IgM Augments Complement Bactericidal Activity with Serum from a Patient with a Novel CD79a Mutation

Antibody replacement therapy for patients with antibody deficiencies contains only IgG. As a result, concurrent IgM and IgA deficiency present in a large proportion of antibody deficient patients persists. Especially patients with IgM deficiency remain at risk for recurrent infections of the gastrointestinal and respiratory tract. The lack of IgM in the current IgG replacement therapy is likely to contribute to the persistence of these mucosal infections because this antibody class is especially important for complement activation on the mucosal surface. We evaluated whether supplementation with IgM increased serum bactericidal capacity in vitro. Serum was collected from a patient with agammaglobulinemia and supplemented with purified serum IgM to normal levels. Antibody and complement deposition on the bacterial surface was determined by multi-color flow cytometry. Bacterial survival in serum was determined by colony-forming unit counts. We present a patient previously diagnosed with agammaglobulinemia due to CD79A (Igα) deficiency revealing a novel pathogenic insertion variant in the CD79a gene (NM_001783.3:c.353_354insT). Despite IgG replacement therapy and antibiotic prophylaxis, this patient developed a Campylobacter jejuni spondylodiscitis of lumbar vertebrae L4–L5. We found that serum IgM significantly contributes to complement activation on the bacterial surface of C. jejuni. Furthermore, supplementation of serum IgM augmented serum bactericidal activity significantly. In conclusion, supplementation of intravenous IgG replacement therapy with IgM may potentially offer greater protection against bacterial infections, also in the context of increasing antibiotic resistance

Alzheimer's disease

In this Seminar, we highlight the main developments in the field of Alzheimer's disease. The most recent data indicate that, by 2050, the prevalence of dementia will double in Europe and triple worldwide, and that estimate is 3 times higher when based on a biological (rather than clinical) definition of Alzheimer's disease. The earliest phase of Alzheimer's disease (cellular phase) happens in parallel with accumulating amyloid β, inducing the spread of tau pathology. The risk of Alzheimer's disease is 60-80% dependent on heritable factors, with more than 40 Alzheimer's disease-associated genetic risk loci already identified, of which the APOE alleles have the strongest association with the disease. Novel biomarkers include PET scans and plasma assays for amyloid β and phosphorylated tau, which show great promise for clinical and research use. Multidomain lifestyle-based prevention trials suggest cognitive benefits in participants with increased risk of dementia. Lifestyle factors do not directly affect Alzheimer's disease pathology, but can still contribute to a positive outcome in individuals with Alzheimer's disease. Promising pharmacological treatments are poised at advanced stages of clinical trials and include anti-amyloid β, anti-tau, and anti-inflammatory strategies

Impact of sharing Alzheimer's disease biomarkers with individuals without dementia:A systematic review and meta-analysis of empirical data

Introduction: We conducted a systematic literature review and meta-analysis of empirical evidence on expected and experienced implications of sharing Alzheimer's disease (AD) biomarker results with individuals without dementia. Methods: PubMed, Embase, APA PsycInfo, and Web of Science Core Collection were searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results from included studies were synthesized, and quantitative data on psychosocial impact were meta-analyzed using a random-effects model. Results: We included 35 publications. Most personal stakeholders expressed interest in biomarker assessment. Learning negative biomarker results led to relief and sometimes frustration, while positive biomarkers induced anxiety but also clarity. Meta-analysis of five studies including 2012 participants (elevated amyloid = 1324 [66%], asymptomatic = 1855 [92%]) showed short-term psychological impact was not significant (random-effect estimate = 0.10, standard error = 0.23, P = 0.65). Most professional stakeholders valued biomarker testing, although attitudes and practices varied considerably. Discussion: Interest in AD biomarker testing was high and sharing their results did not cause psychological harm. Highlights: Most personal stakeholders expressed interest in Alzheimer's disease biomarker assessment. Personal motivations included gaining insight, improving lifestyle, or preparing for the future. There was no short-term psychological impact of sharing biomarker status, implying it can be safe. Most professional stakeholders valued biomarker testing, believing the benefits outweigh the risk. Harmonized guidelines on biomarker testing and sharing results are required.</p

SNIP/p140Cap mRNA expression is an unfavourable prognostic factor in breast cancer and is not expressed in normal breast tissue

The prevalence and clinical relevance of SNIP/p140Cap has not been extensively investigated. Here SNIP/p140Cap mRNA expression was studied in 103 breast tumour biopsies, where it was detected in ∼37% of tumour specimens, but not in any normal breast specimens. Expression correlated significantly with unfavourable overall survival. This suggests that SNIP/p140Cap may be a useful diagnostic and prognostic marker for breast cancer and its expression in breast cancer, but not in normal breast tissue, suggests that it may have potential as a therapeutic target

Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia:A randomised controlled trial

Preclinical research suggests that enhancing CB1 receptor agonism may improve fear extinction. In order to translate this knowledge into a clinical application we examined whether cannabidiol (CBD), a hydrolysis inhibitor of the endogenous CB1 receptor agonist anandamide (AEA), would enhance the effects of exposure therapy in treatment refractory patients with anxiety disorders. Patients with panic disorder with agoraphobia or social anxiety disorder were recruited for a double-blind parallel randomised controlled trial at three mental health care centres in the Netherlands. Eight therapist-assisted exposure in vivo sessions (weekly, outpatient) were augmented with 300 mg oral CBD (n = 39) or placebo (n = 41). The Fear Questionnaire (FQ) was assessed at baseline, mid-and post-treatment, and at 3 and 6 months follow-up. Primary analyses were on an intent-to-treat basis. No differences were found in treatment outcome over time between CBD and placebo on FQ scores, neither across (beta = 0.32, 95% CI [-0.60; 1.25]) nor within diagnosis groups (beta = -0.11, 95% CI [-1.62; 1.40]). In contrast to our hypotheses, CBD augmentation did not enhance early treatment response, within-session fear extinction or extinction learning. Incidence of adverse effects was equal in the CBD (n = 4, 10.3%) and placebo condition (n = 6, 15.4%). In this first clinical trial examining CBD as an adjunctive therapy in anxiety disorders, CBD did not improve treatment outcome. Future clinical trials may investigate different dosage regimens. (c) 2022 Published by Elsevier B.V

Nutritional status and structural brain changes in Alzheimer's disease: The NUDAD project

INTRODUCTION: Weight loss is associated with higher mortality and progression of cognitive decline, but its associations with magnetic resonance imaging (MRI) changes related to Alzheimer's disease (AD) are unknown. METHODS: We included 412 patients from the NUDAD project, comprising 129 with AD dementia, 107 with mild cognitive impairment (MCI), and 176 controls. Associations between nutritional status and MRI measures were analyzed using linear regression, adjusted for age, sex, education, cognitive functioning, and cardiovascular risk factors. RESULTS: Lower body mass index (BMI), fat mass (FM), and fat free mass index were associated with higher medial temporal atrophy (MTA) scores. Lower BMI, FM, and waist circumference were associated with more microbleeds. Stratification by diagnosis showed that the observed associations with microbleeds were only significant in MCI. DISCUSSION: Lower indicators of nutritional status were associated with more MTA and microbleeds, with largest effect sizes in MCI