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Atypical fibroxanthoma (AFX) is a neoplasm that most commonly occurs on sun-damaged skin of the head and neck in elderly patients and that usually exhibits indolent clinical behavior with complete excision. The granular cell variant of AFX demonstrates overlapping histopathologic features with dermal non-neural granular cell tumor (NNGCT), which typically arises on the extremities of young to middle aged adults with rare reports of regional metastasis. A subset of NNGCT harbors ALK rearrangements and expresses ALK by immunohistochemistry. Here, we present 2 cases of granular cell AFX occurring on the scalp of males aged 73 and 87 with ALK expression by immunohistochemistry and no evidence of an ALK rearrangement on fluorescence in situ hybridization, representing a diagnostic pitfall for NNGCT.

Gene therapy using an adeno-associated virus (AAV) vector offers a new treatment option for individuals with monogenetic disorders. The major bottleneck is the presence of pre-existing anti-AAV antibodies, which impacts its use. Even very low titers of neutralizing antibodies (NAb) to capsids from natural AAV infections have been reported to inhibit the transduction of intravenously administered AAV in animal models and are associated with limited efficacy in human trials. Assessing the level of pre-existing NAb is important for determining the primary eligibility of patients for AAV vector-based gene therapy clinical trials. Techniques used to screen AAV-antibodies include AAV capsid enzyme-linked immunosorbent assay (ELISA) and transduction inhibition assay (TIA) for detecting total capsid-binding (TAb) and Nab, respectively. In this study, we screened 521 individuals with hemophilia A from India for TAb and NAb using ELISA and TIA, respectively. The prevalence of TAb and NAb in hemophilia A patients from India were 96% and 77.5%, respectively. There was a significant increase in anti-AAV3 NAb prevalence with age in the hemophilia A patient group from India. There was a trend in anti-AAV3 TAb positivity between the pediatric age group (94.4%) and the adult age group (97.4%).

Sex cord-stromal tumors (SCSTs) account for the second most common category of testicular neoplasms and include several entities that may show overlapping morphologies and present diagnostic challenges. We analyzed a cohort of 120 testicular SCSTs and investigated the diagnostic utility of SRY-box transcription factor 9 (SOX9), forkhead box protein L2 (FOXL2), and steroidogenic factor 1 (SF-1) immunohistochemical stains. The results were compared with the more commonly used SCST markers, inhibin α, calretinin, and Wilms' tumor 1 (WT1). SF-1 was overall the most sensitive stain (91%), followed by inhibin α (70%), calretinin (52%), FOXL2 (50%), SOX9 (47%), and WT1 (37%), but sensitivities varied by tumor type. SOX9 and calretinin were more commonly positive in sex cord elements versus stromal elements (62% vs. 27% and 47% vs. 9%, respectively), whereas FOXL2 was more commonly positive in stromal elements versus sex cord elements (100% vs. 55%) when excluding Leydig cell tumors from the stromal category. Although no individual stain was diagnostically specific, some immunophenotypic patterns were noted that may help in the subclassification of SCSTs. We conclude that SOX9, FOXL2, and SF-1 are useful immunohistochemical stains for confirming sex cord-stromal differentiation in testicular tumors and provide increased sensitivity as well as additional diagnostic information, especially when combined with the more commonly used inhibin α, calretinin, and WT1 immunostains. Although morphology is paramount for subclassification of SCSTs, knowledge of certain immunohistochemical patterns may be helpful for diagnostically challenging cases.

Background Liquid biopsy using cell-free DNA (cfDNA) presents new opportunities for solid tumor genotyping. While studies have demonstrated the utility of cfDNA from plasma, cfDNA from other body fluids remains underexplored. Methods We evaluated the molecular features and clinicopathologic correlates of cfDNA from serous body cavity fluids by performing hybrid capture-based next-generation sequencing (NGS) on cfDNA isolated from residual effusion supernatants. Twenty-one serous effusions from pleural (n = 15), peritoneal (n = 5), and pericardial (n = 1) cavity were analyzed. Results The supernatants provided a median cfDNA concentration of 10.3 ng/µL. Notably, all effusions were sequenced successfully to a median depth >1000×, revealing a broad range of genetic alterations including single nucleotide variants, small insertions and deletions, amplifications, and fusions. Specifically, pathogenic alterations were identified in all malignant fluids (13/13), all fluids suspicious for malignancy (2/2), and 1 benign fluid (1/6) from a patient with metastatic cancer. To validate our findings, we examined matching results from 11 patients who underwent additional testing using formalin-fixed, paraffin-embedded (FFPE) specimens. In 8 patients, the paired results between FFPE and supernatant testing were concordant, whereas in the remaining 3 patients, supernatant analysis identified additional variants likely associated with resistance to targeted therapies. Additional comparison between FFPE and supernatant testing showed no difference in DNA concentration (P = .5), depth of coverage (P = .6), or allele frequency of pathogenic mutations (P = .7). Conclusion cfDNA isolated from serous body cavity fluids represents a promising source of genomic input for targeted NGS.

A wide range of bacteria possess virulence factors such as aminoacyl-tRNA transferases (ATTs) that are capable of rerouting aminoacyl-transfer RNAs away from protein synthesis to conjugate amino acids onto glycerolipids. We recently showed that, although these pathways were thought to be restricted to bacteria, higher fungi also possess ergosteryl-3β-O-L-aspartate synthases (ErdSs), which transfer the L-Asp moiety of aspartyl-tRNA

Squamous cell carcinoma (SCC) of the prostate is a rare and clinically aggressive entity that may arise de novo or through transformation of prostatic adenocarcinoma, typically following hormonal or radiation therapy. Confirmation of prostatic origin, especially when evaluating a metastatic focus, often requires correlation with clinical and imaging findings, as the morphologic and immunohistochemical features of SCC are not organ-specific. Comprehensive genomic profiling (CGP) may provide additional information useful for confirming the primary site and for identifying potential targeted therapy options. CGP data may also contribute to our understanding of the molecular basis of squamous differentiation in prostatic malignancies. However, these data are limited, and to our knowledge, there are only three previously published cases of prostatic SCC with reported CGP findings. Herein, we report a case of metastatic keratinizing SCC diagnosed by core needle biopsy in a 68-year-old man with a history of prostatic adenocarcinoma status post radical prostatectomy and androgen deprivation therapy (ADT). NKX3.1 immunohistochemistry was negative. CGP was performed, and a TMPRSS2-ERG fusion, among other genetic alterations, was detected, supporting a diagnosis of metastatic SCC transformed from prostatic adenocarcinoma following ADT. This case supports the use of CGP or other molecular techniques not only to query potential targeted therapy options but also to refine the diagnosis and confirm the primary site of disease in cases with non-specific morphologic and immunophenotypic features, such as SCC.

