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Cytosine deaminases AID/APOBEC proteins act as potent nucleic acid editors, playing important roles in innate and adaptive immunity. However, the mutagenic effects of some of these proteins compromise genomic integrity and may promote tumorigenesis. Here, we demonstrate that human APOBEC3G (A3G), in addition to its role in innate immunity, promotes repair of double-strand breaks (DSBs) in vitro and in vivo. Transgenic mice expressing A3G successfully survived lethal irradiation, whereas wild-type controls quickly succumbed to radiation syndrome. Mass spectrometric analyses identified the differential upregulation of a plethora of proteins involved in DSB repair pathways in A3G-expressing cells early following irradiation to facilitate repair. Importantly, we find that A3G not only accelerates DSB repair but also promotes deamination-dependent error-free rejoining. These findings have two implications: (a) strategies aimed at inhibiting A3G may improve the efficacy of genotoxic therapies used to cure malignant tumours; and (b) enhancing A3G activity may reduce acute radiation syndrome in individuals exposed to ionizing radiation.

Human apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G (hA3G), a member of the APOBEC family, was described as an anti-HIV-1 restriction factor, deaminating reverse transcripts of the HIV-1 genome. Several types of cancer cells that express high levels of A3G, such as diffuse large B-cell lymphoma cells and glioblastomas, show enhanced cell survival after ionizing radiation and chemotherapy treatments. Previously, we showed that hA3G promotes (DNA) double-strand breaks repair in cultured cells and rescues transgenic mice from a lethal dose of ionizing radiation. Here, we show that A3G rescues cells from the detrimental effects of DNA damage induced by ultraviolet irradiation and by combined bromodeoxyuridine and ultraviolet treatments. The combined treatments stimulate the synthesis of cellular proteins, which are exclusively associated with A3G expression. These proteins participate mainly in nucleotide excision repair and homologous recombination DNA repair pathways. Our results implicate A3G inhibition as a potential strategy for increasing tumor cell sensitivity to genotoxic treatments.

RNA polymerase (Pol) III has a noncanonical role of viral DNA sensing in the innate immune system. This polymerase transcribes viral genomes to produce RNAs that lead to induction of type I interferons (IFNs). However, the genetic and functional links of Pol III to innate immunity in humans remain largely unknown. Here, we describe a rare homozygous mutation (D40H) in the POLR3E gene, coding for a protein subunit of Pol III, in a child with recurrent and systemic viral infections and Langerhans cell histiocytosis. Fibroblasts derived from the patient exhibit impaired induction of type I IFN and increased susceptibility to human cytomegalovirus (HCMV) infection. Cultured cell lines infected with HCMV show induction of POLR3E expression. However, induction is not restricted to DNA virus, as sindbis virus, an RNA virus, enhances the expression of this protein. Likewise, foreign nonviral DNA elevates the steady-state level of POLR3E and elicits promoter-dependent and -independent transcription by Pol III. Remarkably, the molecular mechanism underlying the D40H mutation of POLR3E involves the assembly of defective initiation complexes of Pol III. Our study links mutated POLR3E and Pol III to an innate immune deficiency state in humans.

Lopinavir (LPV), an efficient drug for HIV infection treatment, was incorporated into biodegradable PLGA nanocapsules (NCs) embedded in microparticles (MCPs) using the spray-drying technique in an attempt to bypass the P-gp efflux and protect the drug from CYP3A pre-systemic metabolism without ritonavir (RTV). SEM observations confirmed the formation of NCs and their entrapment in the MCPs. LPV-loaded NCs and free LPV were released from the MCPs at pH of 7.4 as evidenced by in vitro release studies. Results obtained from rat studies showed a two-fold higher bioavailability of LPV following oral administration of the optimal formulation than Kaletra®, the marketed drug, showing that when properly entrapped, LPV can be effectively protected from CYP degradation in the gut as well as from the liver following systemic absorption. It was also shown that serum derived from rats following LPV oral administration in two formulations and Kaletra® significantly decreased the multiplication of HIV-1 in cultured SupT1 cells. Furthermore, the LPV formulations markedly restricted the titre of infectious HIV-1 production compared with Kaletra® confirming the improved antiviral activity of LPV delivered in the rat blood circulation by the nanocapsules embedded in microparticle formulations.

Impairments in social cognition and interactions are core psychopathologies in schizophrenia, often manifesting as an inability to appropriately relate to the intentions and feelings of others. Neuroimaging has helped to demarcate the dynamics of two distinct functional connectivity circuits underlying the social-affective processes related to mentalization (known as Theory of Mind, ToM) and somatic-affiliation (known as Embodied Simulation, ES). While evidence points to abnormal activation patterns within these networks among those suffering from schizophrenia, it is yet unclear however, if these patients exhibit this abnormal functional connectivity in the context of social-affective experiences. The current fMRI study, investigated functional connectivity dynamics within ToM and ES networks as subjects experienced evolving cinematic portrayals of fear. During scanning, schizophrenia patients and healthy controls passively watched a cinematic scene in which a mother and her son face various threatening events. Participants then provided a continuous and retrospective report of their fear intensity during a second viewing outside the scanner. Using network cohesion index (NCI) analysis, we examined modulations of ES-related and ToM-related functional connectivity dynamics and their relation to symptom severity and the continuous emotional ratings of the induced cinematic fear. Compared to patients, healthy controls showed higher ES-NCI and marginally lower ToM-NCI during emotional peaks. Cross-correlation analysis revealed an intriguing dynamic between NCI and the inter-group difference of reported fear. Schizophrenia patients rated their fear as lower relative to healthy controls, shortly after exhibiting lower ES connectivity. This increased difference in rating was also followed by higher ToM connectivity among schizophrenia patients. The clinical relevance of these findings is further highlighted by the following two results: (a) ToM-NCI was found to have a strong correlation with the severity of general symptoms during one of the two main emotional peaks (Spearman R = 0.77); and (b) k-mean clustering demonstrated that the networks’ NCI dynamic during the social-affective context reliably differentiated between patients and controls. Together, these findings point to a possible neural marker for abnormal social-affective processing in schizophrenia, manifested as the disturbed balance between two functional networks involved in social-affective affiliation. This in turn suggests that exaggerated mentalization over somatic-affiliative processing, in response to another’s’ distress may underlie social-affective deficits in schizophrenia.

