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Congenital long QT syndrome [LQTS] is a channelopathy characterized by QT prolongation and polymorphic VT. LQTS however need not be a purely electrical disease. Defects in ion channels may cause myocardial architectural disruption leading to ventricular non compaction [VNC]. It is defined as the presence of prominent ventricular trabeculations and deep intertrabecular recesses within the endomyocardium. We describe the in-utero management of a foetus who was later found to have LQTS with VNC. The detection of ventricular tachycardia and complete heart block in utero should arouse the suspicion of LQTS. It would be wise to avoid QT prolonging antiarrhythmics in this subset of patients.

High-grade B-cell lymphomas with MYC, BCL2, and BCL6 rearrangements (triple hit lymphoma) are uncommon. We studied the clinicopathologic features of 40 patients with triple hit lymphoma and compared them to 157 patients with MYC/BCL2 double hit lymphoma and 13 patients with MYC/BCL6 double hit lymphoma. The triple hit lymphoma group included 25 men and 15 women with a median age of 61 years (range, 34−85). Nine patients had a history of B-cell lymphoma. Histologically, 23 (58%) cases were diffuse large B-cell lymphoma and 17 cases had features of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. Most cases of triple hit lymphoma were positive for CD10 (100%), BCL2 (95%), BCL6 (82%), MYC (74%), and 71% with MYC and BCL2 coexpression. P53 was overexpressed in 29% of triple hit lymphoma cases. The clinicopathological features of triple hit lymphoma patients were similar to patients with MYC/BCL2 and MYC/BCL6 double hit lymphoma, except that triple hit lymphoma cases were more often CD10 positive compared with MYC/BCL6 double hit lymphoma (p

Genetic and environmental models of neuropsychiatric disease have grown exponentially over the last 20 years. One measure that is often used to evaluate the translational relevance of these models to human neuropsychiatric disease is prepulse inhibition of startle (PPI), an operational measure of sensorimotor gating. Deficient PPI characterizes several neuropsychiatric disorders but has been most extensively studied in schizophrenia. It has become a useful tool in translational neuropharmacological and molecular genetics studies because it can be measured across species using almost the same experimental parameters. Although initial studies of PPI in rodents were pharmacological because of the robust predictive validity of PPI for antipsychotic efficacy, more recently, PPI has become standard common behavioral measures used in genetic and neurodevelopmental models of schizophrenia. Here we review “two hit” models of schizophrenia and discuss the utility of PPI as a tool in phenotyping these models of relevant risk factors. In the review, we consider approaches to rodent models of genetic and neurodevelopmental risk factors and selectively review “two hit” models of gene × environment and environment × environment interactions in which PPI has been measured.

Introduction Multiple myeloma (MM) patients (pts) with high-risk cytogenetic abnormalities (CA) have a shorter survival as compared to the standard-risk ones. In the FORTE study, carfilzomib-lenalidomide-dexamethasone induction/consolidation with ASCT (KRd-ASCT) significantly improved progression-free survival (PFS) vs KRd without ASCT (KRd12) or carfilzomib-cyclophosphamide-dexamethasone (KCd) plus ASCT (KCd-ASCT). KR maintenance also prolonged PFS vs R. The primary aim of this analysis was to evaluate the impact of treatment on PFS and 1-year sustained MRD negativity (1y-MRD neg) rates according to pt cytogenetic risk. Methods Pts were randomized to KRd-ASCT vs KCd-ASCT vs KRd12 and, thereafter, to KR vs R maintenance. High risk (HiR) was defined as the presence of ≥1 HiR CA [del17p, t(4;14), t(14;16), del1p and 1q gain (3 copies) or amp1q (≥4 copies)], double hit (DH) as the presence of ≥2 HiR CA, standard risk (SR) as the absence of all evaluated HiR CA. Results 396 out of 474 enrolled pts with complete fluorescence in situ hybridization (FISH) data were included in the analysis: 243 HiR, 105 DH and 153 SR pts. Among HiR pts, 60 had del17p, 65 t(4;14), 20 t(14;16), 44 del1p, 126 1q gain and 49 amp1q. SR pts benefited from intensification with KRd-ASCT vs KRd12 (HR 0.47, p=0.05) and KCd-ASCT (HR 0.38, p=0.01), with a 4-year PFS of 80%, 67% and 57%, respectively. In HiR pts, KRd-ASCT improved PFS vs KRd12 (HR 0.6, p=0.04) and KCd-ASCT (HR 0.57, p=0.01), with a 4-year PFS of 62%, 45% and 45%, respectively. The advantage with KRd-ASCT vs KRd12 (HR 0.53, p=0.07) and KCd-ASCT (HR 0.49; p=0.03) was also observed in DH pts (4-year PFS 55%, 31% and 33%, respectively). Despite the limited number of patients in each subgroup, a trend towards a PFS benefit from KRd-ASCT vs KRd12 was observed in pts with del17p (HR 0.61, p=0.3), t(4;14) (HR 0.59, p=0.2) and 1q gain (HR 0.45, p=0.02). In pts with del1p, KRd-ASCT (HR 0.24, p=0.06) and KRd12 (HR 0.33, p=0.09) showed superiority over KCd-ASCT, while amp1q pts had the worst outcome regardless of treatment (KRd-ASCT vs KCd-ASCT, HR 1.16, p=0.73; KRd12 vs KCd-ASCT, HR 1.34, p=0.45). KR improved PFS vs R in SR (3-year PFS 90% vs 73%, HR 0.42, p=0.06), HiR (3-year PFS 69% vs 56%, HR 0.6, p=0.04) and DH pts (3-year PFS 67% vs 42%, HR 0.53, p=0.1). Despite the small subgroups, a beneficial trend with KR vs R was observed in pts with del17p (HR 0.59, p=0.37), t(4;14) (HR 0.59, p=0.3), 1q gain (HR 0.54, p=0.07) and del1p (HR 0.23, p=0.08), while amp1q pts showed the worst outcome and no benefit from KR vs R (HR 0.83, p=0.7). Conclusion KRd-ASCT and KR maintenance are highly effective in SR and also in HiR and DH pts, with impressive 4-year PFS from diagnosis (KRd-ASCT: HiR 62%, DH 55%) and 3-year PFS from maintenance (KR: HiR 69%, DH 67%), thus providing an effective option in HiR pts, who still represent an unmet medical need.

