The chimeric anti-CD20 antibody rituximab induces apoptosis in B-cell chronic lymphocytic leukemia cells through a p38 mitogen activated protein-kinase-dependent mechanism

Antibodies against CD20 can activate complement and induce antibody-dependent cellular cytotoxicity (ADCC) in B lymphocytes. In B-cell lines, such antibodies also induce apoptosis. In this study, the expression and function of CD20 on B-cell chronic lymphocytic leukemia (B-CLL) cells were analyzed. Flow cytometric analysis demonstrated that B-CLL cells express CD20 with a fluorescence intensity that is significantly weaker than that of normal CD5(+) and CD5(-) B cells and that of malignant CD5(-) low-grade non-Hodgkin lymphoma cells. A small population of cells from healthy donors that have an expression pattern of CD5 and CD20 identical to that of B-CLL cells were identified, and this population was confirmed to be of T lineage, not B lineage. Culture of freshly isolated B-CLL cells in the presence of the chimeric anti-CD20 antibody rituximab and a cross-linking F(ab)(2) fragment, resulted in dose- and time-dependent induction of apoptosis. The induction of apoptosis occurred under conditions in which the influence of complement activation and ADCC was negligible. Cross-linking of rituximab induced strong and sustained phosphorylation of the 3 mitogen activated protein (MAP) kinases c-Jun NH2-terminal protein kinase, extracellular signal-regulated kinase, and p38. Introduction of the p38 inhibitor SB203580 into the system completely blocked signaling downstream of p38, as evidenced by the absence of MAPKAP K2 activity, and significantly reduced the degree of anti-CD20-induced apoptosis. These results demonstrate that cross-linking of rituximab bound to CD20 on freshly isolated B-CLL cells induces apoptosis through a signaling pathway that is dependent on p38 MAP-kinase activation.     

Neck Vessel Cross‐Sectional Area Measured with MRI: Scan‐Rescan Reproducibility for Longitudinal Evaluations

BACKGROUND AND PURPOSE

The cross‐sectional area (CSA) of common carotid arteries‐internal carotid arteries (CCA‐ICAs), vertebral arteries (VAs), and internal jugular veins (IJVs) is influenced by aging. However, the neck vessel CSA can be affected by other factors as well, including subject positioning, hydration, and respiration, especially in longitudinal studies. This study aimed to assess scan‐rescan reproducibility of CCA‐ICAs, VAs, and IJVs CSA measurements in order to evaluate their feasibility for longitudinal CSA assessments, and to apply the segmentation method on a longitudinal pilot dataset.

METHODS

Two set of 2‐dimensional neck magnetic resonance angiography (MRA) images were acquired on a 3‐T scanner from two separate datasets: 9 healthy individuals (HIs) were scanned 5 days apart (scan‐rescan dataset) and 12 HIs were acquired 5 years apart (baseline‐follow‐up dataset). CCA‐ICAs, VAs, and IJVs were segmented along the whole vessel length between C3 and C7 intervertebral spaces. Repeated measure analysis of covariance, adjusted for cervical level and sample, and Wilcoxon signed‐rank sum test were used to assess the scan‐rescan and baseline‐follow‐up CSA differences. Intraclass correlation coefficient (ICC) was also computed to evaluate scan‐rescan reliability.

RESULTS

No significant CSA differences were found for the scan‐rescan and baseline‐follow‐up CSA comparisons, using the whole vessel length or single cervical level measurements. ICC analysis showed good degree of scan‐rescan reproducibility (considering whole vessel measures: ICC > .9, P‐value < .001 for CCA‐ICAs, ICC > .6, P‐value < .001 for VAs, and ICC > .7, P‐value < .001 for IJVs).

CONCLUSIONS

Scan‐rescan reproducibility of CCA‐ICAs, VAs, and IJVs CSA measurements is high, making longitudinal studies feasible.     

New-onset atrial fibrillation in critically ill adult patients—an SSAI clinical practice guideline

Background

Acute or new-onset atrial fibrillation (NOAF) is the most common cardiac arrhythmia in critically ill adult patients, and observational data suggests that NOAF is associated to adverse outcomes.

