Ofatumumab plus HyperCVAD/HD-MA induction leads to high rates of minimal residual disease negativity in patients with newly diagnosed mantle cell lymphoma: Results of a phase 2 study.

BACKGROUND: Ofatumumab is a humanized type 1 anti-CD20 monoclonal antibody. Preclinical studies show improved complement-mediated cytotoxicity (CMC) compared to rituximab in mantle cell lymphoma (MCL). This study evaluates the safety and efficacy of combining ofatumumab with HyperCVAD/MA (O-HyperCVAD) in newly diagnosed MCL. METHODS: In this single-arm phase 2 study, 37 patients were treated with the combination of O-HyperCVAD for 4 or 6 cycles, followed by high dose chemotherapy and autologous stem cell transplant. Primary objectives were overall response rate (ORR) and complete response (CR) rate at the end of therapy. Secondary objectives included minimal residual disease (MRD) negativity, progression-free survival (PFS), and overall survival (OS). RESULTS: Median age was 60 years; ORR was 86% and 73% achieved a CR by modified Cheson criteria. The MRD negativity rate was 78% after 2 cycles of therapy, increasing to 96% at the end of induction; median PFS and OS were 45.5 months and 56 months, respectively. Achieving a post-induction CR by both imaging and flow cytometry was associated with improved PFS and OS. Early MRD negativity (post-2 cycles) was also associated with an improved PFS but not OS. There were 3 deaths while on therapy, and grades 3 and 4 adverse events (AEs) were observed in 22% and 68% of the patients. CONCLUSION: The addition of ofatumumab to HyperCVAD/HD-MA led to high rates of MRD negativity by flow cytometry in patients with newly diagnosed MCL. Achieving a CR post-induction by both imaging and flow cytometry is associated with improved overall survival.

Mitochondrial complex II regulates a distinct oxygen sensing mechanism in monocytes.

Mutations in mitochondrial complex II (succinate dehydrogenase; SDH) genes predispose to paraganglioma tumors that show constitutive activation of hypoxia responses. We recently showed that SDHB mRNAs in hypoxic monocytes gain a stop codon mutation by APOBEC3A-mediated C-to-U RNA editing. Here, we test the hypothesis that inhibition of complex II facilitates hypoxic gene expression in monocytes using an integrative experimental approach. By RNA sequencing, we show that specific inhibition of complex II by atpenin A5 in normoxic conditions mimics hypoxia and induces hypoxic transcripts as well as APOBEC3A-mediated RNA editing in human monocytes. Myxothiazol, a complex III inhibitor, has similar effects in normoxic monocytes. Atpenin A5 partially inhibits oxygen consumption, and neither hypoxia nor atpenin A5 in normoxia robustly stabilizes hypoxia-inducible factor (HIF)-1α in primary monocytes. Several earlier studies in transformed cell lines suggested that normoxic stabilization of HIF-1α explains the persistent expression of hypoxic genes upon complex II inactivation. On the contrary, we find that atpenin A5 antagonizes the stabilization of HIF-1α and reduces hypoxic gene expression in transformed cell lines. Accordingly, compound germline heterozygosity of mouse Sdhb/Sdhc/Sdhd null alleles blunts chronic hypoxia-induced increases in hemoglobin levels, an adaptive response mainly regulated by HIF-2α. In contrast, atpenin A5 or myxothiazol does not reduce hypoxia-induced gene expression or RNA editing in monocytes. These results reveal a novel role for mitochondrial respiratory inhibition in induction of the hypoxic transcriptome in monocytes and suggest that inhibition of complex II activates a distinct hypoxia signaling pathway in a cell-type specific manner.

A neurodevelopment and neuroplasticity-based framework for early intervention in psychotic disorders.