Participation in meaningful occupation is associated with recovery in serious mental illnesses, however, few evidence-based, occupation-focused interventions for hospital settings exist. This study investigated the effectiveness of "Occupational Connections" (OC), a manualized, short-term, group intervention, addressing issues in daily-life occupations' participation and functioning of people with serious mental illness as early as during hospitalization.Thirty-three inpatients with schizophrenia completed single-blind, pre-post study procedures (up to 10 weeks) in two groups: OC group intervention and open leisure activity group (control condition), in addition to treatment as usual. They were assessed for occupation and participation dimensions, perceptions of services as recovery-oriented, comprehensive cognitive functioning and schizophrenia symptoms. The sampling was convenience with sequential group allocation.Improvements were found in the study group in the following measurements: intention to participate in daily activities (t(15) = -2.62, p .05), participation diversity (t(15) = -2.11, p .05), experience the recovery orientation of the service (t(15) = -3.15, p .01), functional capacity (t(15) = -3.44, p .01), cognitive abilities of language understanding, memory and shifting (-4.5t(15)3.3, p .05), and schizophrenia symptoms (positive, negative and general: 8.47t(15)9.12, p .01). The control group has improved on attention (t(16) = -2.89, p .05), visual-motor organization (t(16) = 2.14, p .05) and schizophrenia symptoms (4.4t(16)6.6, p .01) only.The study provides initial evidence for the effectiveness of OC. The results suggest that interventions with a focus on personal, meaningful daily life occupations such as the OC, may be a useful tool contributing to a positive experience of the in-patient staying and successful community reintegration after acute psychiatric hospitalization.

Background. Participation in occupations is a basic human right. Although people with schizophrenia commonly experience restrictions in participation, there is a paucity of research in this area. Purpose. This study aimed to compare the participation patterns of people with schizophrenia to people without mental illness (control group). Method. A total of 140 people of similar age and sex completed the Adults Subjective Assessment of Participation and provided demographic and health-related data. Findings. People with schizophrenia tend to participate in fewer activities and to participate alone. However, they participate with similar intensity as those in the control group. Implications. The participation patterns of people with schizophrenia are both unique and similar to those of the general population. The differences in participation raise concerns due to signs of restriction and social exclusion. However, it appears that people with schizophrenia benefit from occupation and community-based services that promote and support participation with others in diverse activities.

Pathological gamblers (PGs) perform differently on neurocognitive tests than do healthy controls (HC). The aim of this study was to assess "waiting ability" - a major components of inhibition control-using a modified Stop Signal Task (SST) in a population of male PGs (N=55), and HCs (N=53). Results indicated no differences between PGs and HCs in reaction times, intra-individual response variability, or number of false alarms and misses. In conclusion, PGs were not impaired in their ability to manipulate their on-line response strategy during the experimental task and were instead able to change their strategy to decrease the number of false alarms. However, much more empirical and theoretical work needs to be carried out in order to understand the key neural basis of impulsivity among PGs.

Bipolar disorder is a chronic condition, characterized by high distress in patients and high suicide rates (30%). Most patients suffer from medical and other psychiatric comorbidities, which worsen the psychiatric symptoms and decrease the likelihood of remission. More than 70% of bipolar patients have cardio-metabolic symptoms, with higher rates compared to other psychiatric disorders. Cardiovascular disease is the major cause of high mortality rates in these patients, with 1.5-2 fold increased risk of mortality, compared to the general population without psychiatric symptoms. The rates of cardiovascular risk factors and their resulting increased mortality rates are similar to those found in schizophrenia. In addition to cardio-metabolic conditions, 50% of patients with bipolar disorder suffer from other medical symptoms, which are also associated with worse outcomes. Therefore, the current perspective is that bipolar disorder is not only a psychiatric disorder, but rather a multi-system illness, affecting the entire body. The optimal treatment for these patients should include diagnosis, monitoring and treatment of both psychiatric and physical symptoms, which would improve their prognosis.

Background Tobacco smoking is the leading cause of preventable death in developed countries. Our previous studies in animal models and humans suggest that repeated activation of cue-induced craving networks followed by electromagnetic stimulation of the dorsal prefrontal cortex (PFC) can cause lasting reductions in drug craving and consumption. We hypothesized that disruption of these circuitries by deep transcranial magnetic stimulation (TMS) of the PFC and insula bilaterally can induce smoking cessation. Methods Adults ( N = 115) who smoke at least 20 cigarettes/day and failed previous treatments were recruited from the general population. Participants were randomized to receive 13 daily sessions of high-frequency, low-frequency or sham stimulation following, or without, presentation of smoking cues. Deep TMS was administered using an H-coil version targeting the lateral PFC and insula bilaterally. Cigarette consumption was evaluated during the treatment by measuring cotinine levels in urine samples and recording participants' self-reports as a primary outcome variable. Dependence and craving were assessed using standardized questionnaires. Results High (but not low) frequency deep TMS treatment significantly reduced cigarette consumption and nicotine dependence. The combination of this treatment with exposure to smoking cues enhanced reduction in cigarette consumption leading to an abstinence rate of 44% at the end of the treatment and an estimated 33% 6 months following the treatment. Conclusions This study further implicates the lateral PFC and insula in nicotine addiction and suggests the use of deep high-frequency TMS of these regions following presentation of smoking cues as a promising treatment strategy.

Deamination of cytidine residues in viral DNA is a major mechanism by which APOBEC3G (A3G) inhibits vif-deficient human immunodeficiency virus type 1 (HIV-1) replication. dC-to-dU transition following RNase-H activity leads to viral cDNA degradation, production of non-functional proteins, formation of undesired stop codons and decreased viral protein synthesis. Here, we demonstrate that A3G provides an additional layer of defense against HIV-1 infection dependent on inhibition of proviral transcription. HIV-1 transcription elongation is regulated by the trans-activation response (TAR) element, a short stem-loop RNA structure required for elongation factors binding. Vif-deficient HIV-1-infected cells accumulate short viral transcripts and produce lower amounts of full-length HIV-1 transcripts due to A3G deamination of the TAR apical loop cytidine, highlighting the requirement for TAR loop integrity in HIV-1 transcription. We further show that free single-stranded DNA (ssDNA) termini are not essential for A3G activity and a gap of CCC motif blocked with juxtaposed DNA or RNA on either or 3'+5' ends is sufficient for A3G deamination. These results identify A3G as an efficient mutator and that deamination of (-)SSDNA results in an early block of HIV-1 transcription.