Methods

We prepared this guideline according to the Grading of Recommendations Assessment, Development and Evaluation methodology. We posed the following clinical questions: (1) what is the better first-line pharmacological agent for the treatment of NOAF in critically ill adult patients?, (2) should we use direct current (DC) cardioversion in critically ill adult patients with NOAF and hemodynamic instability caused by atrial fibrillation?, (3) should we use anticoagulant therapy in critically ill adult patients with NOAF?, and (4) should critically ill adult patients with NOAF receive follow-up after discharge from hospital? We assessed patient-important outcomes, including mortality, thromboembolic events, and adverse events. Patients and relatives were part of the guideline panel.

Results

The quantity and quality of evidence on the management of NOAF in critically ill adults was very limited, and we did not identify any relevant direct or indirect evidence from randomized clinical trials for the prespecified PICO questions. We were able to propose one weak recommendation against routine use of therapeutic dose anticoagulant therapy, and one best practice statement for routine follow-up by a cardiologist after hospital discharge. We were not able to propose any recommendations on the better first-line pharmacological agent or whether to use DC cardioversion in critically ill patients with hemodynamic instability induced by NOAF. An electronic version of this guideline in layered and interactive format is available in MAGIC: https://app.magicapp.org/#/guideline/7197 .

Conclusions

The body of evidence on the management of NOAF in critically ill adults is very limited and not informed by direct evidence from randomized clinical trials. Practice variation appears considerable.     

Are we passing the acceptable? Standard setting of theoretical proficiency tests for foreign-trained dentists

Introduction

Dentists educated outside the EU, EEA and Switzerland have the option to undergo proficiency testing to practice dentistry in Sweden. A standardised evidence-based procedure for proficiency tests is crucial. This paper explores if the standard setting of the theoretical examination in the Swedish proficiency test for foreign dentists is fit to differentiate candidates who meet the acceptable standard for licensure from those who do not, by analysis of inter-rater reliability and credibility of Angoff panels and the test's ability to differentiate candidates regarding learning outcomes and dental disciplines.

Materials and Methods

In a cohort study design, test results were collected from seven examinations during 2018–2019 (n = 316), combined with Angoff judgements and demographic data from The National Board of Health and Welfare. Intraclass correlation, Pearson correlation and linear regression were calculated.

Results

All exams demonstrated substantial judge inter-rater reliability using the Angoff procedure (0.65–0.82). Item difficulty predicted by the expert panels showed significant positive correlations with the item difficulty by candidate results (0.69–0.77). Candidates who did not meet the requirements for pass mark in the theoretical test revealed a significantly reduced performance overall in professional qualifications (i.e., learning outcomes) and reduced performance within dental disciplines.

Conclusions

The results indicate that a modified Angoff method is a feasible, simple, and defensible method for setting the pass mark for the theoretical examinations. The standard setting appears to differentiate candidates who do not meet the requirements of the professional qualifications of the dental degree. Adjustments could be undertaken to further discriminate for competence within single dental disciplines.     

Symptoms of Autism Among Children with Congenital Deafblindness

Associations between congenital deafness or blindness and autism have been found. The main consequences of congenital sensory impairment, being barriers for communication, language and social interaction development, may lead to symptoms of autism. To date only few studies have been reported concerning individuals with congenital deafblindness. This study examines symptoms of autism among 71 children with congenital deafblindness using the Autism Behavior Checklist. The cohort of children with congenital deafblindness was found to have symptoms of autism on a level similar to children with another developmental disorder than autism for example intellectual disability. No association was found between severity of congenital sensory impairment and severity or type of symptoms of autism.     

Isolation and characterization of 55 novel microsatellite markers for the pink-footed goose (Anser brachyrhynchus)

Here we present 55 new microsatellite markers isolated from the pink-footed goose (Anser brachyrhynchus), using next generation sequencing. Of these, 44 markers were found to be polymorphic, and the number of alleles ranged from two to ten with a mean of 4.23 alleles per locus. Mean observed heterozygosity was 0.44, and 33 polymorphic markers were in Hardy?CWeinberg equilibrium in our sample population. These newly developed molecular markers could prove to be a useful tool for further studies of pink-footed goose populations.