In recent years there has been growing interest in early intervention in psychotic disorders and a number of clinical and research programmes have been developed. The clinical staging model has been an essential part of early intervention as it provides the rationale of existing programmes. In medicine, clinical staging is a valuable approach in disorders where primary pathology is progressive in nature. However, the clinical staging model of psychosis has been proposed without establishing first that schizophrenia is a primarily progressive disorder. In reviewing existing evidence, this current paper argues that cross-sectional data interpreted as supportive of clinical staging data does not consider the effects of sampling bias, problems in reliability in assessing 'soft symptoms', or false positives. Longitudinal neurobiological studies do not provide a convincing case for primarily progressive pathology in schizophrenia. Clinical progression in schizophrenia can be better conceptualised as neuroplastic changes in response to interaction between core developmental pathology and environmental stimuli. An alternative rationale for early and continuous intervention targeting neurodevelopmental abnormality and neuroplastic changes, as well as medical and psychological comorbidities, is proposed in this paper.

Meta-analysis of longitudinal studies of cognition in bipolar disorder: comparison with healthy controls and schizophrenia.

BACKGROUND: Bipolar disorder (BP) is associated with significant cognitive impairment. Recent evidence suggests that cognitive deficits are already evident after first-episode mania. However, it is not clear whether BP is associated with further decline in cognitive functions in individuals with established illness. Aim of this meta-analytic review was to examine longitudinal neurocognitive changes in BP and to compare trajectory of cognitive deficits in BP with schizophrenia and healthy controls. METHODS: Electronic databases were searched for the studies published between January 1987 and November 2016. In total 22 reports were included in the current meta-analysis. The main analysis assessed the longitudinal change in cognition in 643 patients with BP. Further analyses were conducted in studies investigating cognitive changes in BP along with healthy controls (459 BP and 367 healthy controls) and schizophrenia (172 BP and 168 schizophrenia). RESULTS: There was no cognitive decline overtime neither in short-term (mean duration = 1.5 years) nor in long-term (mean duration = 5.5 years) follow-up studies in BP. In contrast, there was evidence for modest improvements in task performance in memory and working memory at follow-up. The trajectory of cognitive functioning in BP was not significantly different from changes in schizophrenia and healthy controls. CONCLUSIONS: Together with the findings in early BP and individuals at genetic risk for BP, current findings suggest that neurodevelopmental factors might play a significant role in cognitive deficits in BP and do not support the notion of progressive cognitive decline in most patients with BP.

Neurocognitive impairment in deficit and non-deficit schizophrenia: a meta-analysis.

BACKGROUND: Most studies suggested that patients with deficit schizophrenia have more severe impairment compared with patients with non-deficit schizophrenia. However, it is not clear whether deficit and non-deficit schizophrenia are associated with differential neurocognitive profiles. METHODS: The aim of this meta-analytic review was to compare cognitive performances of deficit and non-deficit patients with each other and with healthy controls. In the current meta-analysis, differences in cognitive abilities between 897 deficit and 1636 non-deficit patients with schizophrenia were examined. Cognitive performances of 899 healthy controls were also compared with 350 patients with deficit and 592 non-deficit schizophrenia. RESULTS: Both deficit (d = 1.04-1.53) and non-deficit (d = 0.68-1.19) schizophrenia were associated with significant deficits in all cognitive domains. Deficit patients underperformed non-deficit patients in all cognitive domains (d = 0.24-0.84) and individual tasks (d = 0.39-0.93). The relationship between deficit syndrome and impairment in olfaction, social cognition, verbal fluency, and speed-based cognitive tasks were relatively stronger. CONCLUSIONS: Our findings suggest that there is consistent evidence for a significant relationship between deficit syndrome and more severe cognitive impairment in schizophrenia.

The relationship between cognitive impairment in schizophrenia and metabolic syndrome: a systematic review and meta-analysis.

BACKGROUND: Individuals with schizophrenia are at greater risk for metabolic syndrome (MetS) which is associated with cognitive deficits in the general population. MetS might be potentially an important contributing factor to cognitive impairment in schizophrenia. METHOD: In the current systematic review and meta-analysis, the findings of 18 studies investigating the association between MetS (and its components) with cognitive impairment in schizophrenia are reviewed. RESULTS: Co-morbidity of MetS (d = 0.28) and diabetes mellitus (d = 0.28) were both associated with more severe cognitive deficits in schizophrenia. There was also evidence for a significant relationship between cognitive impairment in schizophrenia and each of the components of MetS including hypertension, dyslipidemia, abdominal obesity and diabetes. CONCLUSIONS: MetS is significantly associated with cognitive impairment in schizophrenia and can potentially contribute to functional decline observed in some patients with schizophrenia throughout the course of illness.