Antipsychotics, especially atypical ones, are in common use in children and adolescents with psychotic or affective spectrum disorders, as well as in various other psychopathologies. The adverse effects of atypical antipsychotics in children and adolescents are similar to those seen in adults, and include weight gain, elevated blood glucose levels, and hyperlipidemia. In this retrospective chart review, we compared these adverse events in children who were treated with typical, atypical, or no antipsychotic treatment.The medical charts of 72 children, 65 boys and 7 girls, were reviewed. All children were 6-13 years old (mean age 9.5±1.7 years). In total, 48 children received antipsychotic treatment, and 24 children were in the control group. Data were extracted from the medical charts, including weight, height, body mass index (BMI), blood pressure, aspartate transaminase (AST), alanine transaminase (ALT), triglycerides, total cholesterol, and glucose blood levels. We examined the values in the beginning of the antipsychotic treatment and at release from the hospital in the study group, and at admission and in the end of the drug-free period or at release from the hospital (a duration of at least 4 weeks) in the control group.The average weight gain was 3.9±3.8 kg in the atypical antipsychotic treatment (AAT) group, 1.1±4.4 kg in the typical antipsychotic treatment (TAT) group, and 0.23±2.9 kg in the control group. The average increase in BMI was 15.1±22.0 percentiles in the AAT group, 6.4±14.2 percentiles in the TAT group, and 1.6±12.5 percentiles in the control group. No statistically significant difference was found in the increase in height percentile. There were no significant differences in the rates of elevated values of serum triglycerides, cholesterol, AST, ALT, or fasting blood glucose.We found a significant increase in both absolute weight gain and BMI percentile following atypical antipsychotic treatment. In contrast, typical antipsychotic treatment did not affect weight gain significantly, and the same was true for the control group. In addition, the rates of elevated values of biochemical parameters (AST, ALT, total cholesterol, triglycerides, and fasting blood glucose levels) were very low at the beginning of the study, and were not significantly altered by the various treatments.

There are very few studies in the literature regarding clozapine use in children13 years of age. In this retrospective chart review, we compared the safety of clozapine--as determined by hematological and cardiometabolic changes - to that of non-clozapine antipsychotics used in the treatment of childhood-onset schizophrenia (COS).The clozapine treatment group (CTG) consisted of 17 COS patients (mean age 10.4 ± 2 years) who were hospitalized in a psychiatric ward between the years 2005 and 2012. The control group consisted of 19 COS patients (mean age 10.1 ± 1.4 years) who were hospitalized in the same ward during the same time period, and were treated with non-clozapine antipsychotics. A retrospective chart review was conducted. Hematological (white blood cells, absolute neutrophil count [ANC], red blood cells, platelets), metabolic (aspartate transaminase, alanine transaminase, triglycerides, total cholesterol, bilirubin) and cardiac (heart rate) values were extracted from the medical charts.The average follow-up periods for the CTG and the control group were 332.9 ± 200.5 days and 291.7 ± 157 days, respectively. In the CTG, moderate neutropenia (ANC1500/mm(3)) and mild neutropenia (1500/mm(3)ANC2000/mm(3)) were observed in two children (12%) and one child (6%), respectively. The neutropenia was transient in all cases. Treatment with clozapine was permanently discontinued only in one child (6%). There were no cases of agranulocytosis or severe infection in the CTG. In the control group, two children (11%) showed hematological abnormalities. Hyperlipidemia was observed in one child (6%) in the CTG at release from the hospital. Significantly more children (47%) in the CTG had tachycardia (heart rate100 beats per minute) at release from the hospital, compared with only one child (5%) in the control group (p=0.006).It appears that clozapine use in very early onset schizophrenia is safe. Although hematological adverse effects did occur in our study, the rates were not much higher than those seen in the control group. We found that the hematological abnormalities in the CTG were mostly transient, and that treatment with clozapine can be safely continued or renewed.

Selecting for antibodies against specific cell-surface proteins is a difficult task due to many unrelated proteins that are expressed on the cell surface. Here, we describe a method to screen antibody-presenting phage libraries against native cell-surface proteins. We applied this method to isolate antibodies that selectively recognize CCR5, which is the major co-receptor for HIV entry (consequently, playing a pivotal role in HIV transmission and pathogenesis). We employed a phage screening strategy by using cells that co-express GFP and CCR5, along with an excess of control cells that do not express these proteins (and are otherwise identical to the CCR5-expressing cells). These control cells are intended to remove most of the phages that bind the cells nonspecifically; thus leading to an enrichment of the phages presenting anti-CCR5-specific antibodies. Subsequently, the CCR5-presenting cells were quantitatively sorted by flow cytometry, and the bound phages were eluted, amplified, and used for further successive selection rounds. Several different clones of human single-chain Fv antibodies that interact with CCR5-expressing cells were identified. The most specific monoclonal antibody was converted to a full-length IgG and bound the second extracellular loop of CCR5. The experimental approach presented herein for screening for CCR5-specific antibodies can be applicable to screen antibody-presenting phage libraries against any cell-surface expressed protein of interest.

We previously demonstrated that the addition of the selective norepinephrine reuptake inhibitor reboxetine attenuates olanzapine-induced weight gain. Using the same study sample, we also sought to determine whether reboxetine's weight-attenuating effect was accompanied by a beneficial effect on metabolic and endocrine parameters relevant to antipsychotic-induced weight gain and obesity.Blood samples at baseline and at the end of the 6-week trial were available for 54 participants who participated in previous double-blind, placebo-controlled studies of reboxetine (4 mg BID) addition to olanzapine-treated schizophrenia patients. Fasting glucose, lipid profile, insulin, leptin, cortisol, dehydroepiandrosterone (DHEA), prolactin, and thyroid-stimulating hormone (TSH) were analyzed.In contrast to the olanzapine/placebo group, the olanzapine/reboxetine group exhibited a reduction in blood triglyceride (p 0.05) and leptin (p 0.05) levels, and elevation in cortisol (p 0.05) and DHEA (p 0.008) levels. No significant between-group differences were detected in the changes in cholesterol, glucose, insulin, TSH, and prolactin.Reboxetine addition resulted in meaningful improvement of some metabolic and endocrine measures associated with olanzapine-induced weight gain. The potential role of reboxetine in the prevention of olanzapine-induced weight gain and cardio-metabolic morbidity merits further large-scale, long-term investigation.

