and leflunomide (n=3).Results:Complete remission was initially achieved in 78% of patients within a median time of 3 months, irrespective of age at disease onset. Partial clinical and laboratory response was evident in 20%. Canakinumab was discontinued in one patient with resistant disease (primary failure) and in 6 out of 10 initial responders, who relapsed during treatment (secondary failure). Of 39 patients in complete remission, increase in drug administration interval and/or drug dose reduction was attempted in 7, of which only 1 relapsed, whereas drug discontinuation was attempted in 19 patients for a median time of 8 months (range 3-68), of which 8 relapsed. Overall, in half of all disease flares, canakinumab re-introduction or intensification was successful. Canakinumab had a significant CS sparing effect permitting weaning in 21 of 41 cases. Infections (20%, severe 4%) and leucopenia (6%) led to treatment cessation in one patient.Conclusion:In this largest so far real-life patient cohort with refractory Still’s disease, high rates of sustained remission were induced by canakinumab both in adolescent and adult patients.Disclosure of Interests:Katerina Laskari: None declared, Panagiotis Athanassiou Grant/research support from: MSD, Genesis pharma, Janssen, Consultant of: Roche, Genesis pharma, Janssen, Speakers bureau: MSD, Janssen, Roche, Genesis pharma, Athanasios Georgiadis: None declared, Charalampos Gerodimos: None declared, Georgia Gkoni: None declared, Dimitrios Daoussis: None declared, Theodoros Dimitroulas: None declared, Despoina Dimopoulou: None declared, Chrysoula Iliou: None declared, Ioannis Kallitsakis Grant/research support from: MSD, Speakers bureau: Genesis pharma, Bristol-Myers Squibb, Dimitrios Karamitsos: None declared, Christina Katsiari: None declared, Stamatis-Nick Liossis: None declared, Clio Mavragani: None declared, CHARALAMPOS PAPAGORAS: None declared, Dimitrios Pikazis: None declared, Ioannis Raftakis: None declared, Theodosios Sarikoudis: None declared, Loukas Settas: None declared, Prodromos Sidiropoulos: None declared, Despoina Soukera: None declared, Evangelos Theodorou: None declared, Panagiota Tsatsani: None declared, Eleni Tsiakou: None declared, Dimitrios Vassilopoulos: None declared, PANAYIOTIS VLACHOYIANNOPOULOS: None declared, Georgios Vosvotekas: None declared, Paraskevi V. Voulgari: None declared, Marina Zakalka: None declared, Maria Tektonidou Grant/research support from: AbbVie, MSD, Novartis and Pfizer, Consultant of: AbbVie, MSD, Novartis and Pfizer, Petros Sfikakis Grant/research support from: Grant/research support from Abvie, Novartis, MSD, Actelion, Amgen, Pfizer, Janssen Pharmaceutical, UCB

scholarly journals Sex-Bias in Irritable Bowel Syndrome: Linking Steroids to the Gut-Brain Axis

2021 ◽  
Vol 12 ◽  
Author(s):  
Sik Yu So ◽  
Tor C. Savidge
Keyword(s):  
Irritable Bowel Syndrome ◽  
Sex Steroids ◽  
Disease Onset ◽  
Gastrointestinal Disorder ◽  
Underlying Disease ◽  
Disease Mechanism ◽  
Psychological Conditions ◽  
Nervous System Function ◽  
Irritable Bowel ◽  
Insight Into

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that is more common in females. Despite its high global incidence, the disease mechanism is still unclear and therapeutic options remain limited. The sexual dimorphism in IBS incidence suggests that sex steroids play a role in disease onset and symptoms severity. This review considers sex steroids and their involvement in IBS symptoms and the underlying disease mechanisms. Estrogens and androgens play important regulatory roles in IBS symptomology, including visceral sensitivity, gut motility and psychological conditions, possibly through modulating the gut-brain axis. Steroids are regulators of hypothalamic-pituitary-adrenal activity and autonomic nervous system function. They also modulate gut microbiota and enteric nervous systems, impacting serotonin and mast cell signaling. Sex steroids also facilitate bidirectional cross-talk between the microbiota and host following bacterial transformation and recycling of steroids by the intestine. The sex-specific interplay between sex steroids and the host provides neuroendocrinology insight into the pathophysiology, epigenetics and treatment of IBS patients.

Use of interferon-α in laryngeal papillomatosis: eight years of the Cuban national programme

1997 ◽  
Vol 111 (2) ◽  
pp. 134-140 ◽  
Author(s):  
L. Deuñas ◽  
V. Alcantud ◽  
F. Alvarez ◽  
J. Arteaga ◽  
A. Benítez ◽  
...  
Keyword(s):  
Side Effects ◽  
Disease Onset ◽  
Interferon Α ◽  
Surgical Removal ◽  
Bronchial Secretion ◽  
Laryngeal Papillomatosis ◽  
National Programme ◽  
Ifn Treatment ◽  
One Year ◽  
The One

