The European Lambert-Eaton Myasthenic Syndrome Registry: Long-Term Outcomes Following Symptomatic Treatment.

INTRODUCTION: Lambert-Eaton myasthenic syndrome (LEMS) is characterized by autoantibodies against voltage-gated calcium channels (VGCC) at the neuromuscular junction causing proximal muscle weakness, decreased tendon reflexes, and autonomic changes. The European LEMS registry aimed to collate observational safety data for 3,4-diaminopyridine phosphate (3,4-DAPP) and examine long-term outcomes for patients with LEMS. METHODS: Thirty centers across four countries participated in the non-interventional European LEMS registry. Any patients diagnosed with LEMS by means of clinical assessment and abnormal neurophysiological testing, or clinical assessment and positive for VGCC antibodies were eligible to participate. Patients were monitored using standard assessments for LEMS-related clinical manifestations. RESULTS: Among 96 evaluable participants, 50 (52.1%) were being treated with 3,4-DAPP, 21 (21.9%) with 3,4-diaminopyridine (3,4-DAP), and 25 (26.0%) with other treatments (e.g., pyridostigmine, corticosteroids, immunoglobulins, and azathioprine); 74 participants (77.1%) were exposed to 3,4-DAPP at any time. Quantitative myasthenia gravis scores were similar across treatment groups. Muscle strength was generally good and maintained during follow-up. Cerebellar ataxia, defined as a negative Romberg's test and at least one other positive ataxia test, was observed in 30 (56.6%) patients. Most participants had reduced reflex tone and limited functioning. Sustained or improved functioning was observed in participants administered 3,4-DAPP. Inconsistent and sporadic functional improvement and regression was observed with 3,4-DAP and other treatments. Fifty-five treatment-related adverse events (AEs) were reported by 32 (33.3%) participants. Eight (8.3%) participants reported nine treatment-related serious AEs. No new safety signals were identified. CONCLUSION: No new safety signals were observed following long-term management of LEMS with 3,4-DAPP.

Economic impact of 13-valent pneumococcal conjugate vaccine in Finnish adults ≥50 years with underlying chronic medical conditions.

RATIONALE, AIMS AND OBJECTIVES: Invasive pneumococcal diseases (IPD) are associated with substantial burden in adults (≥50 years). Moreover, adults with vascular, metabolic or respiratory diseases have been shown to have a 3-6 times higher risk of IPD when compared with their healthy controls. These persons at higher risk are likely to benefit most from pneumococcal vaccinations. The 13-valent pneumococcal conjugate vaccine (PCV13) was recently introduced to prevent the 13 most prevalent serotypes causing invasive pneumococcal disease in adults. The objective of this study was to estimate the expected 5-year economic impact of targeted PCV13 vaccination compared with no vaccination in Finnish adults (≥50 years) at moderate or high risk for IPD. METHODS: A budget impact model was developed to predict the impact of PCV13 vaccination in terms of the costs and IPD events avoided for years 2012-2016. RESULTS: Approximately 35% of the 2.2 million Finns over 50 years of age can be considered to be at moderate or high risk for IPD because of underlying chronic medical conditions. Vaccination of these people with PCV13 could provide an estimated net budget savings of about €218 million compared with the current no-vaccination situation over the next 5 years. Among the risk groups considered, the largest absolute net savings (€66.2 million) could be expected to be obtained by vaccinating people with heart disease, due to its high prevalence in the target population. CONCLUSION: In Finland, the immunization with PCV13 vaccine, of adults (≥50 years) at moderate and high risk of IPD, is estimated to lead to substantial cost savings in the 5 years after vaccination.

Inhibition of PI3-kinase-Akt pathway enhances dexamethasone-induced apoptosis in a human follicular lymphoma cell line.

