[The etiology of 340 infants with early-onset epilepsy].

Objective: To investigate the etiology of epilepsy onset before 6 months old and improve clinical understanding. Methods: The medical history, electroencephalogram, brain imaging, genetic examination and other clinical data of 340 patients who were diagnosed with epilepsy with onset under 6 months of age and were hospitalized in the Department of Neurology, Beijing Children's Hospital, Capital Medical University between January 2017 and December 2018 were retrospectively analyzed. Rank sum test was used to compare the ages of onset of different etiologic groups. Results: Of the 340 patients, 196 were males and 144 were females. The age of onset was 90.5 (48.0, 135.5) days. In the 250 (73.5%) underwent genetic test, 103 (41.2%) had pathogenic or likely pathogenic variants, involving 43 single gene variants and 2 chromosomal abnormalities. Seventy-nine patients (23.2%) had genetic etiology, 66 (19.4%) had structural etiology, 19 (5.6%) had metabolic etiology, 13 (3.8%) had multiple etiologies, and 163 (47.9%) had unknown etiology. In the 79 cases with genetic etiology, 30 single gene variants were detected, including 19 cases of PRRT2, 10 cases of KCNQ2, 7 cases of SCN1A, 6 cases of SCN2A, 6 cases of STXBP1, 5 cases of CDKL5, 2 cases of ARX, and 1 case of each of 23 gene variants. Two cases had chromosomal abnormalities which were 21-trisomy and 16p11.2 microdeletion syndrome respectively. Among the 66 cases with structural etiologies, 37 cases had acquired factors such as perinatal brain injury, 28 cases had congenital factors such as cortical malformation and 1 case was perinatal brain injury combined megalencephaly. The onset age of genetic etiology was 95 (26, 128) days, that of structural etiology was 90 (58, 30) days, and that of metabolic etiology was 57 (30, 90) days. The onset age of metabolic etiology was earlier than that of structural etiology (U=436.500, P=0.044). Conclusions: Genetic etiology is the most common defined etiology of infants with early-onset epilepsy aged 0-6 months, and there are certain differences in the age of onset between different etiologies. Proper application of genetic test is helpful to identify the etiology and guide treatment.

Ergothioneine and melatonin attenuate oxidative stress and protect against learning and memory deficits in C57BL/6J mice treated with D-galactose.

Male C57BL/6J mice treated with D-galactose (DG) were used to examine the effects of ergothioneine (EGT), melatonin (MEL), or their combination (EGT+MEL) on learning and memory abilities. The mice were divided into five groups and injected subcutaneously with DG (0.3 mL of 1% DG/mouse) except for group 1 (normal controls). Group 3 was orally supplemented with EGT [0.5 mg/kg body weight (bw)], group 4 with MEL (10 mg/kg bw, p.o.), and group 5 with EGT+MEL. EGT and MEL were provided daily for 88 days, while DG was provided between days 7 to 56. Active avoidance task and Morris water-maze task were used to evaluate learning and memory abilities. DG treatment markedly increased escape latency and decreased the number of avoidance in the active avoidance test, whereas EGT and MEL alone significantly improved the performance. DG also impaired the learning and memory abilities in the water-maze task, and EGT and MEL alone also significantly improved the performance. EGT+MEL produced the strongest effects in both tasks. EGT and MEL alone markedly decreased ß-amyloid protein accumulation in the hippocampus and significantly inhibited lipid peroxidation and maintained glutathione/glutathione disulfide ratio and superoxide dismutase activity in brain tissues of DG-treated mice. MEL alone completely prevented the rise in brain acetylcholine esterase activity induced by DG, whereas EGT and EGT+MEL were only partially effective. Overall, EGT, MEL, and, in particular, the combination of EGT and MEL effectively protect against learning and memory deficits in C57BL/6J mice treated with DG, possibly through attenuation of oxidative damage.

Menin mediates epigenetic regulation via histone H3 lysine 9 methylation.

Menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, is a tumor suppressor that leads to multiple endocrine tumors upon loss of its function. Menin functions as a transcriptional activator by tethering MLL complex to mediate histone H3 K4 methylation. It also functions as a repressor. However, the molecular mechanism of how menin contributes to the opposite outcome in gene expression is largely unknown. Here, we investigated the role of menin in the epigenetic regulation of transcription mediated by histone covalent modification. We show that the global methylation level of histone H3 K9, as well as H3 K4, was decreased in Men1(-/-) MEF cells. Consistently, menin was able to interact with the suppressor of variegation 3-9 homolog family protein, SUV39H1, to mediate H3 K9 methylation. This interaction decreased when patient-derived MEN1 mutation was introduced into the SUV39H1-interaction domain. We show that menin mediated different chromatin changes depending on target genes. Chromatin immunoprecipitation studies showed that menin directly associated with the GBX2 promoter and menin-dependent recruitment of SUV39H1 was essential for chromatin remodeling and transcriptional regulation. These results provide a molecular basis of how menin functions as a transcriptional repressor and suggest that menin-dependent integration of H3 K9 methylation might play an important role in preventing tumors.

GATE: a simulation toolkit for PET and SPECT.

Monte Carlo simulation is an essential tool in emission tomography that can assist in the design of new medical imaging devices, the optimization of acquisition protocols and the development or assessment of image reconstruction algorithms and correction techniques. GATE, the Geant4 Application for Tomographic Emission, encapsulates the Geant4 libraries to achieve a modular, versatile, scripted simulation toolkit adapted to the field of nuclear medicine. In particular, GATE allows the description of time-dependent phenomena such as source or detector movement, and source decay kinetics. This feature makes it possible to simulate time curves under realistic acquisition conditions and to test dynamic reconstruction algorithms. This paper gives a detailed description of the design and development of GATE by the OpenGATE collaboration, whose continuing objective is to improve, document and validate GATE by simulating commercially available imaging systems for PET and SPECT. Large effort is also invested in the ability and the flexibility to model novel detection systems or systems still under design. A public release of GATE licensed under the GNU Lesser General Public License can be downloaded at http:/www-lphe.epfl.ch/GATE/. Two benchmarks developed for PET and SPECT to test the installation of GATE and to serve as a tutorial for the users are presented. Extensive validation of the GATE simulation platform has been started, comparing simulations and measurements on commercially available acquisition systems. References to those results are listed. The future prospects towards the gridification of GATE and its extension to other domains such as dosimetry are also discussed.

Inhibitory effects of Cassia tora L. on benzo[a]pyrene-mediated DNA damage toward HepG2 cells.

The effects of water extracts from Cassia tora L. (WECT) treated with different degrees of roasting on benzo[a]pyrene (B[a]P)-induced DNA damage in human hepatoma cell line HepG2 were investigated via the comet assay without exogenous activation mixtures, such as S9 mix. WECT alone, at concentrations of 0.1-2 mg/mL, showed neither cytotoxic nor genotoxic effect toward HepG2 cells. B[a]P-induced DNA damage in HepG2 cells could be reduced by WECT in a dose-dependent manner (P < 0.05). At a concentration of 1 mg/mL, the inhibitory effects of WECT on DNA damage were in the order unroasted (72%) > roasted at 150 degrees C (60%) > roasted at 250 degrees C (23%). Ethoxyresorufin-O-dealkylase activity of HepG2 cells was effectively inhibited by WECT, and a similar trend of inhibition was observed in the order unroasted (64%) > roasted at 150 degrees C (42%) > roasted at 250 degrees C (18%). The activity of NADPH cytochrome P-450 reductase was also decreased by unroasted and 150 degrees C-roasted samples (50% and 38%, respectively). Furthermore, glutathione S-transferase activity was increased by treatment with unroasted (1.26-fold) and 150 degrees C-roasted (1.35-fold) samples at 1 mg/mL. In addition, the contents of anthraquinones (AQs) in WECT, including chrysophanol, emodin, and rhein, were decreased with increasing roasting temperature. Each of these AQs also demonstrated significant antigenotoxic activity in the comet assay. The inhibitory effects of chrysophanol, emodin, and rhein on B[a]P-mediated DNA damage in HepG2 cells were 78, 86, and 71%, respectively, at 100 microM. These findings suggested that the decreased antigenotoxicity of the roasted samples might be due to a reduction in their AQs content.

DNA cytometric proliferative index predicting organ confinement in clinical stage-B prostate cancer.