AbstractLaryngeal papillomatosis is one of the first diseases where interferon (IFN) was found to be effective. In 1983, a programme for the treatment of all such cases started in Cuba. Up to December 1991, 125 patients (92 children, 33 adults) have been treated: 102 with leucocyte IFN-α, 12 with recombinant IFN-α-2b, and 11 have received both preparations. Case management consisted of surgical removal of the lesions followed by an IFN schedule starting with 105 IU/kg of weight in children or 6 × 106 IU in adults, i.m. daily. The dose was progressively reduced, as long as no relapses occurred. At the end of the one-year schedule the doses were reduced to 5 × 104 IU/kg in children or 3 × 106 IU in adults, weekly. If there was a relapse, it was removed surgically and the patient returned to a higher dose level. Most cases (89; 71 per cent) have not relapsed after the treatment; 60 of them have been followed for more than three years. In those with relapses, the frequency of recurrence decreased in all but four patients. The treatment seemed to be more effective if initiated less than three months after the disease onset. The tracheostomy could be removed in five out of seven patients who needed it before the IFN treatment and was necessary in only three new cases during IFN treatment. In two of these, decannulation was possible later on. In a total of 14 patients relapses persisted after several cycles of IFN treatment. They were considered resistant to such treatment. No severe side effects were reported. The most frequent ones were fever, drowsiness, increased bronchial secretion, chills and headache. The establishment of this programme has maintained the disease under control in Cuba.

Clinical Characteristics and Adverse Clinical Outcomes of Invasive Haemophilus influenzae Serotype a Cases—United States, 2011–2015

2020 ◽  
Author(s):  
Catherine H Bozio ◽  
Amy Blain ◽  
Karen Edge ◽  
Monica M Farley ◽  
Lee H Harrison ◽  
...  
Keyword(s):  
United States ◽  
Haemophilus Influenzae ◽  
Clinical Outcomes ◽  
Hospital Discharge ◽  
Clinical Characteristics ◽  
Disease Onset ◽  
The United States ◽  
Serotype A ◽  
Bacteremic Pneumonia ◽  
One Year

Abstract Background Incidence of invasive disease due to Haemophilus influenzae serotype a (Hia) increased an average of 13% annually from 2002 through 2015. We describe clinical characteristics and adverse clinical outcomes of US invasive Hia cases detected through multistate surveillance during 2011–2015. Methods Medical record data were abstracted for cases reported in 8 jurisdictions conducting active population- and laboratory-based surveillance for invasive Hia disease across the United States. Isolates from sterile sites were serotyped using real-time polymerase chain reaction. Adverse clinical outcomes were defined as any possible complication of meningitis, bacteremic pneumonia, or bacteremia (including hearing loss and developmental delay, but excluding death) and were assessed at hospital discharge and one-year post-disease onset. Results During 2011–2015, 190 Hia cases were reported to the 8 participating sites; 169 (88.9%) had data abstracted. Many patients were aged <5 years (42.6%). Meningitis was the most common clinical presentation among those aged <1 year (71.4%); bacteremic pneumonia was the most common presentation among persons aged ≥50 years (78.7%). Overall, 95.9% of patients were hospitalized. Among those hospitalized, 47.5% were admitted to an intensive care unit and 6.2% died during hospitalization. At hospital discharge and one-year post-disease onset, adverse outcomes were identified in 17.7% and 17.8% of patients overall and in 43.9% and 48.5% of patients with meningitis (primarily children). Conclusions Hia infection can cause severe disease that requires hospitalization and may also cause short- and long-term adverse clinical outcomes, especially among children. Novel vaccines could prevent morbidity and mortality.

scholarly journals Children with type 1 diabetes of early age at onset – immune and metabolic phenotypes

2019 ◽  
Vol 32 (9) ◽  
pp. 935-941
Author(s):  
Madalena Sales Luis ◽  
Margarida Alcafache ◽  
Sara Ferreira ◽  
Ana Laura Fitas ◽  
Joana Simões Pereira ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Age At Onset ◽  
Disease Onset ◽  
Inverse Correlation ◽  
Early Age ◽  
Insulin Requirements ◽  
Age Related ◽  
One Year ◽  
Immune Imbalance

Abstract Objectives We aimed to evaluate children with type 1 diabetes (T1D) with early age at onset (EAO) for clinical, immune and metabolic features in order to identify age-related disease phenotypes. Methods Comparative study of two groups of T1D children: EAO (≤5 years) and later age at onset (LAO; >5 years), regarding the presence of other autoimmune (AI) diseases, diabetes ketoacidosis and immunologic profile at onset and metabolic data 1 year after diagnosis. Statistical analysis was performed with significance set for p < 0.05. Results The study included 137 children (EAO = 52, mean age 3.6 ± 1.5 [mean ± standard deviation (SD)] and LAO = 85, mean age 10.4 ± 2.9). EAO was more associated with concomitant AI diseases (p = 0.032). Despite no differences in disease onset, EAO presented with lower C-peptide levels (p = 0.01) and higher absolute lymphocyte number (p < 0.0001), with an inverse correlation between these two variables (p = 0.028). Additionally, the EAO group had a higher frequency of serum detection of three antibodies (Abs) (p = 0.0008), specifically insulin Abs (p = 0.0001). One year after diagnosis, EAO had higher total daily insulin (TDI) dose (p = 0.008), despite similar hemoglobin A1c (HbA1c). Conclusions Our data show an association of EAO T1D with more AI diseases, higher number of Abs, lower initial insulin reservoir and higher insulin requirements 1 year after diagnosis. In this group, immune imbalance seems more evident and disease progression faster, probably reflecting distinct “immune environment” with different ages at disease onset. Further studies in the field of immunogenetics and immune tolerance are required, to improve patient stratification and find novel targets for therapeutic intervention.

