[Incidence of sudden death in epilepsy (SUDEP): update and limitations]. / Inzidenz des plötzlichen Epilepsietodes (SUDEP): Update und Limitationen.

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is in most cases probably due to a fatal complication of tonic-clonic seizures and plays a significant role in the premature mortality of individuals with epilepsy. The reported risks of SUDEP vary considerably depending on the study population, so that an up-dated systematic review of SUDEP incidence including most recent studies is required to improve the estimated SUDEP risk and the counseling of individuals with epilepsy. OBJECTIVE: To provide an overview of the current research landscape concerning SUDEP incidence across different patient populations and discuss potential conclusions and existing limitations. MATERIAL AND METHODS: A systematic literature review on SUDEP incidence was conducted in MEDLINE and EMBASE, supplemented by a manual search in June 2023. Out of a total of 3324 publications, 50 were reviewed for this study. RESULTS: The analyzed studies showed significant heterogeneity concerning cohorts, study design and data sources. Studies conducted without specific criteria and relying on comprehensive registers indicated an incidence of 0.78-1.2 per 1000 patient-years. Research providing incidences across various age groups predominantly show an increase with age, peaking in middle age. DISCUSSION: Due to varying methods of data collection and incidence calculation, comparing between studies is challenging. The association with age might be due to an underrepresentation of children, adolescents and patients over 60 years. CONCLUSION: Considering all age groups and types of epilepsy it is estimated that about 1 in 1000 individuals with epilepsy dies of SUDEP annually. With an assumed epilepsy prevalence of 0.6% in Germany, this could lead to more than one SUDEP case daily. Standardization of research methods is essential to gain more profound insights.

Consequences of long-term oral corticosteroid therapy and its side-effects in severe asthma in adults: a focused review of the impact data in the literature.

This review provides an overview of the role of long-term treatment of severe asthma with oral corticosteroids (OCS) and its associated side-effects in adults. It is based on a systematic literature search conducted in MEDLINE, Embase and the Cochrane Library to identify relevant studies. After a short overview of severe asthma and its treatment we present studies showing a dose-response relationship in asthmatic patients treated with OCS and then consider by organ systems the undesired effects demonstrated in clinical and epidemiological studies in patients with OCS-dependent asthma. It was found that the risk of developing various OCS-related complications, including infections, diabetes and osteoporosis as well as psychiatric disorders, was higher for patients with long-term exposure to OCS compared with control groups. In addition, studies showed a significant increase in healthcare resource utilisation due to OCS treatment. Therefore, it is incumbent on every clinician to carefully weigh the potential benefit of preventing loss of asthma control against this risk before opting to prescribe long-term OCS therapy. Effective corticosteroid-sparing strategies must be used and should aim at short-term use with the lowest effective dose and start tapering as soon as possible until OCS therapy is terminated.

Senescence-associated release of transmembrane proteins involves proteolytic processing by ADAM17 and microvesicle shedding.

Cellular senescence, a state of persistent cell cycle arrest, has emerged as a potent tumor suppressor mechanism by restricting proliferation of cells at risk for neoplastic transformation. Senescent cells secrete various growth factors, cytokines, and other proteins that can either elicit the clearance of tumor cells or potentially promote tumor progression. In addition, this senescence-associated secretory phenotype (SASP) includes various factors that are synthesized as transmembrane precursors and subsequently converted into their soluble counterparts. Despite the importance of the SASP to tumor biology, it is virtually unknown how transmembrane proteins are released from senescent cancer cells. Here we show in different models of senescence that the metalloprotease A disintegrin and metalloproteinase 17 (ADAM17) is activated and releases the epidermal growth factor receptor ligand amphiregulin and tumor necrosis factor receptor I (TNFRI) from the surface of senescent cells by ectodomain shedding. ADAM17 activation involves phosphorylation of its cytoplasmic tail by mitogen-activated protein kinase (MAPK) p38. Interestingly, unlike amphiregulin and TNFRI, full-length intercellular adhesion molecule 1 (ICAM1) is released from senescent cells by microvesicles independently of ADAM17. Thus, our results suggest that transmembrane proteins can be released by two distinct mechanisms and point to a crucial role for ADAM17 in shaping the secretory profile of senescent cells.

Constitutively active mutant gp130 receptor protein from inflammatory hepatocellular adenoma is inhibited by an anti-gp130 antibody that specifically neutralizes interleukin 11 signaling.

Ligand-independent constitutively active gp130 mutants were described to be responsible for the development of inflammatory hepatocellular adenomas (IHCAs). These variants had gain-of-function somatic mutations within the extracellular domain 2 (D2) of the gp130 receptor chain. Cytokine-dependent Ba/F3 cells were transduced with the constitutively active variant of gp130 featuring a deletion in the domain 2 from Tyr-186 to Tyr-190 (gp130ΔYY). These cells showed constitutive phosphorylation of signal transducer and activator of transcription-3 (STAT3) and cytokine-independent proliferation. Deletion of the Ig-like domain 1 (D1) of gp130, but not anti-gp130 mAbs directed against D1, abolished constitutive activation of gp130ΔYY, highlighting that this domain is involved in ligand-independent activation of gp130ΔYY. Moreover, soluble variants of gp130 were not able to inhibit the constitutive activation of gp130ΔYY. However, the inhibition of constitutive activation of gp130ΔYY was achieved by the anti-gp130 mAb B-P4, which specifically inhibits gp130 signaling by IL-11 but not by other IL-6 type cytokines. IL-11 but not IL-6 levels were found previously to be up-regulated in IHCAs, suggesting that mutations in gp130 are leading to IL-11-like signaling. The mAb B-P4 might be a valuable tool to inhibit the constitutive activation of naturally occurring gp130 mutants in IHCAs and rare cases of gp130-associated hepatocellular carcinoma.

The disintegrin domain of ADAM17 antagonises fibroblast­carcinoma cell interactions.

The malignant phenotype of carcinoma cells depends on their ability to invade into their microenvironment promoting metastasis. Therefore, carcinoma cells overexpress many proteins, including A disintegrin and metalloproteases (ADAMs). ADAM17 is expressed by different cancer cell lines and possesses adhesive as well as enzymatic activities. To address the adhesive properties in tumour progression the recombinantly expressed soluble disintegrin domain of ADAM17 was employed. Fibroblasts and carcinoma cells adhere to the immobilized disintegrin domain. Additionally, the soluble disintegrin domain impaired fibroblast-carcinoma cell interactions and increased the shedding activity of ADAM17. Silencing of ADAM17 in fibroblasts or in carcinoma cells decreases cell-cell interaction between these cells. In summary, our results show that the adhesive properties of ADAM17 are mediated by its disintegrin domain and enables carcinoma cells to interact with their microenvironment.