Transient overexpression of exogenous APOBEC3A causes C-to-U RNA editing of thousands of genes.

APOBEC3A cytidine deaminase induces site-specific C-to-U RNA editing of hundreds of genes in monocytes exposed to hypoxia and/or interferons and in pro-inflammatory macrophages. To examine the impact of APOBEC3A overexpression, we transiently expressed APOBEC3A in HEK293T cell line and performed RNA sequencing. APOBEC3A overexpression induces C-to-U editing at more than 4,200 sites in transcripts of 3,078 genes resulting in protein recoding of 1,110 genes. We validate recoding RNA editing of genes associated with breast cancer, hematologic neoplasms, amyotrophic lateral sclerosis, Alzheimer disease and primary pulmonary hypertension. These results highlight the fundamental impact of APOBEC3A overexpression on human transcriptome by widespread RNA editing.

Meta-analysis of social cognition in attention-deficit/hyperactivity disorder (ADHD): comparison with healthy controls and autistic spectrum disorder.

BACKGROUND: Impairment in social cognition is an established finding in autism spectrum disorders (ASD). Emerging evidence suggests that attention-deficit/hyperactivity disorder (ADHD) might be also associated with deficits in theory of mind (ToM) and emotion recognition. However, there are inconsistent findings, and it has been debatable whether such deficits persist beyond childhood and how similar social cognitive deficits are in ADHD v. ASD. METHOD: We conducted a meta-analysis of social cognition, including emotion recognition and ToM, studies in ADHD compared with healthy controls and ASD. The current meta-analysis involved 44 studies comparing ADHD (n = 1999) with healthy controls (n = 1725) and 17 studies comparing ADHD (n = 772) with ASD (n = 710). RESULTS: Facial and vocal emotion recognition (d = 0.40-0.44) and ToM (d = 0.43) abilities were significantly impaired in ADHD. The most robust facial emotion recognition deficits were evident in anger and fear. Social cognitive deficits were either very subtle (emotion recognition) or non-significant (ToM) in adults with ADHD. Deficits in social cognition, especially ToM, were significantly more pronounced in ASD compared with ADHD. General cognitive impairment has contributed to social cognitive deficits in ADHD. CONCLUSIONS: Performance of individuals with ADHD on social cognition lies intermediate between ASD and healthy controls. However, developmental trajectories of social cognition probably differ between ADHD and ASD as social cognitive deficits in ADHD might be improving with age in most individuals. There is a need for studies investigating a potential subtype of ADHD with persistent social cognitive deficits and exploring longitudinal changes in social cognition during development.

Meta-analysis of Theory of Mind (ToM) impairment in bipolar disorder.

BACKGROUND: Theory of mind (ToM) dysfunction is prominent in a number of psychiatric disorders, in particular, autism and schizophrenia, and can play a significant role in poor functioning. There is now emerging evidence suggesting that ToM abilities are also impaired in bipolar disorder (BP); however, the relationship between ToM deficits and mood state is not clear. METHOD: We conducted a meta-analysis of ToM studies in BP. Thirty-four studies comparing 1214 patients with BP and 1097 healthy controls were included. BP groups included remitted (18 samples, 545 BP patients), subsyndromal (12 samples, 510 BP patients), and acute (manic and/or depressed) (10 samples, 159 BP patients) patients. RESULTS: ToM performance was significantly impaired in BP compared to controls. This impairment was evident across different types of ToM tasks (including affective/cognitive and verbal/visual) and was also evident in strictly euthymic patients with BP (d = 0.50). There were no significant differences between remitted and subsyndromal samples. However, ToM deficit was significantly more severe during acute episodes (d = 1.23). ToM impairment was significantly associated with neurocognitive and particularly with manic symptoms. CONCLUSION: Significant but modest sized ToM dysfunction is evident in remitted and subsyndromal BP. Acute episodes are associated with more robust ToM deficits. Exacerbation of ToM deficits may contribute to the more significant interpersonal problems observed in patients with acute or subsyndromal manic symptoms. There is a need for longitudinal studies comparing the developmental trajectory of ToM deficits across the course of the illness.