High frequency of cytidine to thymidine conversions was identified in the genome of several types of cancer cells. In breast cancer cells, these mutations are clustered in long DNA regions associated with single-strand DNA (ssDNA), double-strand DNA breaks (DSB), and genomic rearrangements. The observed mutational pattern resembles the deamination signature of cytidine to uridine carried out by members of the APOBEC3 family of cellular deaminases. Consistently, APOBEC3B (A3B) was recently identified as the mutational source in breast cancer cells. A3G is another member of the cytidine deaminases family predominantly expressed in lymphoma cells, where it is involved in mutational DSB repair following ionizing radiation treatments. This activity provides us with a new paradigm for cancer cell survival and tumor promotion and a mechanistic link between ssDNA, DSBs, and clustered mutations. Cancer Res; 73(12); 3494–8. ©2013 AACR.

HIV-1 integrase (IN) catalyzes viral DNA integration into the host genome and facilitates multifunctional steps including virus particle maturation. Competency of IN to form multimeric assemblies is functionally critical, presenting an approach for anti-HIV strategies. Multimerization of IN depends on interactions between the distinct subunit domains and amongst the flanking protomers. Here we elucidate an overlooked docking cleft of IN core domain that anchors the N-terminal helix-turn-helix (HTH)-motif in a highly preserved and functionally critical configuration. Crystallographic structure of IN core domain in complex with Fab specifically targeting this cleft reveals a steric overlap that would inhibit HTH-docking, C-terminal domain contacts, DNA binding and subsequent multimerization. While Fab inhibits in vitro IN integration activity, in vivo it abolishes virus particle production by specifically associating with preprocessed IN within Gag-Pol and interfering with early cytosolic Gag/Gag-Pol assemblies. The HTH-docking cleft may offer a fresh hotspot for future anti-HIV intervention strategies.

People with mental health conditions (MHCs) frequently experience participation and functional restrictions. Today, hospitals still serve a significant number of people with MHCs. However, there is little evidence for occupation-oriented interventions to support participation, health, and well-being in these hospital settings. This article describes a newly developed, short-term, structured intervention for the inpatient setting, Occupational Connections (OC), that focuses on promoting everyday functions and participation in daily life and presents preliminary findings for its effectiveness. Ten people with schizophrenia participated in the program during their stay in acute open inpatient units and completed evaluations both pre- and postintervention. Statistics for a small-sample study design were applied to investigate OC’s impact. The results showed OC’s contribution to participation dimensions, functional capacity, cognitive functioning, and reduction in schizophrenia symptoms. On the basis of this pilot study’s results, extended research is now being conducted to strengthen the evidence for OC’s effectiveness.

Participation in day-to-day activities of people with schizophrenia is restricted, causing concern to them, their families, service providers and the communities at large. Participation is a significant component of health and recovery; however, factors predicting participation are still not well established. This study examines whether the parameters obtained during acute hospitalization can predict the intensity and diversity of participation in day-to-day activities six months after discharge.In-patients with chronic schizophrenia (N = 104) were enrolled into the study and assessed for cognitive functioning, functional capacity in instrumental activities of daily living (IADL), and symptoms. Six months after discharge, the intensity and diversity of participation in day-to-day activities were evaluated (N = 70).Multiple correlations were found between parameters obtained during hospitalization and participation diversity, but not participation intensity. The model that is better suited to the prediction of participation diversity contains cognitive ability of construction, negative symptoms and number of previous hospitalizations. The total explained variance is 37.8% (FThis study provides evidence for ecological validity of the in-patient evaluation process for the prediction of participation diversity in day-to-day activities six months after discharge. Participation diversity is best predicted through a set of factors reflecting personal and environmental indicators. Implications for rehabilitation Results of in-patient evaluations can predict the diversity of participation in day-to-day activities six months after discharge. Higher prediction of participation diversity is obtained using a holistic evaluation model that includes assessments for cognitive abilities, negative symptoms severity and number of hospitalizations.

Participation in occupations is a basic human right. Although people with schizophrenia commonly experience restrictions in participation, there is a paucity of research in this area.This study aimed to compare the participation patterns of people with schizophrenia to people without mental illness (control group).A total of 140 people of similar age and sex completed the Adults Subjective Assessment of Participation and provided demographic and health-related data.People with schizophrenia tend to participate in fewer activities and to participate alone. However, they participate with similar intensity as those in the control group.The participation patterns of people with schizophrenia are both unique and similar to those of the general population. The differences in participation raise concerns due to signs of restriction and social exclusion. However, it appears that people with schizophrenia benefit from occupation and community-based services that promote and support participation with others in diverse activities.

article i nfo Keywords: Language fMRI DMN Schizophrenia Reduced functional connectivity (FC) in schizophrenia has been demonstrated either in task related or 'de- fault network' areas, but not between these networks, which interact meaningfully. We examined the role of FC between the inferior frontal gyrus (IFG) and medial prefrontal cortex (mPFC) in determining language-lateralization during a language task, and its association with structural integrity of the corpus-callosum. Only schizophrenia patients presented increased mPFC-IFG FC during task, which addition- ally corresponded to decreased white-matter organization of the corpus-callosum. These findings suggest that inability to suppress irrelevant internally-generated information while processing external stimuli might be the basis of functional psychopathology in schizophrenia.