PURPOSE: To assess nuclear activity by DNA flow cytometry (FCM), Gleason score and serum prostate-specific antigen (PSA) levels in predicting extracapsular tumour involvement in patients with prostate cancer. DESIGN: Retrospective pathologic study. PATIENTS: Forty patients with clinical stage-B prostate cancer who underwent radical prostatectomy. INTERVENTIONS: The relationship between the pathologic state and each of the proliferative index (PI). Gleason score and PSA level was analysed retrospectively with the use of archival specimens. Preoperative serum PSA levels, were measured by the Hybritech assay. Gleason score was determined by 2 of the authors. Tumours were classified as stage B (confined to prostate), C1 (focal capsular penetration) or C2 (involvement of seminal vesicles or capsular perforation). FCM PI measurements were performed on deparaffinized tumour specimens. RESULTS: All 40 specimens were diploid. There were 9 pathologic stage-B, 16 stage-C1 and 15 stage-C2 tumours. The serum PSA level was 20 ng/mL or less for all patients except 2, for whom the levels were 27.8 ng/mL and 45.9 ng/mL, respectively. A Gleason score lower than 7 had a 76.0% sensitivity and 53.5% specificity in predicting organ confinement. In contrast, a PI of 21 or lower had a 84.0% sensitivity and a 73.0% specificity in predicting organ confinement, with a positive predictive value of 84.0%. Of the 17 tumours with both "favourable" features (Gleason score lower than 7 and PI of 21 or lower), only 1 (5.9%) had extracapsular involvement (stage C2). Of the 6 tumours with both "unfavourable" features (Gleason score higher than 7 and PI of 21 or higher) 5 of 6 were stage C2 and 1 was stage C1. CONCLUSION: The single most consistent predictor of organ confinement was PI alone.

Management of vesical calculi: comparison of lithotripsy devices.

Although endoscopic lithotripsy of bladder stones has been well described and is widely practiced, comparison of the main modalities of mechanical, electrohydraulic, and ultrasonic lithotripsy is lacking. The exact role of these and other modalities such as the Swiss Lithoclast and extracorporeal shockwave lithotripsy is not clearly defined. The safety and efficacy of the various lithotripsy modalities available to treat bladder calculi were reviewed retrospectively over an 18-year period. A total of 106 patients were treated with some form of intracorporeal lithotripsy. In general, all devices proved to be effective with a low rate of complications. The addition of transurethral resection of the prostate to bladder stone management under the same anesthetic was also found to be a safe procedure for moderate benign prostatic hyperplasia. In summary, transurethral endoscopic lithotripsy is a safe and effective method of bladder stone management both alone and in combination with transurethral prostatectomy. All modalities of intracorporeal lithotripsy are effective; however, devices such as ultrasound lithotripters or the Swiss Lithoclast that utilize larger, rigid probes may be more efficient for patients with large or particularly hard vesical calculi.

Prognostic value of angiogenesis and vascular invasion in muscle-invasive bladder cancer.

Angiogenesis is important in the pathogenesis of tumors and correlates with clinical outcome in certain malignancies. Recent advances in staining techniques have raised doubts about the prognostic value of vascular invasion in muscle-invasive bladder cancer, for which relatively few predictors for survival exist. Twenty-one radical cystectomy specimens from patients with stage pT2-3NOMO transitional cell tumors were examined by staining with Hematoxylin and Eosin (H&E). Factor VIII-related antigen (FVIII RAG) which is specific for vascular endothelium, and MOVAT which highlights large vessels. Angiogenesis, estimated by microvessel density, and presence of vascular invasion were then correlated with survival in the follow-up period which ranged from 3 to 141 months. Six of 21 patients survived disease-free with follow-up ranging from 47 to 141 months. Twelve patients had lower microvessel density than 178/mm2 and five of these survived, whereas only one of nine patients having higher microvessel density survived. Twelve of 21 patients had vascular invasion and three survived whereas three of nine patients without vascular invasion survived. There was no correlation found between vascular invasion and survival in this study. Analysis by Kaplan-Meir survival curves demonstrated trends which were not statistically significant between high and low angiogenesis groups. The preliminary data suggest that further assessment of the prognostic role of angiogenesis and vascular invasion in muscle-invasive bladder cancer is indicated.