Background Fine‐needle aspiration with flow cytometry (FNA‐FC) is routinely used in the evaluation of lymph nodes suspicious for lymphoma, yet data comparing immunophenotype distributions and outliers in benign lymph nodes sampled by fine‐needle aspiration (FNA) versus excision are lacking. Methods Flow cytometry data from 289 benign lymph node FNA cases were assessed for the overall antigen distribution, with a focus on outliers relevant to the diagnosis of lymphoma. Distributions and outlier proportions were compared with those of a separate cohort of 298 excisional biopsies. Results Compared with excisional biopsies, FNA specimens overrepresented CD3+ events (72% vs 63%), underrepresented CD19+ events (22% vs 29%), and had 25% fewer large cell–gated events. Normalized antigen distributions in FNA were equivalent to those in excisional biopsy. Twenty‐three percent of FNA‐FC cases exhibited an outlier, including a skewed kappa:lambda light‐chain ratio, increased CD5+ or CD10+ B‐cell events, a skewed CD4:CD8 ratio, and increased CD7 loss on T cells, with no significant differences in frequency or type in comparison with excisional specimens. Outliers for the light‐chain ratio and T‐cell antigens were enriched among older patients and included patients with a variety of autoimmune/rheumatologic conditions. Conclusions Benign lymph node FNA yields flow immunophenotypes remarkably similar to those from excisional biopsies. Outlier flow immunophenotypes are identified in benign lymph nodes sampled by FNA at a frequency similar to that with excisional biopsies. Older patients, who have a higher baseline risk of lymphoma, are more likely to exhibit lymphoma‐mimicking outliers such as a light‐chain predominance on B cells and skewed CD4:CD8 ratios or increased CD7 loss on T cells, and they warrant additional diagnostic caution., Fine‐needle aspiration–based flow cytometry of lymph nodes is comparable to excisional biopsy and exhibits similar outliers. The reference ranges provided in this study can aid pathologists and contribute in the long term to computational flow analysis and biomedical research.

It has been recently suggested that fluency may impact recognition memory performance when the fluency context varies from trial-to-trial. Surprisingly, such an effect has proved difficult to detect in the masked priming paradigm, one of the most popular means to increase fluency-based memory judgements. We conducted a functional magnetic resonance imaging (fMRI) experiment in which participants encoded words at study and, at test, performed a recognition memory task within a masked priming procedure. In order to optimise the chances of finding priming effects on recognition memory performance, we used low-frequency words, which have been shown to increase hits relative to false alarms and enhance masked priming effects. Fluency context was manipulated by either mixing primed and unprimed trials [Random context (RC) experiment] or blocking primed and unprimed trials [Blocked context (BC) experiment]. Behaviourally, priming affected high-confidence memory performance only in the RC experiment. This behavioural effect correlated positively with neural priming in several recognition memory regions. Moreover, we observed a functional coupling between the left middle temporal gyrus and the left parietal and posterior cingulate cortices that was greater for primed relative to unprimed words. In contrast, in the BC experiment, despite similar activity in recognition-memory-related regions, we did not find any significant correlations between neural and behavioural priming. Finally, we observed striking differences in the neural correlates of masked priming between the RC and BC experiments not only in location but also in direction of the neural response. Possible implications of these findings are discussed.

Multiple myeloma (MM) presents a poor prognosis and high lethality of patients due to development of drug resistance. P-glycoprotein (P-gp), a drug-efflux transporter, is upregulated in MM patients post-chemotherapy and is involved in the development of drug resistance since many anti-myeloma drugs (including proteasome inhibitors) are P-gp substrates. Hypoxia develops in the bone marrow niche during MM progression and has long been linked to chemoresistance. Additionally, hypoxia-inducible transcription factor (HIF-1α) was demonstrated to directly regulate P-gp expression. We found that in MM patients P-gp expression positively correlated with the hypoxic marker, HIF-1α. Hypoxia increased P-gp protein expression and its efflux capabilities in MM cells in vitro using flow cytometry. We reported herein that hypoxia-mediated resistance to carfilzomib and bortezomib in MM cells is due to P-gp activity and was reversed by tariquidar, a P-gp inhibitor. These results suggest combining proteasome inhibitors with P-gp inhibition for future clinical studies.

Associative recognition requires discriminating between old items and conjunction lures constructed by recombining elements from two different study items. This task can be solved not only by recollection but also by familiarity if the to-be-remembered stimuli are perceived as a unitized representation. In two event-related potential (ERP) studies, we provide evidence for the integration of internal and external facial features by showing that the early frontal old-new effect (considered a correlate of familiarity) is modulated by the specific combination of facial features. Participants studied faces consisting of internal features (eyes, eyebrows, nose, and mouth) paired with external features (hair, head shape, and ears). During the testing phase, intact, recombined, and new faces were presented. Recombined faces consisted of internal and external features taken from two different studied faces. The results showed that at the frontal sites, during the time window from 300 to 500 ms, ERPs to intact faces were more positive than those to new and recombined faces; the latter two did not differ from one another. The late parietal effect was observed only after a more extended study phase in Experiment 2. We take the modulation of the early frontal old-new effect as evidence for the contribution of familiarity to associative recognition for combinations of internal and external facial features.

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and recently described entity associated with hereditary leiomyomatosis and RCC syndrome. FH-deficient RCC may show variable clinical and pathologic findings, but commonly presents with locally advanced and metastatic disease and carries a poor prognosis. We identified 32 patients with FH-deficient RCC, confirmed by FH immunohistochemistry (IHC) and/or FH mutation analysis, and performed a retrospective review of the clinical and pathologic features. Median age at presentation was 43 years (range, 18 to 69 y), and the M:F ratio was 2.2:1. Median tumor size was 6.5 cm (range, 2.5 to 28 cm), and 71% presented at stage ≥pT3a. After a median follow-up of 16 months (range, 1 to 118 mo) in 26 patients, 19% showed no evidence of disease, 31% were alive with disease, and 50% were dead of disease. The vast majority of cases showed multiple histologic growth patterns, with papillary (52%) being the most common predominant pattern, followed by solid (21%), cribriform/sieve-like (14%), sarcomatoid (3%), tubular (3%), cystic (3%), and low-grade oncocytic (3%). Viral inclusion-like macronucleoli with perinucleolar clearing were present in almost all cases (96%). All cases were evaluated using FH IHC, and 3 cases (9%) showed retained FH expression. Nineteen cases had germline or tumor mutation analysis confirming a FH mutation, with 79% (11/14) of cases showing mutations within coding regions and 21% (3/14) showing mutations within intronic splice-sites. By IHC, 97% (32/33) of cases were negative for CK7, 93% (27/29) were negative for p63, and 52% (15/29) were negative for GATA3. All cases stained were positive for PAX8 and showed retained succinate dehydrogenase B expression. Our overall findings show that FH-deficient RCC is considerably heterogenous in morphology and frequently behaves aggressively. Suspicion for this entity should be raised even in the absence of predominantly papillary architecture and characteristic nucleolar features. We have included cases with uncommonly seen features, including 4 cases with predominantly cribriform/sieve-like architecture as well as one case with pure low-grade oncocytic morphology (9 y of clinical follow-up without evidence of disease). Although FH IHC is a useful tool for identifying cases of FH-deficient RCC, not all cases of FH-deficient RCC show loss of FH staining, and FH mutation analysis should be considered for patients with suspicious clinical or pathologic features, even in cases with retained FH IHC expression.