Background: Football (soccer) betting, as a strategic form of betting, became one of the favorite wagers for pathological gamblers. Previous studies demonstrated the psychological and biological significance of the ‘illusion of control’ (personal control) and ‘near miss’ results in gambling. In our study, we explored whether knowledge and expertise of pathological sports gamblers can ensure a successful bet. Sample and Methods: Participants were divided into three groups of individuals – pathological gamblers, amateurs and laypersons – and were asked to predict in advance the general result and the exact result of football matches in the European Champions League Round of 16. Results: The 165 participants included 53 pathological sports gamblers (52 males and 1 female), 78 laypersons (45 females and 33 males) and 34 amateurs (all males). After a thorough statistical analysis, we found no significant differences between the groups, no matter what kind of previous knowledge they had acquired. Conclusion: This study demonstrates that the ‘illusion of control’ of pathological gamblers, attained by knowledge of the game and its latest data and information (especially in a strategic gamble as football betting), has no factual background. Moreover, our study demonstrates without a doubt that there is no significant difference between the male pathological sports gamblers group and the male/female laypersons group.

APOBEC3 proteins catalyze deamination of cytidines in single-stranded DNA (ssDNA), providing innate protection against retroviral replication by inducing deleterious dC > dU hypermutation of replication intermediates. APOBEC3G expression is induced in mitogen-activated lymphocytes; however, no physiologic role related to lymphoid cell proliferation has yet to be determined. Moreover, whether APOBEC3G cytidine deaminase activity transcends to processing cellular genomic DNA is unknown. Here we show that lymphoma cells expressing high APOBEC3G levels display efficient repair of genomic DNA double-strand breaks (DSBs) induced by ionizing radiation and enhanced survival of irradiated cells. APOBEC3G transiently accumulated in the nucleus in response to ionizing radiation and was recruited to DSB repair foci. Consistent with a direct role in DSB repair, inhibition of APOBEC3G expression or deaminase activity resulted in deficient DSB repair, whereas reconstitution of APOBEC3G expression in leukemia cells enhanced DSB repair. APOBEC3G activity involved processing of DNA flanking a DSB in an integrated reporter cassette. Atomic force microscopy indicated that APOBEC3G multimers associate with ssDNA termini, triggering multimer disassembly to multiple catalytic units. These results identify APOBEC3G as a prosurvival factor in lymphoma cells, marking APOBEC3G as a potential target for sensitizing lymphoma to radiation therapy.

ObjectivesMental health conditions (MHC) have been associated with restrictions in daily life participation and functioning affecting health and well-being. Substantial numbers of people with MHC experience hospitalizations, however, there is limited evidence supporting functional interventions in the in-patient setting to promote recovery. The OC is an intervention implemented during sub-acute hospitalization, which attempts to promote activity and participation of people with MHC, both during the in-patient stay and upon return to the community, with a view to enabling recovery. To facilitate its implementation, we investigate the OC effectiveness.AimsInvestigate the OC contribution to cognition, symptoms and functional capacity among inpatients with schizophrenia.MethodsThis is a quasi-experimental, prospective, pre/post-designed study with convenience sampling. Inpatients with schizophrenia were enrolled into the study group participating in the OC intervention (n = 16); or the control group participating in hospital treatment as usual (n = 17). The study participants completed evaluations at baseline and at discharge or after 10 weeks with: Neurocognitive State Examination, Trail Making Test, Ray Complex Figure, and Category Fluency Test for aspects of cognition; Positive and Negative Syndrome Scale for symptoms severity, and Observed Tasks of Daily Living-Revised for functional capacity.ResultsStatistically significant improvement in cognitive functioning, symptoms severity and functional capacity was found in the study group after the intervention. These changes were not observed in the control group.ConclusionThe results support the OC effectiveness for cognitive and functional capacity improvement and symptomology relief. The findings advance the body of evidence for functional interventions in hospital settings.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Background Numerous studies have shown that anxiety and depression are more prevalent among patients suffering from chronic skin disorders. Objectives The aims of this study were to assess the prevalences of depression and anxiety in patients suffering from chronic skin disorders, focusing particularly on allergic skin conditions. Additionally, we investigated resilience to disease progression using the Sense of Coherence Scale. Methods A total of 112 consecutive patients without known psychiatric disease were interviewed and asked to complete questionnaires in order to assess psychiatric symptomatology. The following scales were completed: the Mini International Neuropsychiatric Interview; the Hamilton Anxiety Scale (HAS); the Hamilton Depression Rating Scale (HDRS); and the self-administered questionnaire for the Sense of Coherence Scale (SoCS). Results Rates of anxiety and depression in patients with allergic and non-allergic conditions were considerably higher than those in the general population. This difference was notable in patients with allergic skin diseases, reaching 58.3 and 48.3%, compared with 15.4 and 23.1% for participants with non-allergic conditions, as measured by the HAS and HDRS, respectively (P

Background Transcranial magnetic stimulation (TMS) enables non-surgical activation of specific brain areas. TMS over the prefrontal cortex (PFC) is emerging as a significant tool that can augment or replace non/partially effective antidepressant medications. Deep TMS (DTMS) utilizes newly developed coils that enable effective stimulation of deeper cortical layers involved in the pathophysiology of depression. Objectives We aimed to assess the H1-DTMS coil as an add-on to antidepressants in treating patients with major depression. We also intended to evaluate whether the antidepressant outcome of DTMS treatment is affected by a cognitive–emotional procedure performed during stimulation. Methods 57 patients were enrolled in the study that included 4 weeks of daily 20 Hz stimulation sessions and additional 4 weekly sessions as a short maintenance phase. Two subgroups of patients received either positive or negative cognitive–emotional reactivation along with the stimulation sessions. Results 21 of 46 patients (46%) who received at least 10 stimulation sessions achieved response (improvement of ≥ 50% in the Hamilton Depression Rating Scale (HDRS)) and 13 of them (28%) achieved remission (HDRS-24 ≤ 10) by the end of the daily treatment phase. Improvements were smaller in the negatively reactivated group and Beck Depression Inventory scores were not significantly improved in this group. Conclusions DTMS over the PFC proved to be safe and effective in augmenting antidepressant medications. Negative cognitive–emotional reactivation can disrupt the therapeutic effect of DTMS. A large sham controlled study is required to further establish the effectiveness of DTMS as an augmentation treatment and the role of cognitive reactivation during stimulation.