Alopecia areata: pathogenesis and potential for therapy

2006 ◽  
Vol 8 (14) ◽  
pp. 1-19 ◽  
Author(s):  
Wei Lu ◽  
Jerry Shapiro ◽  
Mei Yu ◽  
Armin Barekatain ◽  
Blanche Lo ◽  
...  
Keyword(s):  
Hair Loss ◽  
Alopecia Areata ◽  
Disease Onset ◽  
Inflammatory Cells ◽  
Disease Development ◽  
Therapeutic Approaches ◽  
Disease Mechanism ◽  
Disease Pathogenesis ◽  
Significant Challenge ◽  
Cd4 Lymphocytes

Although the complete picture for alopecia areata (AA) pathogenesis has yet to be determined, recent research has made much progress in our understanding of the disease mechanism. Numerous circumstantial evidence supports the notion that AA is fundamentally a disease mediated by inflammatory cells and may be autoimmune in nature. Recent research has shown the hair-loss phenotype is precipitated predominantly by CD8+ lymphocytes, but the disease mechanism is driven by CD4+ lymphocytes. Although genetic susceptibility is a key contributor to disease development, disease onset and phenotypic presentation are probably modified by complex environmental interplay. On the basis of our current understanding of AA disease pathogenesis, several experimental and theoretical therapeutic approaches might be possible. However, the pathogenetic disease mechanism is particularly robust and the development of a cure for AA will be a significant challenge.

scholarly journals KAWASAKI DISEASE IN INFANTS LESS THAN ONE YEAR OF AGE: AN ITALIAN COHORT FROM A SINGLE CENTER

2019 ◽  
Author(s):  
Greta Mastrangelo ◽  
Rolando Cimaz ◽  
Giovan Battista Calabri ◽  
Gabriele Simonini ◽  
Donatella Lasagni ◽  
...  
Keyword(s):  
Kawasaki Disease ◽  
Severe Disease ◽  
Disease Onset ◽  
Retrospective Chart Review ◽  
Ivig Treatment ◽  
New Finding ◽  
Mucosal Changes ◽  
One Year ◽  
Few Data ◽  
Italian Cohort

Abstract Background and aims Few data are currently available for Kawasaki disease (KD) below 12 months especially in Caucasians. This study aims to analyze clinical and laboratory features of KD among an Italian cohort of infants. Methods A retrospective chart review of KD children aged less than one year at time of disease onset between January 2008-December 2017 was performed. Clinical data, laboratory parameters, instrumental findings, treatment and outcome were collected in a customized database. Results Among 113 KD patients, 32 (28.3%) were younger than 1 year. Nineteen patients aged below 6 months, and three below 3 months. The median age was 5.7 ±2.7 months. The mean time to diagnosis was 7±3 days and was longer in the incomplete forms (8 ± 4 vs 6 ± 1 days). Conjunctival injection was present in 26 patients (81.2%); rash in 25 (78.1%); extremity changes in 18 (56.2%); mucosal changes in 13 (40.6%,) and lymphadenopathy only in 7 (21.8%). Mucosal changes were the least common features in incomplete forms (18.2%). Twenty-two patients (68.7%) had incomplete KD. Nineteen (59.4%) had cardiac involvement, of whom 13 (59.0%) had incomplete form. ESR, PCR and platelet values were higher in complete KD; especially, ESR resulted significantly higher in complete forms (80 ± 25.7 mm/h vs 50 ± 28.6 mm/h; p = 0.01). Conversely, AST level was statistically significant higher in patients with incomplete forms (95.4 ± 132.7 UI/L vs 29.8 ± 13.2 UI/L; p = 0.03). All patients received IVIG. Response was reported in 26/32 patients; 6 cases needed a second dose of IVIG and one required a dose of anakinra. Conclusion In our cohort, incomplete disease was commonly found, resulting in delayed diagnoses and poor cardiac prognosis. Infants with incomplete KD seem to have a more severe disease and a greater predilection for coronary involvement than those with complete KD. AST was significantly higher in incomplete forms, thus AST levels might be a new finding in incomplete forms’ diagnosis. Eventually, we highlight a higher resistance to IVIG treatment. To our knowledge this is the first study involving an Italian cohort of patients with KD below 12 months.

44. One-year experience of enzymatic diagnosis of lysosomal storage diseases in China

2008 ◽  
Vol 93 (2) ◽  
pp. 25
Author(s):  
Zhang Huiwen ◽  
Jun Ye ◽  
Wenjun Qiu ◽  
Lianshu Han ◽  
Xuefan Gu
Keyword(s):  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
One Year
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