Cognitive control is supported by a dynamic interplay of transient (i.e., trial-related) brain activation across fronto-parietal networks and sustained (i.e., block-related) activation across fronto-striatal networks. Older adults show disturbances in this dynamic functional recruitment. There is evidence suggesting that cognitive-control training may enable older adults to redistribute their brain activation across cortical and subcortical networks, which in turn can limit behavioral impairments. However, previous studies have only focused on spatial rather than on temporal aspects of changes in brain activation. In the present study, we examined training-related functional plasticity in old age by applying a hybrid fMRI design that sensitively tracks the spatio-temporal interactions underlying brain-activation changes. Fifty healthy seniors were assigned to a task-shifting training or an active-control group and their pretest/posttest activation-change maps were compared against 25 untrained younger adults. After training, older adults showed the same performance as untrained young adults. Compared to the control group, task-shifting training promoted proactive (i.e., early, cue-related) changes in transient mechanisms supporting the maintenance and top-down biasing of task-set representations in a specific prefrontal circuitry; reactive (i.e., late, probe-related) changes in transient mechanisms supporting response-selection processes in dissociable fronto-parietal networks; overall reductions of sustained activation in striatal circuits. Results highlight the importance of spatio-temporal interactions in training-induced neural changes in age.

Recognition memory judgments can be influenced by a variety of signals including fluency. Here, we investigated whether the neural correlates of memory illusions (i.e., misattribution of fluency to prior study) can be modulated by fluency context. Using a masked priming/recognition memory paradigm, we found memory illusions for low confidence decisions. When fluency varied randomly across trials, we found reductions in perirhinal cortex (PrC) activity for primed trials, as well as a (pre)cuneus-PrC (BA 35) connectivity. When the fluency context was unchanging, there was increased PrC activity for primed trials, with the (pre)cuneus showing greater connectivity with PrC (BA 36). Thus, our results tentatively suggest two neural mechanisms via which fluency can lead to memory illusions.

In contrast to long-term memory, age-related association deficits in working memory are found only inconsistently. The authors hypothesized that type of binding is critical for the occurrence of such deficits. Relational binding abilities (associating separate visual units) should degrade with age, whereas more automatic conjunctive binding abilities (associating features within an object) should not. They contrasted associative memory and item memory using a change-detection task with colors and shapes in younger (18-33 years) and older (64-82 years) healthy adults. Color was either a surface feature of the shape (conjunctive binding) or a feature of a shape-external frame (relational binding). In a direct test of associative memory, participants memorized color-shape associations; in an indirect item memory test, participants were required to memorize only the shapes, and the authors measured the costs of ignoring task-irrelevant color changes from study to test. In the direct test, associative memory was poorer when relational binding was required rather than conjunctive binding, and associative memory was poorer in the older group, but no age-related association deficit was apparent. In the indirect test, by contrast, type of binding interacted with age: younger participants showed study-test congruence effects independent of the type of binding, but older adults showed enhanced congruence effects for conjunctive stimuli, indicating intact or even enhanced conjunctive binding, and practically no costs for relational stimuli, indicating poor relational binding. This stimulus-specific effect of a task-irrelevant feature change indicates that relational and conjunctive binding in working memory are differently affected by healthy aging. (PsycINFO Database Record

BACKGROUND The classification of renal neoplasms is essential for oncologic risk stratification and clinical management, and an accurate pretreatment pathologic diagnosis can provide useful guidance for active surveillance, minimally invasive ablative therapy, or surgical resection and can reduce the incidence of overtreatment. Previous studies evaluating the diagnostic accuracy of fine-needle aspiration (FNA) and core-needle biopsy (CNB) for renal masses are limited and show variable results. METHODS Two hundred forty-seven renal FNA cases with or without concurrent CNB performed and/or reviewed at the Stanford University School of Medicine over the course of 20 years were identified. Cytohistopathologic correlation was performed for 77 cases with subsequent resection specimens. All available case materials were reviewed, and select cases were worked up further and reclassified as necessary. RESULTS Cytohistopathologic correlation showed 96% diagnostic specificity and 83% sensitivity for renal FNA with or without concurrent CNB. Discordant cases were mostly attributed to sampling errors or suboptimal specimens (79%) and also included 2 non-renal cell carcinoma entities (1 case of angiomyolipoma and 1 case of a benign peripheral nerve sheath tumor) and 1 case involving misclassification of the renal cell carcinoma subtype. CONCLUSIONS There is considerable value in FNA/CNB for the initial diagnosis of renal masses because of the high diagnostic specificity and sensitivity. Sensitivity is predominantly dependent on sufficient sampling, and additional potential diagnostic pitfalls include nonepithelial and rare entities. Judicious use of ancillary techniques is encouraged, especially when one is presented with a limited specimen, and this article presents a practical algorithmic approach to the diagnosis of renal masses using salient morphologic features and results from ancillary studies. Fine-needle aspiration is an accurate method for the diagnosis of renal masses. A practical diagnostic algorithm, based on salient morphologic and ancillary findings, is presented.

Introduction CD13 is a myeloid associated antigen, which may be expressed by a subset of B cell lymphomas; however, the significance of its expression along with other B cell associated antigens is not well characterized. Methods Two hundred and eighty-six mature B cell neoplasms with flow cytometric analysis performed at the time of diagnosis were identified. Expression of CD13, CD45, CD19, CD20, CD5, CD10, CD38, CD22, CD23, FMC7, and kappa and lambda light chains was assessed for each case and correlated with clinicopathologic features. Results CD13 expression was associated specifically with cases of lymphoplasmacytic lymphoma (LPL) (16/26)- and FMC7-positive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (11/30). No cases of follicular lymphoma (FL) expressed CD13 (0/48). Across all B cell neoplasms, CD13 expression positively correlated with FMC7 co-expression and kappa light chain restriction and negatively correlated with CD10 co-expression and lambda light chain restriction. No significant association of CD13 with overall or disease free survival in B cell neoplasms was seen. Conclusion CD13 expression is present more often in LPL- and FMC7-positive CLL/SLL than other mature B cell lymphoma subtypes and absent in cases of FL and may be a useful feature for diagnostic subtyping.

The right cerebral hemisphere (RH) appears to be more effective in representing visual objects as distinct exemplars than the left hemisphere (LH) which is presumably biased towards coding objects at the level of abstract prototypes. As of yet, relatively little is known about the role that asymmetries in exemplar-specificity play at the level of explicit memory retrieval. In the present study, we addressed this issue by examining hemispheric asymmetries in the putative event-related potential (ERP) correlates of familiarity (FN400) and recollection (LPC). In an incidental study phase, pictures of familiar objects were presented centrally. At test, participants performed a memory inclusion task on identical repetitions and different exemplars of study items as well as new items which were presented in only one visual hemifield using the divided visual field technique. With respect to familiarity, we observed exemplar-specific FN400 old/new effects that were more pronounced for identical repetitions than different exemplars, irrespective of the hemisphere governing initial stimulus processing. In contrast, LPC old/new effects were subject to some hemispheric asymmetries indicating that exemplar-specific recollection was more extensive in the RH than in the LH. This further corroborates the idea that hemispheric asymmetries should not be generalized but need to be distinguished not only in different domains but also at different levels of processing.