Introduction: Repetitive transcranial magnetic stimulation (rTMS) has proven effective. Recently, a greater intracranial penetration coil has been developed. We tested the efficacy of the coil in the treatment of resistant major depression. Methods: Our sample included seven patients suffering from major depression who were treated using Brainsway's H1-coil connected to a Magstim rapid 2 stimulator. Deep TMS treatment was given to each patient in five sessions per week over a period of 4 weeks. Patients were treated with 120% intensity of the motor threshold and a frequency of 20 HZ with a total of 1,680 pulses per session. Results: Five patients completed 20 sessions: one attained remission (Hamilton Depression Rating Scale (HDRS)=9); three patients reached a reduction of more than 50% in their pre-treatment HDRS; and one patient achieved a partial response (i.e., the HDRS score dropped from 21 to 12). Average HDRS score dropped to 12.6 and average Hamilton Anxiety Rating Scale score dropped to 9.Two patients dropped out: one due to insomnia and the second due to a lack of response. Discussion: Compared to the pooled response and remission rates when treating major depression with rTMS, deep TMS as used in this study is at least similarly effective. Still, a severe limitation of this study is its small sample size, which makes the comparison of the two methods in terms of their effectiveness or side effects impossible. Greater numbers of subjects should be studied to achieve this aim. Conclusions: An H1 deep TMS coil could be used as an alternative treatment for major depressive disorder. Depression and Anxiety, 2010. © 2010 Wiley-Liss, Inc.

Background Numerous neuropsychological studies reported impaired Stroop performance in major depressive disorder (MDD) patients. Methods The present study attempted to identify possible neuropsychological mechanisms involved in this impairment in untreated MDD outpatients (n = 75) as compared to healthy subjects (n = 83). Inspection Time, Finger Tapping, Simple and Choice Reaction Time were considered as measures of perceptual, motor, psychomotor speed, and response selection, respectively. Results MDD patients performed significantly slower than healthy controls in the neutral and the congruent conditions, but not in the incongruent ones. In order to identify predictors of Stroop performance, linear hierarchical regressions analyses were performed. Age, motor and psychomotor speed were predictors of response time and accuracy on Stroop performance. Significant correlations between response time and the number of errors in all three Stroop conditions were found in MDD patients, while such a correlation was obtained in the healthy controls only in the incongruent condition. Limitations Although education was included as a covariate in our analyses, suggesting that the observed effects could not be ascribed to education differences, further testing with education-matched samples is warranted. Conclusions Our study shows that the Stroop task performance is affected by both aging and MDD. Impairment in the Stroop performance can be predicted by psychomotor slowness and by vigilance level in MDD outpatients, but not by impairment of selective attention per se.

Aquacultured koi and common carp (Cyprinus carpio) are intensively bred for ornamental purposes and for human consumption worldwide. The carp and koi farming industries have suffered enormous economic losses over the past decade due to an epizootic disease caused by Cyprinus herpesvirus-3 (CyHV-3) also known as koi herpesvirus and carp interstitial nephritis gill necrosis virus. CyHV-3 is a large dsDNA virus, morphologically similar to herpesviruses, yet contains genetic elements similar to those of pox, irido- and herpesviruses. Considering the phylogenic distance between CyHV-3 and higher vertebrate herpesviruses, CyHV-3 represents the prototype of viruses assigned to the novel family Alloherpesviridae. Although emergence of a new virus rarely initiates a pandemic so severe that it reduces the life expectancy of a population, CyHV-3 is exceptional because of its enormous impact on the world carp population. High population density is the major contributing factor to the epizootic disease caused by CyHV-3.

Introduction: Impulsivity has been shown to be a major variable in the etiology of suicide and aggression, but has not been researched as much in the schizophrenic population, which is characterized by serious suicide and aggression risks. Methods: 68 male schizophrenia patients responded to a battery of measures including the Positive and Negative Syndrome Scale (PANSS), the impulsivity control scale (IS), the Suicide Risk Scale (SRS) and the Overt Aggression Scale. Results: We divided our subjects into those who received scores above and below the median on the IS. The high- impulsivity group had higher present and past rates of suicidal ideation and showed a trend for more lifetime suicidal attempts than the low-impulsivity group. The impulsivity score correlated positively with the SRS score and with some of the scores of the PANSS (the positive symptoms score, the general psychopathology score and the total score). A multiple regression analysis revealed that an older age, higher levels of aggression, high impulsivity and an elevated score on the general psychopathology subscale of the PANSS contributed positively and significantly to the explained variance of the SRS. Conclusions: Our study supports the contention that high impulsivity in schizophrenia patients is significant in the etiology of suicide in schizophrenia. However, the relationship between impulsivity and aggression in schizophrenia patients, and also the amelioration of impulsivity by pharmacological interventions, require further study.

Background Most antidepressant medications in current use have several disadvantages: a delayed therapeutic effect, side effects, stigmatization and concerns about safety for the developing fetus during pregnancy. Several chronobiologic techniques which are free of these disadvantages were proposed as an alternative. The current article reports the design and the initial outcome results of a new chronobiologic multistage intervention (CMI) that is comprised of the following techniques: (i) partial sleep deprivation during the second half of the night (wake therapy – WT), (ii) medium (green) wavelength light in combination with dawn simulation (DS), (iii) bright light therapy (BLT), and (iv) sleep phase advance (SPA). Methods The study was conducted as a set of 12 single-case designs with moderate-to-severe depressive volunteering patients. Depression, anxiety and tension measurements were taken on a daily basis beginning with a baseline measurement (T0), followed by a set of four consecutive morning measurements during the therapeutic intervention (T1–T4),and with a final measurement carried out at the end of 4 weeks of follow-up (T5). Results A clinically significant rapid improvement of the depressive symptoms was demonstrated and maintained for at least 4 weeks after the end of the intervention. No dropouts or compliance difficulties were observed. Patient satisfaction was high, and other than having to sleep for four nights at the Research and Development Unit, participants were not inconvenienced by the nature of the therapeutic design. Sleepiness in the late afternoon hours was reported by several of the participants, but did not reach a level that interfered with their ability to function. Levels of tension did not show a consistent improvement along the intervention procedure and were not maintained in follow-up. There was some unexpected improvement in the level of anxiety that persisted at follow-up. This latter finding requires further validation by additional studies. Conclusions These initial findings showed the procedure to be effective and well tolerated. It affords many advantages, such as the achievement of a rapid response, no extinction of the therapeutic effect after 4 weeks of follow-up, safety, high patient compliance and cost effectiveness. These encouraging results warrant validation in further randomized controlled clinical trials.