Neurodevelopmental origin of cognitive impairment in schizophrenia.

Cognitive impairment is a common feature of schizophrenia; however, its origin remains controversial. Neurodevelopmental abnormalities clearly play a role in pre-morbid cognitive dysfunction in schizophrenia, yet many authors believe that schizophrenia is characterized by illness-related cognitive decline before and after onset of the psychosis that can be the result of neurodegenerative changes. The main reasons behinds such arguments include, first, the evidence showing that effect sizes of the cognitive deficits in subjects who develop adult schizophrenia gradually increase in the first two decades of life and, second, the fact that there is functional decline in many patients with schizophrenia over the years. In this Editorial, I argue that current evidence suggests that illness-related cognitive impairment is neurodevelopmental in origin and characterized by slower gain (developmental lag) but not cognitive decline continuing throughout the first two decades of life. I introduce a model suggesting that neurodevelopmental abnormality can in fact explain the course of cognitive dysfunction and variations in the trajectory of functional decline throughout the life in individuals with schizophrenia. In this model, the severity of underlying neurodevelopmental abnormality determines the age that cognitive deficits first become apparent and contributes to the cognitive reserve of the individual. Interaction of neurodevelopmental abnormality with clinical symptoms, especially negative symptoms and aging, vascular changes, psychological and iatrogenic factors contributes to the heterogeneity of the functional trajectory observed in this disorder.

Divergent effects of first-generation and second-generation antipsychotics on cortical thickness in first-episode psychosis.

BACKGROUND: Whether there are differential effects of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) on the brain is currently debated. Although some studies report that FGAs reduce grey matter more than SGAs, others do not, and research to date is limited by a focus on schizophrenia spectrum disorders. To address this limitation, this study investigated the effects of medication in patients being treated for first-episode schizophrenia or affective psychoses. METHOD: Cortical thickness was compared between 52 first-episode psychosis patients separated into diagnostic (i.e. schizophrenia or affective psychosis) and medication (i.e. FGA and SGA) subgroups. Patients in each group were also compared to age- and sex-matched healthy controls (n = 28). A whole-brain cortical thickness interaction analysis of medication and diagnosis was then performed. Correlations between cortical thickness with antipsychotic dose and psychotic symptoms were examined. RESULTS: The effects of medication and diagnosis did not interact, suggesting independent effects. Compared with controls, diagnostic differences were found in frontal, parietal and temporal regions. Decreased thickness in FGA-treated versus SGA-treated groups was found in a large frontoparietal region (p < 0.001, corrected). Comparisons with healthy controls revealed decreased cortical thickness in the FGA group whereas the SGA group showed increases in addition to decreases. In FGA-treated patients cortical thinning was associated with higher negative symptoms whereas increased cortical thickness in the SGA-treated group was associated with lower positive symptoms. CONCLUSIONS: Our results suggest that FGA and SGA treatments have divergent effects on cortical thickness during the first episode of psychosis that are independent from changes due to illness.

Sequencing of the CFTR gene in selected Turkish patients with cystic fibrosis.

AIM: Common mutation detection panels are usually used in clinical practice in most of the centers of our country in order to demonstrate mutations of cystic fibrosis (CF) patients. But heterogenicity of CFTR mutations in Turkey makes identification of CFTR mutations extremely difficult while using common mutation detection panels. METHODS: In this report, we described our experience and findings in offering sequencing of the CFTR gene to 17 patients in which no mutations were identified by common mutation analysis. RESULTS: Overall allele informativity increased from 4/34 (11.76%) to 13/34 (38.2%) after whole exon sequencing of CFTR in our patients. CONCLUSION: Genotype of CF patients could be entirely described in some of our patients by CFTR sequencing but there is still a group of patients, independently from their clinical classification whose mutations can not be determined by CFTR sequencing.