Episodic memory declines during healthy aging, with a particular reduction in the ability to encode associations. We investigated the role of alternating attentional focus between two items of a pair in order to generate associative links, as well as working memory based elaborative processes in this age-related memory deficit. While their eye gaze behavior and ERPs were recorded, 19 young and 22 elderly (64–79 years) participants used interactive imagery to encode pairs of spatially separated objects. In a subsequent recognition test, older adults showed a larger reduction in associative than item memory, relative to young adults. For both age groups the number of eye gaze transitions between objects at encoding was correlated with associative recognition performance, suggesting that alternating attentional focus between items aids the generation of relational links necessary to encode associative memories. However, the relative time course of eye gaze transitions over the encoding interval for trials that were subsequently retrieved vs. forgotten differed between age groups. Furthermore, the ERPs of older adults exhibited strongly reduced frontal slow wave “subsequent memory effects”, suggesting that they engaged to a lesser extent in working memory-based elaboration of the associative link. Based on these results, we propose that older adults exhibit a reduced tendency to generate and elaborate on internal representations of inter-item associative links. Rather, they use a less effective encoding strategy that disproportionally relies on the external stimulus display, resulting in lower associative memory performance.

It is still unclear which role the right hemisphere (RH) preference for perceptually specific and the left hemisphere (LH) bias towards abstract memory representations play at the level of episodic memory retrieval. When stimulus characteristics hampered the retrieval of abstract memory representations, these hemispheric asymmetries have previously only modulated event-related potential (ERP) correlates of recollection (late positive complex, LPC), but not of familiarity (FN400). In the present experiment, we used stimuli which facilitated the retrieval of abstract memory representations. With the divided visual field technique, new items, identical repetitions and color-modified versions of incidentally studied object pictures were presented in either the right (RVF) or the left visual field (LVF). Participants performed a memory inclusion task, in which they had to categorize both identically repeated and color-modified study items as ‘old’. Only ERP, but not behavioral data showed hemispheric asymmetries: Compared to identical repetitions, FN400 and LPC old/new effects for color-modified items were equivalent with RVF/LH presentation, but reduced with LVF/RH presentation. By promoting the use of abstract stimulus information for memory retrieval, we were thus able to show that hemispheric asymmetries in accessing abstract or specific memory representations can modulate ERP correlates of familiarity as well as recollection processes.

Chronic hepatitis B infection (HBV) is major cause of morbidity and mortality throughout the world. Currently there is limited understanding on the cellular proteins and related molecules involved in the critical steps of viral entry into the cytoplasm and persistent viral replication in cell culture. In order to address these fundamental questions, we designed and implemented a new model of hepatitis B: infectious transgenic hepatitis B virus composed of a complete virus plus a foreign gene. The foreign gene allows identification of cells that are infected by the transgenic virus. The transgenic virus was used in a functional assay to identify cellular proteins necessary for viral replication. This assay repeatedly identified the protein UQCR10. After restoring UQCR10 levels in HepG2 and Huh7 cells, they can be infected by intact virions of transgenic hepatitis B. These results demonstrate the usefulness of this new transgenic hepatitis B model.

Previous studies have shown that we need to distinguish between means and end information about actions. It is unclear how these two subtypes of action information relate to each other with theoretical accounts postulating the superiority of end over means information and others linking separate means and end routes of processing to actions of differential meaningfulness. Action meaningfulness or familiarity differs between cultures. In a cross-cultural setting, we investigated how action familiarity influences recognition memory for means and end information. Object directed actions of differential familiarity were presented to Chinese and German participants. Action familiarity modulated the representation of means and end information in both cultures in the same way, although the effects were based on different stimulus sets. Our results suggest that, in the representation of actions in memory, end information is superordinate to means information. This effect is independent of culture whereas action familiarity is not.

For mental rotation, introspection, theories, and interpretations of experimental results imply a certain type of mental representation, namely, visual mental images. Characteristics of the rotated representation can be examined by measuring the influence of stimulus characteristics on rotational speed. If the amount of a given type of information influences rotational speed, one can infer that it was contained in the rotated representation. In Experiment 1, rotational speed of university students (10 men, 11 women) was found to be influenced exclusively by the amount of represented orientation-dependent spatial-relational information but not by orientation-independent spatial-relational information, visual complexity, or the number of stimulus parts. As information in mental-rotation tasks is initially presented visually, this finding implies that at some point during each trial, orientation-dependent information is extracted from visual information. Searching for more direct evidence for this extraction, we recorded the EEG of another sample of university students (12 men, 12 women) during mental rotation of the same stimuli. In an early time window, the observed working memory load-dependent slow potentials were sensitive to the stimuli's visual complexity. Later, in contrast, slow potentials were sensitive to the amount of orientation-dependent information only. We conclude that only orientation-dependent information is contained in the rotated representation. (PsycINFO Database Record (c) 2013 APA, all rights reserved).

Elderly people do not categorize emotional facial expressions as accurately as younger people, particularly negative emotions. Although age-related impairments in decoding emotions in facial expressions are well documented, the causes of this deficit are poorly understood. This study examined the potential mechanisms that account for this age-related categorization deficit by assessing its dependence on presentation time.Thirty young (19-27 years old) and 31 older (68-78 years old) Chinese adults were asked to categorize the six basic emotions in facial expressions, each presented for 120, 200, 600, or 1000 ms, before and after exposure to a neutral facial expression.Shortened presentation times caused an age-related deficit in the recognition of happy faces, whereas no deficit was observed at longer exposure times. An age-related deficit was observed for all negative emotions but was not exacerbated by shorter presentation times.Age-related deficits in categorization of positive and negative emotions are caused by different mechanisms. Because negative emotions are perceptually similar, they cause high categorization demands. Elderly people may need more evidence in favor of the target emotion than younger people, and they make mistakes if this surplus of evidence is missing. In contrast, perceptually distinct happy faces were easily identified, and elderly people only failed when the presentation time was too short for their slower perceptual processing.

Object recognition is a central human ability. In everyday life, the conditions under which objects have to be recognized are usually not perfect. Often, viewing conditions change in between two encounters with an object; typical are changes in illumination or in the object-observer distance. With such changes, object recognition sometimes feels slightly delayed. We examined this phenomenon empirically by measuring the latency of the well-established electrophysiological correlate of recollection, the late posterior component (LPC), in an object-recognition task. Although the cognitive processes underlying successful recognition are well examined, thus far the consequences of changed viewing conditions on the timing of these processes have not been investigated. The ERP technique is well suited for investigating this question, because it allows differentiating between processes contributing to recognition times (in particular, recollection from familiarity as indexed by the FN400 component) and measuring their time course with high temporal precision. In the present study, participants' task was to differentiate previously studied (old) objects from a set of new objects. Viewing conditions for old objects changed slightly, changed strongly, or remained identical between learning and test. We found that the latency of the LPC in response to an old object was delayed whenever viewing conditions changed. Moreover, this delay in LPC latency scaled with the size of the change. These effects were absent for the FN400. This is the first examination of effects of changes in viewing conditions on the latency of recollection and the first dissociation of FN400 and LPC latencies.