Glucocorticoids are commonly used in the treatment of various lymphoid malignancies. In the present study, we show that dexamethasone (Dex) induced depolarization of mitochondrial membrane, release of cytochrome c and DNA fragmentation in a human follicular lymphoma cell line, HF28RA. New protein synthesis was required before Dex-induced mitochondrial changes, and the kinetics of the apoptotic events correlated with the upregulation of the Bim protein. Furthermore, we studied whether specific inhibitors of known survival pathways would potentiate Dex-induced apoptosis. Our results show that inhibition of PKC and ERK pathways had no effect on apoptosis. In contrast, inhibition of PI3-kinase or Akt markedly enhanced Dex-induced apoptosis. The enhancement was seen at the mitochondrial level, and the kinetics of apoptosis was notably accelerated. In addition, inhibition of PI3-kinase did not alter levels of Bax, Bcl-2, Bcl-X(L) or Bim proteins in mitochondria but caused translocation of the pro-apoptotic protein Bad to mitochondria. However, inhibition of PI3-kinase-Akt pathway and subsequent translocation of Bad to mitochondria did not induce apoptosis itself. Based on these results and our current understanding of Bim and Bad action, it seems that both proteins play a synergistic role in this process. Thus, these results indicate that inhibitors of PI3-kinase-Akt pathway might be combined in future with glucocorticoids to improve the treatment of lymphoid malignancies.

Use of vaccine surveillance data in the evaluation of safety of vaccines.

In this article we discuss some of the most widely used methods of the routine vaccine safety surveillance. The main problems inherently associated with these passive techniques are also addressed. The vaccine safety surveillance in Finland is used as an example. Finally, we are giving a brief introduction to more advanced surveillance tools, namely record linkage and electronic vaccine registers, which are now being investigated in Finland as a part of the European Research Programme for Improved Vaccine Safety Surveillance (EUSAFEVAC)-project.

Kinetics and signaling requirements of CD40-mediated protection from B cell receptor-induced apoptosis.

In the present study we used a human follicular lymphoma cell line, HF1A3, as an in vitro model for the antigen-driven selection process in germinal centers. Apoptosis can be induced in HF1A3 cells by B cell receptor (BCR) stimulation, but the molecular mechanisms and kinetics of this process are largely unknown. We demonstrate here that there is over 12 h delay between receptor activation and the execution phase of apoptosis, i.e. disruption of mitochondrial membrane potential, release of cytochrome c from mitochondria, caspase-3 activation and DNA fragmentation. New protein synthesis is required for mitochondrial alterations and subsequent apoptosis to occur, as these processes are completely blocked by the protein synthesis inhibitor cycloheximide. All the apoptotic events induced by BCR triggering are completely reversed by CD40 ligation with anti-CD40 antibody. CD40 ligation can reverse the apoptotic process in HF1A3 cells almost until the first mitochondrial events take place demonstrating that CD40-mediated protection operates very fast and at or before mitochondrial phase of apoptosis. Using specific inhibitors of cell signaling we could demonstrate that Raf-extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, p38 or protein kinase C activation pathways are not involved in CD40-mediated protection from BCR-induced apoptosis in HF1A3 cells.

Deficiency of the adaptor SLP-65 in pre-B-cell acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) is the commonest form of childhood malignancy, and most cases arise from B-cell clones arrested at the pre-B-cell stage of differentiation. The molecular events that arrest pre-B-cell differentiation in the leukaemic pre-B cells have not been well characterized. Here we show that the differentiation regulator SLP-65 (an adaptor protein also called BLNK or BASH) inhibits pre-B-cell leukaemia in mice. Reconstitution of SLP-65 expression in a SLP-65-/- pre-B-cell line led to enhanced differentiation in vitro and prevented the development of pre-B-cell leukaemia in immune-deficient mice. Tyrosine 96 of SLP-65 was required for this activity. The murine SLP-65-/- pre-B-cell leukaemia resembles human childhood pre-B ALL. Indeed, 16 of the 34 childhood pre-B ALL samples that were tested showed a complete loss or drastic reduction of SLP-65 expression. This loss is probably due to the incorporation of alternative exons into SLP-65 transcripts, leading to premature stop codons. Thus, the somatic loss of SLP-65 and the accompanying block in pre-B-cell differentiation might be one of the primary causes of childhood pre-B ALL.