Mitochondrial complex II and genomic imprinting in inheritance of paraganglioma tumors.

Germ line heterozygous mutations in the structural subunit genes of mitochondrial complex II (succinate dehydrogenase; SDH) and the regulatory gene SDHAF2 predispose to paraganglioma tumors which show constitutive activation of hypoxia inducible pathways. Mutations in SDHD and SDHAF2 cause highly penetrant multifocal tumor development after a paternal transmission, whereas maternal transmission rarely, if ever, leads to tumor development. This transmission pattern is consistent with genomic imprinting. Recent molecular evidence supports a model for tissue-specific imprinted regulation of the SDHD gene by a long range epigenetic mechanism. In addition, there is evidence of SDHB mRNA editing in peripheral blood mononuclear cells and long-term balancing selection operating on the SDHA gene. Regulation of SDH subunit expression by diverse epigenetic mechanisms implicates a crucial dosage-dependent role for SDH in oxygen homeostasis. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.

Cognitive deficits in youth with familial and clinical high risk to psychosis: a systematic review and meta-analysis.

OBJECTIVE: It is likely that cognitive deficits are vulnerability markers for developing schizophrenia, as these deficits are already well-established findings in first-episode psychosis. Studies at-risk adolescents and young adults are likely to provide information about cognitive deficits that predate the onset of the illness. METHOD: We conducted meta-analyses of studies comparing familial-high risk (FHR) or ultra-high risk (UHR; n = 2113) and healthy controls (n = 1748) in youth studies in which the mean age was between 15 and 29. RESULTS: Compared with controls, high risk subjects were impaired in each domain in both UHR (d = 0.34-0.71) and FHR (d = 0.24-0.81). Heterogeneity of effect sizes across studies was modest, increasing confidence to the findings of the current meta-analysis (I(2) = 0-0.18%). In both risk paradigms, co-occurrence of genetic risk with attenuated symptoms was associated with more severe cognitive dysfunction. In UHR, later transition to psychosis was associated with more severe cognitive deficits in all domains (d = 0.31-0.49) except sustained attention. However, cognitive impairment has a limited capacity to predict the outcome of high-risk patients. CONCLUSION: Cognitive deficits are already evident in adolescents and young adults who have familial or clinical risk for psychosis. Longitudinal developmental studies are important to reveal timing and trajectory of emergence of such deficits.

Evaluation of the healing and protective properties of adipose-derived mesenchymal stem cells from cisplatin-induced liver and kidney damage.

OBJECTIVE: The occurrence of nephrotoxicity and hepatotoxicity as a result of cisplatin administration is a major concern in clinical practice. This study examined the potential protective effects of administering mesenchymal stem cells (MSCs) on the renal and hepatic damage caused by cisplatin. Moreover, the study investigated the potential protective effects of administering Adipose-Derived Mesenchymal Stem Cells (ADMSC) to counteract the harmful effects of cisplatin-induced kidney and liver damage. MATERIALS AND METHODS: Male Sprague-Dawley rats were divided into three groups: normal control, cisplatin + saline, and cisplatin + ADMSC. Cisplatin was administered to induce toxicity, and ADMSC was administered intravenously as a potential therapeutic intervention. Biochemical parameters and histopathological changes were assessed in the kidney and liver tissues. Statistical analyses were performed using a one-way ANOVA. RESULTS: Cisplatin increased malondialdehyde (MDA), tumor necrosis factor alfa (TNF-alfa), IL-6, alanine transaminase (ALT), creatinine, Galectin-3, Tissue growth factor beta 1 (TGF-beta 1), compared to the normal control group. Cisplatin-MSC reduced these levels. Histopathology showed that cisplatin caused kidney tubular epithelial necrosis, luminal necrotic debris, tubular dilatation, interstitial inflammation, liver sinusoidal and central vein dilatation, congestion, necrosis, and cytoplasmic vacuolization. ADMSC administration significantly reduced histopathological changes. CONCLUSIONS: These findings highlight the potential therapeutic benefits of mesenchymal stem cell (MSC) administration in mitigating cisplatin-induced nephrotoxicity and hepatotoxicity. MSC treatment demonstrated protective effects by reducing oxidative stress, inflammatory markers, and histopathological alterations. Further investigations are warranted to elucidate the precise mechanisms underlying these protective effects and evaluate their clinical implications for managing cisplatin-induced organ damage.