Despite the significant therapeutic advances achieved with proteasome inhibitors (PIs) such as bortezomib and carfilzomib in prolonging the survival of patients with multiple myeloma, the development of drug resistance, peripheral neuropathy, and pharmacokinetic limitations continue to pose major challenges when using these compounds. Ixazomib is a second-generation PI with improved activity over other PIs. Unlike bortezomib and carfilzomib, which are administered by injection, ixazomib is the first oral PI approved by US Food and Drug Administration. This review discusses the biochemical properties, mechanisms of action, preclinical efficacy, and clinical trial results leading to the US Food and Drug Administration approval of ixazomib.

In this training study, we aimed to selectively train participants' filtering mechanisms to enhance visual working memory (WM) efficiency. The highly restricted nature of visual WM capacity renders efficient filtering mechanisms crucial for its successful functioning. Filtering efficiency in visual WM can be measured via the lateralized change detection task with distractors. From an array of items, only a subsample must be memorized (targets), whereas distractors must be filtered out. From the EEG recorded while items are maintained in memory, slow potentials over posterior recording sides can be extracted. In addition, the contralateral delay activity (CDA) can be calculated as the difference wave between contralateral and ipsilateral slow potentials. As the amplitudes of contralateral slow potentials and CDA reflect the number of remembered items, one can infer if distractors were filtered out. Efficient filtering mechanisms are also highly important in multiple object tracking (MOT). We trained participants' filtering ability with the aid of this latter task. Filtering in both tasks is assumed to happen via allocation of selective attention. We observed large training-induced improvements in MOT. However, these improvements did not transfer to improved filtering mechanisms in the change detection task. Instead, we obtained suggestive evidence for an overall improvement in filtering mechanisms in the change detection task for both the training and control group. Apparently, there exist differences in the exact nature of filtering mechanisms that operate in change detection and MOT.

Stimulus material for studying object-directed actions is needed in different research contexts, such as action observation, action memory, and imitation. Action items have been generated many times in individual laboratories across the world, but they are used in very few experiments. For future studies in the field, it would be worthwhile to have a larger set of action stimulus material available to a broader research community. Some smaller action databases have already been published, but those often focus on psycholinguistic parameters and static action stimuli. With this article, we introduce an action database with dynamic action stimuli. The database contains action descriptions of 1,754 object-directed actions that have been rated for familiarity in Germany and in China. For 784 of these actions, action video clips are available. With the use of our database, it is possible to identify actions that differ in familiarity between Western and Eastern cultures. This variable may be of interest to some researchers in the field, since it has been shown that familiarity influences action information processing. Action descriptions are listed and categorized in tables that can be downloaded, along with the corresponding video clips, as supplemental material.

The present ERP study investigated the retrieval of task-irrelevant exemplar-specific information under implicit and explicit memory conditions. Subjects completed either an indirect memory test (a natural/artificial judgment) or a direct recognition memory test. Both test groups were presented with new items, identical repetitions, and perceptually different but conceptually similar exemplars of previously seen study objects. Implicit and explicit memory retrieval elicited clearly dissociable ERP components that were differentially affected by exemplar changes from study to test. In the indirect test, identical repetitions, but not different exemplars, elicited a significant ERP repetition priming effect. In contrast, both types of repeated objects gave rise to a reliable old/new effect in the direct test. The results corroborate that implicit and explicit memory fall back on distinct cognitive representation and, more importantly, indicate that these representations differ in the type of stimulus information stored. Implicit retrieval entailed obligatory access to exemplar-specific perceptual information, despite its being task irrelevant. In contrast, explicit retrieval proved to be more flexible with conceptual and perceptual information accessed according to task demands.

We investigated whether the expertise of a perceiver and the physical complexity of a stimulus influence consolidation of visual short-term memory (VSTM) in a S1–S2 (Stimulus 1–Stimulus 2) change detection task. Consolidation is assumed to make transient perceptual representations in VSTM more durable, and it is investigated by postexposure of a mask shortly after offset of the perceived stimulus (S1; 17 to 483 ms). We presented colours, Chinese characters, pseudocharacters, and novel symbols to novices (Germans) or experts of Chinese language (Chinese readers). Physical complexity was manipulated by the number of strokes. Unfamiliar material was remembered worse than familiar material (Experiments 1, 2, and 3). For novices the absolute VSTM performance was better for physically simple than for complex material, whereas for experts the complexity did not matter—Chinese readers memorized Chinese characters (Experiment 3). Articulatory suppression did not change these effects (Experiment 2). We always observed a strong effect of SOA, but this effect was influenced neither by physical complexity nor by expertise; only the length of the interstimulus interval between S1 and the mask was relevant. This was observed even with short stimulus onset asynchrony (SOA) of 100 ms (Experiment 2) and in comparing colours and characters (Experiment 5). However, masks impaired memory if they were presented at the locations of the to-be-memorized items, but not beside them—that is, interference was location-based (Experiment 6). We explain the effect of SOA by the assumption that it takes time to stop encoding of information presented at item locations with the offset of S1. The increasing resistance against interference by irrelevant material appears as consolidation of S1.

The time taken to decide whether a character is shown in its mirror or normal version has been shown to increase approximately linearly with the angular departure from an up-right position. Additionally, in some studies, decisions took longer for clockwise tilted characters than for counterclockwise tilted ones. Other studies do not report the latter effect. We argue that inconsistencies across studies are caused by variance in participants' strategies. The task employed here was specifically designed to bring these strategies and thereby the direction of rotation under experimental control. From the EEG recorded during the rotation period, we extracted an event-related slow potential whose amplitude is sensitive to the amount of mental rotation. In both strategy conditions, the slow potential's amplitude was lower for clockwise than for counterclockwise rotations. We take this as evidence that mental rotation of alphanumeric characters is easier in a clockwise than in a counterclockwise direction.

Research on the effects of perceptual manipulations on recognition memory has suggested that (a) recollection is selectively influenced by task-relevant information and (b) familiarity can be considered perceptually specific. The present experiment tested divergent assumptions that (a) perceptual features can influence conscious object recollection via verbal code despite being task-irrelevant and that (b) perceptual features do not influence object familiarity if study is verbal-conceptual. At study, subjects named objects and their presentation colour; this was followed by an old/new object recognition test. Event-related potentials (ERP) showed that a study-test manipulation of colour impacted selectively on the ERP effect associated with recollection, while a size manipulation showed no effect. It is concluded that (a) verbal predicates generated at study are potent episodic memory agents that modulate recollection even if the recovered feature information is task-irrelevant and (b) commonly found perceptual match effects on familiarity critically depend on perceptual processing at study.