We report on a young patient with a bicuspid aortic valve operated on for type A acute aortic dissection because of a blunt thoracic trauma. Aortic root replacement and ascending aortic and total arch repair together with the postoperative course were uneventful. Multigenerational genetic analyses revealed mutations in the NOTCH1 and ACTA2 genes in the patient and his father. The screening of his parents and children revealed no bicuspid aortic valve or aortic root dilation. This exceptionally rare case of double-hit mutations and the presence of blunt trauma reveals the complex etiology of aortic dissection in patients with a bicuspid aortic valve.

The main technique employed to characterize the efficiency of water-splitting in photosynthetic preparations in terms of miss and double hit parameters and for the determination of Si (i=2,3,0) state lifetimes is the measurement of flash-induced oxygen oscillation pattern on bare platinum (Joliot-type) electrodes. We demonstrate here that this technique is not innocent. Polarization of the electrode against an Ag/AgCl electrode leads to a time-dependent formation of hydrogen peroxide by two-electron reduction of dissolved oxygen continuously supplied by the flow buffer. While the miss and double hit parameters are almost unaffected by H2O2, a time dependent reduction of S1 to S−1 occurs over a time period of 20min. The S1 reduction can be largely prevented by adding catalase or by removing O2 from the flow buffer with N2. Importantly, we demonstrate that even at the shortest possible polarization times (40s in our set up) the S2 and S0 decays are significantly accelerated by the side reaction with H2O2. The removal of hydrogen peroxide leads to unperturbed S2 state data that reveal three instead of the traditionally reported two phases of decay. In addition, even under the best conditions (catalase+N2; 40s polarization) about 4% of S−1 state is observed in well dark-adapted samples, likely indicating limitations of the equal fit approach. This article is part of a Special Issue entitled: Photosynthesis Research for Sustainability: Keys to Produce Clean Energy.

To determine the current preferred injection technique(s) for endoscopic management of pediatric vesicoureteral reflux (VUR). Since the approval of dextranomer hyaluronic acid copolymer (Dx/HA) in 2001, injection methods have evolved and now include the hydrodistention implantation technique (HIT) and double HIT as well as subureteral transurethral injection (STING) method.In July 2012, 278 pediatric urologists in the United States were contacted to complete a 15-question survey regarding Dx/HA injection technique(s) currently used in their practice.Fifty board-certified pediatric urologists completed the survey for a response rate of 18%. Most respondents (60%) were in a single-specialty group practice, and 12% were affiliated with an academic- or university-based practice. Respondents reported seeing a mean of 159 pediatric patients (range, 40-400 patients) with VUR annually, and 94% used Dx/HA ≥4 times in the past year. Forty-seven respondents (94%) reported using double HIT over the course of their career compared with 36 (72%) for STING and 30 (60%) for HIT (P .05). Double HIT gained widespread acceptance between 2007 and 2008, paralleled by a decline in use of other injection techniques. A significantly higher percentage currently perform double HIT (92%) compared with either STING (24%) or HIT (34%; P .001). Respondents reported the use of double HIT 15 times more often than STING technique and 5 times more often than HIT during the past 12 months (P .001).The double HIT method is currently the most commonly performed technique for endoscopic correction of VUR by pediatric urologists in the United States.