Fisetin ameliorates methotrexate induced liver fibrosis.

OBJECTIVE: Methotrexate (MTX), a widely used chemotherapeutic and immunosuppressive agent, is associated with hepatotoxicity, leading to liver fibrosis and cirrhosis. This study explores the regenerative and reparative effects of fisetin, a flavonoid with known antioxidant and anti-inflammatory properties, on MTX-induced liver fibrosis in a rat model. MATERIALS AND METHODS: Thirty-six male Wistar albino rats were divided into normal, MTX and saline, and MTX and fisetin. Liver injury was induced in the latter two groups using a single intraperitoneal dose of MTX (20 mg/kg). Fisetin (50 mg/kg/day) or saline was administered intraperitoneally for ten days. After sacrifice, liver tissues were subjected to histopathological evaluation and biochemical analyses, including Transforming Growth Factor-ß1 (TGF-beta), sirtuins-1 (SIRT-1), malondialdehyde (MDA), cytokeratin 18, thrombospondin 1, and alanine transaminase (ALT) levels. RESULTS: MTX administration significantly increased liver injury markers, including TGF-beta, MDA, cytokeratin 18, thrombospondin 1, and ALT, while reducing SIRT-1 levels. Fisetin treatment attenuated these effects, demonstrating its potential therapeutic impact. Histopathological analysis confirmed that fisetin mitigated MTX-induced hepatocyte necrosis, fibrosis, and cellular infiltration. CONCLUSIONS: This study proves that fisetin administration can alleviate MTX-induced liver damage in rats. The reduction in oxidative stress, inflammation, and apoptosis, along with the histological improvements, suggests fisetin's potential as a therapeutic agent against MTX-induced hepatotoxicity. Further investigations and clinical studies are warranted to validate these findings and assess fisetin's translational potential in human cases of MTX-induced liver damage.

Is near-infrared spectroscopy a promising predictor for early intracranial hemorrhage diagnosis in the Emergency Department?

Intracranial hemorrhage (ICH) is a serious medical condition that can lead to significant morbidity and mortality if not diagnosed and treated promptly. Early detection and treatment are essential for improving the outcome in patients with ICH. Near-infrared spectroscopy (NIRS) is a non-invasive imaging technique that has been used to detect changes in brain tissue oxygenation and blood flow in various conditions. The aim of this study was to investigate the predictive potential of NIRS for early diagnosis of ICH in patients presenting to the Emergency Department (ED) triage with headache. A total of 378 patients were included in the study. According to the final diagnosis of the patients, 4 groups were formed: migraine, tension-cluster headache, intracranial hemorrhage and intracranial mass, and control group. Cerebral NIRS values "rSO2" were measured at the first professional medical contact with the patient. The right and left rSO2 (RrSO2, LrSO2) were significantly lower and the rSO2 difference was significantly higher in the intracranial hemorrhage group compared to all other patient groups (P<0.001). The cut-off values determined in the receiver operating characteristics (ROC) analysis were RrSO2 ≤67, LrSO2 ≤67, and ΔrSO2 ≥9. This study found that a difference of more than 9 in cerebral right-left NIRS values can be a non-invasive, easy-to-administer, rapid, and reliable diagnostic test for early detection of intracranial bleeding. NIRS holds promise as an objective method in ED triage for patients with intracranial hemorrhage. However, further research is needed to fully understand the potential benefits and limitations of this method.

Social cognition and neurocognition in first-episode bipolar disorder and psychosis: The effect of negative and attenuated positive symptoms.