Within dual-process accounts of recognition memory, familiarity (as opposed to recollection) is often referred to as a rather automatic and context-free process. Thus, in episodic object recognition, familiarity and its electrophysiological ERP signature are supposed to index prior occurrence of an object independent of the context the object was originally encountered in, e.g., [Ecker, U.K.H., Zimmer, H.D., Groh-Bordin, C., in press. Color and context: An ERP study on intrinsic and extrinsic feature binding in episodic memory. Mem. Cogn.]). Yet, contextual sensitivity of familiarity has also been reported (e.g., [Tsivilis, D., Otten, L.J., Rugg, M.D., 2001. Context effects on the neural correlates of recognition memory: An electrophysiological study. Neuron 31, 497-505.]). We argue that considering attentional and perceptual factors of target processing is vital in understanding these conflicting results. Presenting target objects on contextual landscape scenes, we introduced a cueing technique designed to focus subjects' attention on target processing. We demonstrate that context effects on familiarity are diminished if the attentional impact of contextual stimuli is experimentally controlled, arguing that contextual influences on object familiarity are indirect and mediated by factors such as salience and attentional capture. Results suggest that salient context stimuli may elicit an independent familiarity signal instead of directly impacting on the familiarity signal of the target object. We conclude that (a) object familiarity is in principle a rather automatic and context-free process, and that (b) the study of episodic memory can profit substantially from adopting a dynamic processing perspective.

PurposeCoronary artery aneurysms (CAA) may remain silent after Kawasaki disease (KD) until adulthood when myocardial ischemia can lead to sudden death. We postulated that there would be young adults with sudden, unexpected death due to CAA from KD who would have a state-mandated autopsy performed by the San Diego County Medical Examiner's Office (SDCMEO).MethodsWe reviewed all autopsy cases

Visual working memory (WM) has a very limited online capacity making it considerably important to control the gating of encoding into WM. Recent studies have suggested that attention control is of importance in doing so, especially the time needed to disengage. However, the disengagement mechanism operates on a later stage of processing after the initial selection of information has already been initiated. We assume that individual differences in WM capacity are also driven by individual variations in the voluntary engagement of attention. In 2 experiments we investigated whether individuals with high- and low-WM capacity differ in the efficiency and speed of this attention control process. We realised different versions of the task in which different amounts of attention control were necessary, a more automatically triggered allocation of attention and a voluntary initiation of attention engagement, respectively. We further manipulated the time course to look for differences in the latency of attention control. The results revealed that participants with low-WM capacity were less effective to exhibit voluntary attention control processes and they were also slower in doing so compared with high-WM capacity individuals. However, this effect seems to be partly moderated by the ability to update the current task set. If the trial structure did not require task set updating smaller individual differences involving WM capacity could be found.Keywords: working memory capacity, attention control, individual differencesResumeLa memoire de travail (MT) visuelle dispose de capacites tres limitees en ligne. Il devient alors tres important de controler l'encodage selectif dans la MT. Les recentes etudes ont montre que le controle de l'attention joue un role important, particulierement au niveau du temps relie au desengagement. Or, le mecanisme de desengagement se produit a un stade ulterieur du traitement, c'est-a -dire une fois que la premiere selection de l'information a ete initiee. Nous emettons l'hypothese que les differences individuelles au niveau de la capacite de la MT sont egalement le resultat de variations individuelles au niveau de l'engagement volontaire de l'attention. A l'aide de deux experiences, nous avons cherche a savoir si les individus dotes d'une faible capacite de MT et d'une forte capacite de MT divergeaient en ce qui a trait a l'efficacite et a la vitesse de ce procede de controle de l'attention. Nous avons realise differentes versions de la tâche selon lesquelles differents niveaux de controle d'attention etaient requis, une attribution de l'attention davantage declenchee de maniere automatique et une initiation volontaire de l'engagement de l'attention, respectivement. Nous avons ensuite manipule la duree afin de detecter des ecarts au niveau du temps de latence du controle d'attention. Les resultats ont montre que les participants dotes d'une faible capacite de MT etaient moins efficaces a afficher les procedes de controle d'attention volontaire et le faisaient plus lentement comparativement aux individus dotes de forte capacite de MT. Cet effet semble toutefois partiellement modere par la capacite de mise a jour de l'ensemble de tâches actuel. Si la structure de l'essai ne necessitait pas la mise a jour de l'ensemble de tâches, des ecarts individuels plus faibles impliquant la capacite de MT pourraient etre detectes.Mots-cles : capacite de la memoire de travail, controle de l'attention, ecarts individuels.Human visual working memory (WM) is a form of online work space that keeps about three to four objects in an accessible state. The first notion of the term WM goes back to Baddeley and Hitch in the 1970s (Baddeley & Hitch, 1974). They highlighted that WM is more than a passive store for the temporary maintenance of information (see immediate memory, Miller, 1956) but a component that actively maintains, manipulates, and updates attended items. Hence, WM is a cognitive system that allows more than retaining information over a period of time. …

A series of experiments compared short-term memory for object locations in the auditory and visual modalities. The stimulus materials consisted of sounds and pictures presented at different locations in space. Items were presented in pure- or mixed-modality lists of increasing length. At test, participants responded to renewed presentation of the objects by indicating their original position. If two independent modality-specific and resource-limited short-term memories support the remembering of locations, memory performance should be higher in the mixed-modality than in the pure-modality condition. Yet, memory performance was the same for items in both types of list. In addition, responses to the memory load manipulation in both modalities showed very similar declines in performance. The results are interpreted in terms of object files binding object and location information in episodic working memory, independently of the input modality.

A major debate in the mental-rotation literature concerns the question of whether objects are represented holistically during rotation. Effects of object complexity on rotational speed are considered strong evidence against such holistic representations. In Experiment 1, such an effect of object complexity was markedly present. A closer look on individual performance patterns, however, revealed that only some participants showed this effect. For others, rotational speed was independent of object complexity. The assumption that these fast-rotating participants use a holistic representation that equally well holds simple and complex objects would explain these results. Taking error rates into account disproved this explanation: Fast participants simply committed more errors in those conditions for which careful participants invested more rotation time. Whether this speed-accuracy trade-off is a stable personality trait or a somewhat flexible strategic choice was examined in Experiments 2 and 3. In Experiment 2, participants received monetary incentives that encouraged them to minimize errors. In line with a certain degree of flexible strategic control over speed-accuracy trade-offs, a large majority of participants showed effects of object complexity on rotational speed. When, in contrast, time pressure was induced in Experiment 3, error rates increased considerably and most participants' rotational speed became independent of object complexity. Our results indicate that all our participants performed mental rotation on a nonholistic representation and that apparent holistic processing strategies in mental rotation (and potentially also in other spatial tasks) might actually be speed-accuracy trade-offs in disguise.

It is argued that explicit remembering is based on so-called episodic tokens binding together all perceptual features of a visual object. In episodic recognition, these features are collectively reactivated. In support of this view, it has been shown that changing sensory features of a stimulus from study to test decreases subject's performance in an episodic recognition task, even though the changed features are irrelevant for the recognition judgment. On the other hand, repetition priming is unaffected by such manipulations of perceptual specificity. Implicit memory performance is therefore thought to depend on structural representations, so-called types, comprising only invariant perceptual features, but no exemplar-specific details. Event-related potentials (ERPs) in our study revealed electrophysiological evidence for the differential involvement of these perceptual memory traces in explicit and implicit memory tasks. Participants attended either a living-nonliving task or an episodic recognition task with visually presented objects. During test both groups of participants processed new objects and old objects, which were repeated either identically or in a mirror-reversed version. In the implicit task ERPs showed an occipitoparietal repetition effect, which was the same for identically repeated items and mirror reversals. In contrast, in the explicit task an early mid-frontal old/new effect for identical but not for mirror-reversed old objects was observed indicating involuntary access to perceptual information during episodic retrieval. A later portion of the old/new effect solely differentiated both types of old items from new ones.