Although a lot of data are available in the literature on the recrystallization behavior of plain carbon and microalloyed steels, comparisons are often difficult to make due to the effect of different experimental techniques and the type of tests used to obtain these data. Few systematic comparisons can be found in the literature to correlate the different techniques and methods. A previous paper by the present authors concentrates on the analysis of torsion methods. The present study focuses on the recrystallization kinetics determined by using double hit and stress relaxation tests in plane strain compression mode. The specificity of the test and the strain distribution across the section has been incorporated into the analysis, by means of finite element methods. A good correlation has been obtained between the kinetics for stress relaxation and double hit tests. However, some rules should be respected in order to determine the true recrystallization/softening kinetics comparable with those obtained for other deformation modes like torsion.

Different recrystallization models are now available in the literature for plain carbon and microalloyed steels. However, the attempts made to unify these models have been unsuccessful due to the considerable scatter in experimental results that support the corresponding equations. In fact, kinetics results can be separated into different groups depending on the testing procedure. In order to cope with this problem and improve the reliability of the different models, the different methods that are currently applied at laboratory need to be re-analyzed. The present work concentrates on the determination of recrystallization/softening kinetics of austenite from torsion tests. To this purpose the softening results obtained by the application of double hit torsion tests to two Nb microalloyed steels and the fraction recrystallized as determined by metallography have been subjected to a direct and an inverse analysis that takes into account the specificity of the torsiontest.

In this issue of Cancer Cell, Diamantopoulou et al. uncover dual mechanisms of inhibiting YAP/TAZ by TIAM1 that oppose invasiveness of colorectal cancer cells: TIAM1 interacts with TAZ in the cytoplasm to promote TAZ degradation by the destruction complex, whereas it antagonizes binding of TAZ/YAP to TEAD in the nucleus.

We report on a test of a straw tube detector design having several anode (sense) wires inside a straw tube. The anode wires form a circle inside the tube and are read out independently. This design could solve several shortcomings of the traditional single wire straw tube design such as double hit capability and stereo configuration.

By using isothermal double hit compression tests and applying the 2% offset method, a new model was developed to predict the microstructural evolution of Nb-bearing steels at temperatures above and below the start temperature of strain-induced precipitation (T P ). The T P was developed as a function of true strain, initial austenite grain size and the Nb content. The activation energy of static recrystallization (Q rex ) was expressed as a function of the content of different alloy elements. It was found that Nb played the most important role in increasing the value of Q rex The microstructural observations and measurements confirmed the validity of the model developed in the present investigation.

During hot forging, the billet is heated to an elevated temperature, forged to the required shape and cooled to room temperature. Most of the hot forged parts produced, meet the specified geometric tolerances, but some do not. Some of the defective parts can be rectified by machining, others are rejected. Restoring a hot forged part demands extra production cost. Defective parts can be attributed to process variations or uncertainties that occur during production. Such manufacturing anomalies in the metal forming industry can induce heavy losses (e.g. premature failure of equipment, under-fill, folds in part and double hit) during mass production. The objectives of this research are, determining the uncertainties that cause defective parts during hot forging and illustrate a method to determine parameters that control the trade-off between rejected parts and rectifiable parts. This information will aid in reducing production costs of the forgings. The uncertainties are demonstrated in this research by simulations of the forging and cooling processes. Since, uncertainties in the field of metal forming have never been considered in the design process, quantifying the effects of the process uncertainties would be the first step towards reducing geometric variation and related production costs. Also, incorporating the process uncertainties into the forging and cooling process design leads to better quality parts.

MYC/BCL2 double hit lymphoma (DHL) is a rare, recently recognised and highly aggressive subtype of non-Hodgkin lymphoma, with an affinity to involve the central nervous system and the head and neck either at initial presentation or during relapse. We present a case of 43-year-old woman with MYC/BCL2 DHL relapse in the nasopharynx with extensive spread to the neck, skull base, and the central nervous system. To our knowledge, this is the first reported case in the literature describing the MRI and CT scan findings and the profound pattern of disease involvement of this rare neoplasm.

A 67-year-old male presented with supraclavicular lymphadenopathy. Morphological and immunohistochemical findings in the excised lymph node were interpreted as those of a B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, with MYC protein and BCL2 protein coexpression. Fluorescence in situ hybridisation of formalin fixed, paraffin embedded tissue confirmed the presence of both IGH/MYC and BCL2 rearrangement, consistent with a so-called ‘double hit' lymphoma.

The rather small size of the Diogene pictorical drift chamber has several unfavourable consequences: not more than 16–18 points to define even the best isolated tracks; high track density and hence missed points due to double hit resolution; strongly bent trajectories and thus many track crossings. In spite of these difficulties, the events can be analyzed. The program takes advantage of the fact that the vertex position is known. Two different methods are used: the first one selects out rather quickly most of the tracks by a simple strategy; the remaining tracks are then searched by a more global but much more time consuming method.