Chloroquin indukálta cardiomyopathia avagy a „pszeudo-Fabry-kór” fatális lefolyású esete = Chloroquine induced cardiomyopathy: a fatal course of „pseudo-Fabry’s-disease”

A chloroquint napjainkban szisztémás autoimmun kórképek kezelésére használják, autoimmun szöveti károsodást gátló és immunomoduláns hatása miatt. Ritka, ám súlyos mellékhatása a szernek, hogy restriktív cardiomyopathia-szerű képet okozhat, ami fenotípus és hisztológiai kép tekintetében egyaránt a Fabry-kór kardiális manifesztációjára emlékeztet. Munkánkban egy 73 éves nőbeteg esetét mutatjuk be, akinek fulmináns lefolyású szívelégtelensége hátterében chloroquin-cardiomyopathia állt. A beteg anamnézisében tartós chloroquinszedés szerepelt, rheumatoid arthritise miatt. 71 éves, korában harmadfokú atrioventricularis blokk miatt igényelt végleges pacemaker-implantációt. 2 évvel később kardiális dekompenzáció miatt került intézeti felvételre. Ekkor transthoracalis echokardiográfia során masszív koncentrikus bal kamrai hipertrófia, közepes fokban csökkent szisztolés balkamra-funkció és restriktív típusú mitrális beáramlási görbe volt észlelhető. A beteg a kéthetes hospitalizáció során kompenzálható volt, azonban 1 hónapon belül súlyos állapotban rehospitalizációra került sor, ami fatális kimenetelű volt. A klinikai kép és az autopsziás lelet alapján felmerült Fabry-betegség gyanúja. Tekintettel azonban a beteg tartós chloroquin szedésére, chloroquin indukálta cardiomyopathiát valószínűsítettünk. A chloroquin kardiális jellegű mellékhatásai – bár az alkalmazási előírásban említésre kerülnek – kevésbé ismertek. Ajánlásokra lenne szükség azzal kapcsolatban, hogy milyen gyakran, milyen módszerrel javasolt a tartósan chloroquint szedő betegek kardiológiai szűrése

The Combination of Single-Cell and Next-Generation Sequencing Can Reveal Mosaicism for BRCA2 Mutations and the Fine Molecular Details of Tumorigenesis

Germline mutations in the BRCA1 and BRCA2 genes are responsible for hereditary breast and ovarian cancer syndrome. Germline and somatic BRCA1/2 mutations may define therapeutic targets and refine cancer treatment options. However, routine BRCA diagnostic approaches cannot reveal the exact time and origin of BRCA1/2 mutation formation, and thus, the fine details of their contribution to tumor progression remain less clear. Here, we establish a diagnostic pipeline using high-resolution microscopy and laser microcapture microscopy to test for BRCA1/2 mutations in the tumor at the single-cell level, followed by deep next-generation sequencing of various tissues from the patient. To demonstrate the power of our approach, here, we describe a detailed single-cell-level analysis of an ovarian cancer patient we found to exhibit constitutional somatic mosaicism of a pathogenic BRCA2 mutation. Employing next-generation sequencing, BRCA2 c.7795G>T, p.(Glu2599Ter) was detected in 78% of reads in DNA extracted from ovarian cancer tissue and 25% of reads in DNA derived from peripheral blood, which differs significantly from the expected 50% of a hereditary mutation. The BRCA2 mutation was subsequently observed at 17–20% levels in the normal ovarian and buccal tissue of the patient. Together, our findings suggest that this mutation occurred early in embryonic development. Characterization of the mosaic mutation at the single-cell level contributes to a better understanding of BRCA mutation formation and supports the concept that the combination of single-cell and next-generation sequencing methods is advantageous over traditional mutational analysis methods. This study is the first to characterize constitutional mosaicism down to the single-cell level, and it demonstrates that BRCA2 mosaicism occurring early during embryogenesis can drive tumorigenesis in ovarian cancer

Prognostic Value of Serum Biomarkers in Patients with Moderate-Severe Traumatic Brain Injury, Differentiated by Marshall Computer Tomography Classification

Prognostication is challenging in patients with traumatic brain injury (TBI) in whom computed tomography (CT) fails to fully explain a low level of consciousness. Serum biomarkers reflect the extent of structural damage in a different way than CT does, but it is unclear whether biomarkers provide additional prognostic value across the range of CT abnormalities. This study aimed to determine the added predictive value of biomarkers, differentiated by imaging severity. This prognostic study used data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study (2014–2017). The analysis included patients aged ‡16 years with a moderate severe TBI (Glasgow Coma Scale [GCS] <13) who had an acute CT and serum biomarkers obtained £24h of injury. Of six protein biomarkers (GFAP, NFL, NSE, S100B, Tau, UCH-L1), the most prognostic panel was selected using lasso regression. The performance of established prognostic models (CRASH and IMPACT) was assessed before and after the addition of the biomarker panel and compared between patients with different CT Marshall scores (Marshall score <3 vs. Marshall score ‡3). Outcome was assessed at six months post-injury using the extended Glasgow Outcome Scale (GOSE), and dichotomized into favorable and unfavorable (GOSE <5). We included 872 patients with moderate-severe TBI. The mean age was 47 years (range 16–95); 647 (74%) were male and 438 (50%) had a Marshall CT score <3. The serum biomarkers GFAP, NFL, S100B and UCH-L1 provided complementary prognostic information; NSE and Tau showed no added value. The addition of the biomarker panel to established prognostic models increased the area under the curve (AUC) by 0.08 and 0.03, and the explained variation in outcome by 13–14% and 7–8%, for patients with a Marshall score of <3 and ‡3, respectively. The incremental AUC of biomarkers for individual models was significantly greater when the Marshall score was <3 compared with ‡3 ( p < 0.001). Serum biomarkers improve outcome prediction after moderate-severe TBI across the range of imaging severities and especially in patients with a Marshall score <3