If configurations of objects are presented in a S1-S2 matching task for the identity of objects a spatial mismatch effect occurs. Changing the (irrelevant) spatial layout lengthens response times. We investigated what causes this effect. We observed a reliable mismatch effect that was not influenced by a secondary task during maintenance. Neither articulatory suppression (Experiment 1), nor unattended (Experiments 2 and 6) or attended visual material (Experiment 3) reduced the effect, and this was independent of the length of the retention interval (Experiment 6). The effect was also rather independent of the visual appearance of the local elements. It was of similar size with color patches (Experiment 4) and with completely different surface information when testing was cross modal (Experiment 5), and the name-ability of the global configuration was not relevant (Experiments 6 and 7). In contrast, the figurative similarity of the configurations of S1 and S2 systematically influenced the size of the spatial mismatch effect (Experiment 7). We conclude that the spatial mismatch effect is caused by a mismatch of the global shape of the configuration stored together with the objects of S1 and not by a mismatch of templates of perceptual records maintained in a visual cache.

Enacting action phrases in subject-performed tasks (SPTs) leads to better free recall than hearing or reading the same materials in verbal tasks (VTs). This enactment effect is usually explained by better item-specific information in SPTs than in VTs. The role of relational information is controversial. In the present paper, we will take the multiple recall approach to study the role of item and relational information in memory for actions by computing the number of item gains and the number of item losses over trials. This approach has previously been applied to lists of unrelated action phrases. We applied it to categorically related lists, also allowing a measure of relational information by clustering scores. It was found that SPTs produced more item gains than VTs. This finding confirmed the assumption that SPTs provide better item-specific information than VTs. The number of item losses did not differ between VTs and SPTs. This finding suggests that relational information is equally provided by VTs and SPTs. However, the organizational scores showed a more differentiated picture. Clustering was greater in SPTs than in VTs with randomly presented lists, but not with blocked lists. We suggested that these results, as well as other findings from the literature, could be explained by distinguishing automatic and strategic processes and the types of item associations that are addressed by these processes.

In three experiments, we investigated the influence of the overt performance of signs on memory. Deaf and hearing participants studied lists of action phrases (Experiment 1) or nouns (Experiment 2) under standard verbal instruction, under the instructions to sign the verbal phrase, to symbolically perform the denoted action, or to carry out a prototypical action corresponding to each noun. Higher recall and recognition performances were observed when actions were performed than in the verbal encoding condition, and signing was as effective for memory as was enactment. Thus, overt signing can induce an enactment effect. In contrast, Experiment 3 demonstrated that performing an unrelated action did not. A unique but unrelated action was not memory efficient.

A new approach was taken to study the question whether the free recall advantage of enacting actions (SPT), over only listening to their verbal descriptions (VT), is due to better relational encoding of SPTs than of VTs. The approach consisted of studying related lists and manipulating the degree of relational encoding by repeated list presentation in Experiment 1 and by presenting the list items at random or blocked in Experiment 2. In both experiments, free recall and adjusted ratio of clustering (ARC) scores increased as to be expected with repeated list presentation and blocking. However, these effects proved to be independent of the type of encoding. There was a clear SPT effect in free recall, but in contrast a slight though nonsignificant advantage of VTs over SPTs in ARC scores. Altogether, the experiments show that the SPT effect in free recall is not due to better relational encoding in SPTs than in VTs, in line with the assumption that this effect is due to good item-specific encoding.

Abstract. Processing colored pictures of objects results in a preference to choose the former color for a specific object in a subsequent color choice test ( Wippich & Mecklenbräuker, 1998 ). We tested whether this implicit memory effect is independent of performances in episodic color recollection (recognition). In the study phase of Experiment 1, the color of line drawings was either named or its appropriateness was judged. We found only weak implicit memory effects for categorical color information. In Experiment 2, silhouettes were colored by subjects during the study phase. Performances in both the implicit and the explicit test were good. Selections of ”old\ colors in the implicit test, though, were almost completely confined to items for which the color was also remembered explicitly. In Experiment 3, we applied the opposition technique in order to check whether we could find any implicit effects regarding items for which no explicit color recollection was possible. This was not the case. We therefore draw the conclusion that implicit color preference effects are not independent of explicit recollection, and that they are probably based on the same episodic memory traces that are used in explicit tests.

We investigated the impact of perceptual processing demands on visual working memory of coloured complex random polygons during change detection. Processing load was assessed by pupil size (Exp. 1) and additionally slow wave potentials (Exp. 2). Task difficulty was manipulated by presenting different set sizes (1, 2, 4 items) and by making different features (colour, shape, or both) task-relevant. Memory performance in the colour condition was better than in the shape and both condition which did not differ. Pupil dilation and the posterior N1 increased with set size independent of type of feature. In contrast, slow waves and a posterior P2 component showed set size effects but only if shape was task-relevant. In the colour condition slow waves did not vary with set size. We suggest that pupil size and N1 indicates different states of attentional effort corresponding to the number of presented items. In contrast, slow waves reflect processes related to encoding and maintenance strategies. The observation that their potentials vary with the type of feature (simple colour versus complex shape) indicates that perceptual complexity already influences encoding and storage and not only comparison of targets with memory entries at the moment of testing.

Implicit memory retrieval is thought to be exemplar-specific in the right hemisphere (RH) but abstract in the left hemisphere (LH). Yet, conflicting behavioral priming results illustrate that the level at which asymmetries take effect is difficult to pinpoint. In the present divided visual field experiment, we tried to address this issue by analyzing ERPs in addition to behavioral measures. Participants made a natural/artificial decision on lateralized visual objects that were either new, identical repetitions, or different exemplars of studied items. Hemispheric asymmetries did not emerge in either behavioral or late positive complex (LPC) priming effects, but did affect the process of implicit memory retrieval proper as indexed by an early frontal negativity (N350/(F)N400). Whereas exemplar-specific N350/(F)N400 priming effects emerged irrespective of presentation side, abstract implicit memory retrieval of different exemplars was contingent on right visual field presentation and the ensuing initial stimulus processing by the LH.