BACKGROUND: Schizophrenia and bipolar disorder are associated with neurocognitive and social-cognitive impairments. To date very few studies investigated social cognition in first-episode bipolar disorder (FEBD). Our main aim was to investigate the differences in social cognition and neurocognition between FEBD and first-episode psychosis (FEP). Another aim was to investigate neurocognitive correlates of negative symptoms and attenuated psychotic symptoms in FEBD. METHODS: This study included 55 FEBD, 64 FEP and 43 healthy controls. A comprehensive neuropsychological battery assessing social cognition, processing speed, verbal and visual memory, working memory, sustained attention, and executive functions was administered to all participants. RESULTS: Both FEBD and FEP were associated with widespread deficits in all neurocognitive domains and social cognition. Both FEP (d = -1.19) and FEBP (d = -0.88) were also impaired in social cognition. In FEP, effect sizes (Cohen's d) of neurocognitive deficits ranged from -0.71 to -1.56. FEBD was also associated with relatively milder but similar neurocognitive deficits (d = -0.61 to-1.17). FEBD group performed significantly better than FEP group in verbal and visual memory, processing speed, and executive function domains (d = -0.40 to-0.52). Negative symptoms and social functioning were associated with neuropsychological impairment in both groups. The severity of attenuated psychotic symptoms was associated with poorer verbal memory in FEBD (r = -0.39, p < 0.01). LIMITATIONS: The cross-sectional nature of the current study is the main limitation. CONCLUSIONS: Neurocognitive and social-cognitive deficits are evident in both FEBD and FEP. In FEBD, more severe memory deficits might be markers of clinical overlap and shared neurobiological vulnerability with psychotic disorders.

Neurocognition and social cognition in youth and young adults at ultra-high-risk for psychosis and bipolar disorder.

BACKGROUND: Schizophrenia and bipolar disorder are associated with significant deficits in neurocognition and social cognition. Unlike the studies in chronic stages of these disorders, very limited information is available regarding neurocognitive and social-cognitive impairment before the onset of bipolar disorder. Our main aim was to investigate the differences in neurocognition and social cognition between individuals at ultra-high risk for psychosis (UHR-P) and bipolar disorder (UHR-BD). METHODS: This study included 152 help-seeking individuals identified as UHR-P (n = 78) and UHR-BD (n = 74), who were compared with a healthy control group (n = 43). A comprehensive neuropsychological battery was administered to all participants. RESULTS: UHR-P was associated with widespread deficits in all neurocognitive and social-cognitive domains. Effect sizes (Cohen's d) of these deficits ranged from -0.57 to -1.34. UHR-BD was associated with significant deficits in processing speed, executive functions, sustained attention and social cognition (d = -0.48 to-0.70, p < 0.05). UHR-P performed significantly worse than UHR-BD in social cognition, processing speed, verbal memory and executive function domains (d = -0.39 to-0.64, p < 0.05). Negative symptoms were associated with impaired social cognition in the UHR-P group and verbal memory deficits in the UHR-BD group. Cognitive impairment was associated with functional impairment in both groups. CONCLUSIONS: While UHR-P is associated with more widespread cognitive impairment, deficits in processing speed, executive functions, sustained attention and social cognition might be common features of both UHR groups. In early intervention services, cognition should be considered as a target for assessment and intervention not only for individuals at high risk for psychosis but also for bipolar disorder.

The implications of APOBEC3-mediated C-to-U RNA editing for human disease.

Intra-organism biodiversity is thought to arise from epigenetic modification of constituent genes and post-translational modifications of translated proteins. Here, we show that post-transcriptional modifications, like RNA editing, may also contribute. RNA editing enzymes APOBEC3A and APOBEC3G catalyze the deamination of cytosine to uracil. RNAsee (RNA site editing evaluation) is a computational tool developed to predict the cytosines edited by these enzymes. We find that 4.5% of non-synonymous DNA single nucleotide polymorphisms that result in cytosine to uracil changes in RNA are probable sites for APOBEC3A/G RNA editing; the variant proteins created by such polymorphisms may also result from transient RNA editing. These polymorphisms are associated with over 20% of Medical Subject Headings across ten categories of disease, including nutritional and metabolic, neoplastic, cardiovascular, and nervous system diseases. Because RNA editing is transient and not organism-wide, future work is necessary to confirm the extent and effects of such editing in humans.