Objective Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood. Principal treatment options for ADHD today include the psychostimulants, mainly methylphenidate (MPH). However, approximately 30% to 50% of children and adults with ADHD either do not respond to or do not tolerate treatment with stimulants. In this 8-week open-label, MPH-controlled, parallel group design study, we investigate the efficacy of reboxetine, a new selective norepinephrine reuptake inhibitor, in the treatment of boys with ADHD with a history of intolerance to MPH therapy. Method Twenty-seven outpatient boys, aged 6 to 16 years, diagnosed with ADHD, participated in the study. Those with a history of intolerance to MPH therapy were assigned to treatment with reboxetine (2-8 mg/d), and the rest were assigned to treatment with MPH (10-20 mg/d) as the control group. The primary outcome measure for this study was the change in rating scores on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, ADHD Scale (DAS) that was assessed at baseline and at 8 weeks. Results At the end of 8 weeks, both reboxetine and MPH treatment regimens resulted in significant improvement in ADHD symptoms. The change in the reduction in the total DAS score and the DAS subscale scores between the reboxetine group and the MPH group was not statistically significant in any of the scores. Conclusions Although preliminary, results of this study indicate that the use of reboxetine, a new selective norepinephrine reuptake inhibitor, in the treatment of ADHD could increase treatment options available for children who have shown intolerance or who are unresponsive to MPH.

Human APOBEC3G (A3G) belongs to a family of polynucleotide cytidine deaminases. This family includes APOBEC1 and AID, which edit APOB mRNA and antibody gene DNA, respectively. A3G deaminates cytidines to uridines in single-strand DNA and inhibits the replication of human immunodeficiency virus-1, other retroviruses, and retrotransposons. Although the mechanism of A3G-catalyzed DNA deamination has been investigated genetically and biochemically, atomic details are just starting to emerge. Here, we compare the DNA cytidine deaminase activities and NMR structures of two A3G catalytic domain constructs. The longer A3G191-384 protein is considerably more active than the shorter A3G198-384 variant. The longer structure has an alpha1-helix (residues 201-206) that was not apparent in the shorter protein, and it contributes to catalytic activity through interactions with hydrophobic core structures (beta1, beta3, alpha5, and alpha6). Both A3G catalytic domain solution structures have a discontinuous beta2 region that is clearly different from the continuous beta2 strand of another family member, APOBEC2. In addition, the longer A3G191-384 structure revealed part of the N-terminal pseudo-catalytic domain, including the interdomain linker and some of the last alpha-helix. These structured residues (residues 191-196) enabled a novel full-length A3G model by providing physical overlap between the N-terminal pseudo-catalytic domain and the new C-terminal catalytic domain structure. Contrary to predictions, this structurally constrained model suggested that the two domains are tethered by structured residues and that the N- and C-terminal beta2 regions are too distant from each other to participate in this interaction.

Patients with schizophrenia exhibit a decrease or loss of normal anatomical brain asymmetry that also extends to functional levels. We applied functional magnetic resonance imaging (fMRI) to investigate language lateralization in patients with schizophrenia during their first episode of illness, thus excluding effects of chronic illness and treatment. Brain regions activated during language tasks of verb generation and passive music listening were explored in 12 first-episode patients with schizophrenia and 17 healthy controls. Regions of interest corresponded to Broca's area in the inferior frontal gyrus (IFG) and Wernicke's area in the superior temporal sulcus (STS). Patients with schizophrenia had significantly smaller lateralization indices in language-related regions than controls. A similar effect was observed in their IFG and STS regions. There was no difference between the groups in the auditory cortex for the music task. Patients with schizophrenia demonstrated greater activation than the controls in temporal regions: the difference was larger in patients with more severe positive symptom subscores. In conclusion, patients with schizophrenia demonstrated loss of normal functional brain asymmetry, as reflected in diminished lateralization of language-related activation in frontal and temporal regions. This phenomenon was already present during their first episode of psychosis, possibly reflecting developmental brain abnormalities of the illness.

Previous neuropsychological studies demonstrated various deficits of impulse control in pathological gamblers (PGs). However, there are limited data available on response-inhibition impairment among PGs. The present study attempted to assess response inhibition in untreated PGs ( N =83), in comparison with normal subjects ( N =84). Go/no-go and target-detection conditions of a computerized task were used as a measure of response-inhibition ability. A repeated measures analysis of covariance (ANCOVA-RM) was used with response time, variability of response time, and number of false alarms and misses as dependent measures; group (PG and controls) as the between-subjects measure; condition (target detection or go/no-go) and time slice (first and second in each condition) as repeated measures within-subject factors; and educational level as a covariate. Our results showed that PGs were significantly more impaired in both target detection and go/no-go task performance than controls. The PGs had significantly more false alarms and misses than controls, and they were slower and less consistent in their responses.

CyHV-3 (Cyprinid herpesvirus-3) is a large DNA virus that causes a fatal disease in koi and common carp. Infection with wild type or attenuated virus induces an immune response that renders the fish resistant to further virus challenges. The kinetics and affinity of the antibody response in immune fish depend on the temperature of the water. Virus-inoculated fish produce anti-CyHV-3 antibodies, which gradually decrease during 280 days post infection to a level slightly above that of naïve fish. The protection against the virus is proportional to the titer of anti-virus antibodies in recently inoculated fish. Nevertheless, these immunized fish, even with no-longer detectable antibodies, are resistant to virus infection, probably due to the subsequent rapid response of high affinity anti-virus antibodies. The fact that anti-virus antibodies neutralize in vitro the pathogenic effects of the virus emphasizes the central role probably played by the antibodies in anti-CyHV-3 protection in vivo.