Background Diabetes mellitus may be present in patients with cystic fibrosis starting in the second decade of life. The prevalence increases rapidly with increasing age. As life-expectancy increases in cystic fibrosis, cystic fibrosis related diabetes will be diagnosed more frequently in the future. Up to date, no data are available to answer the question if cystic fibrosis related diabetes should always initially be treated by insulin therapy. Missing data regarding oral antidiabetic treatment of newly diagnosed cystic fibrosis related diabetes are an important reason to recommend insulin treatment. Several centres report the successful management of cystic fibrosis related diabetes using oral anti-diabetic drugs at least for some years. Oral therapies would be less invasive for a patient group which is highly traumatized by a very demanding therapy. Based on an initiative of the German Mukoviszidosis-Foundation, the present study tries to answer the question, whether oral therapy with repaglinide is as effective as insulin therapy in cystic fibrosis patients with early diagnosed diabetes mellitus. Methods/Design In all cystic fibrosis patients with an age of 10 years or older, an oral glucose tolerance test is recommended. The result of this test is classified according to the WHO cut off values. It is required to have two diabetes positive oral glucose tolerance tests for the diagnosis of diabetes mellitus. This study is a multi-national, multicentre, open labelled, randomized and prospective controlled parallel group’s trial, with 24 months treatment. The primary objective of this trial is to compare the glycaemic control of oral therapy with Repaglinide with insulin injections in patients with cystic fibrosis related diabetes after 2 years of treatment. The trial should include 74 subjects showing cystic fibrosis related diabetes newly diagnosed by oral glucose tolerance test during annual screening for cystic fibrosis related diabetes. Patients are randomised by central fax randomisation. Primary endpoint is mean HbA1c after 24 months of treatment. Secondary endpoints are change in FEV1% predicted and change in BMI-Z-score. Discussion There is only one prospective study comparing oral antidiabetic drugs to insulin in the treatment of CFRD without fasting hyperglycaemia. The results regarding BMI after 6 months and 12 months showed an improvement for the insulin treated patients and were inconsistent for those treated with repaglinide. HbA1c and lung function (FEV1%pred) were unchanged for either group. The authors compared the changes -12 months to baseline and baseline to +12 months separately for each group. Therefore a direct comparison of the effect of repaglinide versus insulin on BMI, HbA1c and FEV1%pred was not presented. According to our protocol, we will directly compare treatment effects (HbA1c, BMI, FEV1%pred) in between both groups. The actual Cochrane report regarding “Insulin and oral agents for managing CFRD” stated that further studies are needed to establish whether there is clear benefit for hypoglycemic agents. We expect that the results of our study will help to address this clinical need. Trial registration ClinicalTrials.gov Identifier: NCT00662714

Subject-performed tasks (SPTs; i.e., carrying out the actions during study) improve free recall of action phrases without enhancing relational information. By this mechanism, items pop into a person's mind without active search, and this process especially extends the recency effect. The authors demonstrated the existence of the extended recency effect and its importance for the SPT recall advantage (Experiments 1 and 2). Carrying out the action and not semantic processing caused the effect (Experiment 3). The extended recency effect was also not a consequence of a deliberate last-in, first-out strategy (Experiment 4), and performing a difficult secondary task (an arithmetic task) during recall reduced memory performances but did not influence the extended recency effect (Experiment 5). These data support the theory that performing actions during study enhances the efficiency of an automatic pop-out mechanism in free recall.

In memory for subject-performed tasks (SPTs), subjects encode a list of simple action phrases (e.g., thumb through a book, knock at the door) by performing these actions during learning. In three experiments, we investigated the size of the levels-of-processing effects in SPTs as compared with those in standard verbal learning tasks (VTs). Subjects under SPT and VT conditions learned lists of action phrases in a surface or a conceptual orienting task. Under both encoding conditions, the subjects recalled fewer items with surface orienting tasks than with conceptual orienting tasks, but the levels-of-processing effects were strongly reduced in the SPT condition. In the SPT condition, items that were encoded in a surface orienting task were still substantially recalled. The items were recalled almost as well as the conceptually encoded items in the VT condition. The distinct reduction of the levels-of-processing effect is caused by the fact that, in SPT encoding even with a verbal surface orienting task, subjects process conceptual information in order to perform the denoted action. We attribute the small conceptual advantage, which remains with SPT despite the conceptual processing for performing, to the fact that items are not as well integrated into memory as they are when conceptual processing is focused on the action component, rather than on the semantic contexts. This lower integration reduces the accessibility of items in the verbal surface task, even with SPT encoding.

Molecular biomarkers offer the potential for refining prognostic determinants in patients undergoing cancer surgery. Among patients with colorectal cancer, KRAS and BRAF are important biomarkers, but their role in patients undergoing surgical therapy for liver metastases is unknown. In this study, the incidence and prognostic significance of KRAS and BRAF mutations were determined in patients undergoing surgical therapy of colorectal liver metastases (CRLM).KRAS and BRAF analysis was performed on 202 patients undergoing surgery for CRLM between 2003 and 2008. Tumor samples were analyzed for somatic mutations using sequencing analysis (KRAS, codon12/13, BRAF, V600E). The frequency of mutations was ascertained, and their impact on outcome was determined relative to other clinicopathologic factors.KRAS gene mutations were detected in 58/202 patients (29%). In contrast, mutation in the BRAF gene was identified in very low frequency in this surgical cohort, found in only 4/202 (2%) patients. On multivariate analysis, KRAS mutation was associated with worse survival (hazard ratio [HR], 1.99; 95% confidence interval [CI], 1.21-3.26), as well as recurrence risk (HR, 1.68; 95% CI, 1.04-2.70). Although other clinicopathologic features, including tumor number, carcinoembryonic antigen, and primary stage were also associated with survival, KRAS status remained independently predictive of outcome. The low incidence of BRAF mutation limited assessment of its prognostic impact.Whereas KRAS mutations were found in approximately one third of patients, BFAF mutations were found in only 2% of patients undergoing surgery for CRLM. KRAS status was an independent predictor of overall and recurrence-free survival. Molecular biomarkers such as KRAS may help to refine our prognostic assessment of patients undergoing surgical therapy for CRLM.

Background Kawasaki disease is an acute, self-limited vasculitis of childhood that can result in structural damage to the coronary arteries. Previous studies have implicated the TGF-β pathway in disease pathogenesis and generation of myofibroblasts in the arterial wall. microRNAs are small non-coding RNAs that modulate gene expression at the post-transcriptional level and can be transported between cells in extracellular vesicles. To understand the role that microRNAs play in modifying gene expression in Kawasaki disease, we studied microRNAs from whole blood during the acute and convalescent stages of the illness. Methodology/Principal Findings RNA isolated from the matched whole blood of 12 patients with acute and convalescent Kawasaki disease were analyzed by sequencing of small RNA. This analysis revealed six microRNAs (miRs-143, -199b-5p, -618, -223, -145 and -145* (complementary strand)) whose levels were significantly elevated during the acute phase of Kawasaki disease. The result was validated using targeted qRT-PCR using an independent cohort (n = 16). miR-145, which plays a critical role in the differentiation of neutrophils and vascular smooth muscle cells, was expressed at high levels in blood samples from acute Kawasaki disease but not adenovirus-infected control patients (p = 0.005). miR-145 was also detected in small extracellular vesicles isolated from acute Kawasaki disease plasma samples. Pathway analysis of the predicted targets of the 6 differentially expressed microRNAs identified the TGF-β pathway as the top pathway regulated by microRNAs in Kawasaki disease. Conclusion Sequencing of small RNA species allowed discovery of microRNAs that may participate in Kawasaki disease pathogenesis. miR-145 may participate, along with other differentially expressed microRNAs, in regulating expression of genes in the TGF-β pathway during the acute illness. If the predicted target genes are confirmed, our findings suggest a model of Kawasaki disease pathogenesis whereby miR-145 modulates TGF-β signaling in the arterial wall.