Neurobiological research has shown the potential involvement of serotonergic, dopaminergic and opioid dysfunction in the pathophysiology of pathological gambling. In this review, we present current theories of the neuropathology of pathological gambling, paying particular attention to the role of the neural circuitry underlying motivation, reward, decision-making and impulsivity. This review also presents a literature review of current pharmacological treatment strategies for pathological gambling, such as selective serotonin reuptake inhibitors (SSRIs), opioid receptor antagonists, anti-addiction drugs and mood stabilizers, and also discusses the role of nonpharmacological interventions. A hypothetical model of the clinical subtypes of pathological gambling is presented, e.g. the impulsive subtype, the obsessive-compulsive subtype and the addictive subtype. This model attempts to integrate current knowledge in the field of pathological gambling regarding neuropathology, psychiatric co-morbidity, family history, genetics, course of illness, gender and response to pharmacological treatment. Finally, it is proposed that the existence of possible clinical subtypes of pathological gambling may provide a potential framework for matching the various subtypes with specific pharmacotherapies.

Supplemental Digital Content is available in the text., Objective: The goal of this study was to explore the tolerability, safety, and treatment response of switching from oral olanzapine to paliperidone extended release (ER). Methods: Adult patients with nonacute schizophrenia who had been treated unsuccessfully with oral olanzapine were switched to flexible doses of paliperidone ER (3 to 12 mg/d). The primary efficacy outcome was a ≥20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint for patients who switched medications because of lack of efficacy with olanzapine and noninferiority versus previous olanzapine treatment (mean endpoint change in PANSS total scores vs. baseline of ≤5 points) for patients who switched for reasons other than lack of efficacy. Safety and tolerability were assessed by monitoring adverse events, extrapyramidal symptoms, and weight change. Results: Of 396 patients, 65.2% were men, mean age was 40.0±12.0 years, and 75.5% had paranoid schizophrenia. Among the patients whose main reason for switching was lack of efficacy, an improvement in the PANSS total score of ≥20% occurred in 57.4% of patients. Noninferiority was confirmed for each subgroup of patients whose main reason for switching was something other than lack of efficacy. Paliperidone ER was generally well tolerated. Extrapyramidal symptoms as measured by total Extrapyramidal Symptom Rating Scale scores showed statistically significant and clinically relevant improvements at endpoint, the average weight decreased by 0.8±5.2 kg at endpoint, and a clinically relevant weight gain of ≥7% occurred in 8.0% of patients. Conclusion: Paliperidone ER flexibly-dosed over 6 months was well tolerated and associated with a meaningful clinical response in patients with nonacute schizophrenia who had previously been unsuccessfully treated with oral olanzapine.

OBJECTIVES: Selective serotonin reuptake inhibitors (SSRIs) are currently considered as the first drug of choice in the treatment of panic disorder (PD). The aim of this long-term, naturalistic comparison study was to compare 4 SSRIs with respect to tolerability and treatment outcome of PD. Outcome measures included relapse rates and adverse effects. METHODS: Two hundred patients with PD were enrolled in our study. All subjects met DSM-IV criteria for PD or PD with agoraphobia (PDA). All patients were assigned to receive SSRI monotherapy for 12 months with either citalopram (n = 50), fluoxetine (n = 50), fluvoxamine (n = 50), or paroxetine (n = 50) in a randomized, nonblinded fashion. Both the treating psychiatrist and the patients were not blind to the assigned treatment, but the clinician raters were blind to the study medication. The study design allowed for assignment of a particular SSRI as indicated according to the clinical judgment of the study psychiatrists. The Panic Self-Questionnaire, which is a self-report scale, was administered at baseline and then once per month during the duration of the 12-month study. The visual analog scale and the Clinical Global Impression Scale were administered at baseline and then once per month during the period of the study. Reports of sexual dysfunction were assessed using a nonstructured clinical interview at monthly visits. The body weight of study subjects was measured at baseline, and then at the 12th month visit end point. RESULTS: Of 200 patients who entered the study, 127 patients (63.5%) completed the full 12-month protocol. Retention rates were highest for paroxetine (76% [38/50]), intermediate for citalopram (68% [34/50]) and fluvoxamine (60% [30/50]), and lowest for fluoxetine (50% [25/50]). Patients who completed the 12-month protocol responded favorably to the study treatment. The paroxetine and the citalopram groups had significantly lower rates of panic symptoms as measured at visits on weeks 4 and 8. At visits on months 3, 6, 9, and 12, however, there were no statistically significant differences between the 4 groups in relapse rates (defined as the occurrence of 1 or more panic attacks during the previous week of treatment) (F1,127 = 0.17; P = 0.13 [not statistically significant]). At the 12th month end point, patients in all 4 treatment groups had a statistically significant increase in body weight. Body weight among the study population increased by 6.1 + 4.9 kg from a mean weight of 72.4 + 7.3 kg at the onset of treatment. Reports of sexual adverse effects at the 12th month visit were similar in the citalopram, fluoxetine, and paroxetine groups, but the fluvoxamine patient group reported fewer sexual adverse effects at the 12th month visit. CONCLUSIONS: Most of our PD patients responded well to 12-month treatment with either citalopram, fluoxetine, fluvoxamine, or paroxetine, and the overall response rate was equal after the first 4 weeks of treatment. Although patients treated with paroxetine had the lowest dropout rates during the initiation phase, they had the highest rate of adverse effects as measured at the 12th month visit. Conversely, patients in the fluvoxamine group had the highest dropout rate (which was primarily caused by adverse effects in the initiation phase of treatment.); however, patients who were able to tolerate fluvoxamine throughout the full course of the study were observed to have lower rates of sexual dysfunction and weight gain compared with patients treated with the other agents. Overall, when measured at the 12th month visit, monotherapy with paroxetine and citalopram was associated with a higher rate of sexual adverse effects than was treatment with fluoxetine or fluvoxamine. In addition, monotherapy with paroxetine, citalopram, and fluoxetine seemed to cause more weight gain than did treatment with fluvoxamine.

While the incidence of criminal offense in individuals with schizophrenia does not necessarily differ from that of the normal population, in contrast, the rate of sexual crimes among individuals with schizophrenia is relatively low. Due to low numbers, description of sexual criminal behavior among schizophrenia patients remains relatively unexplored. In order to investigate clinical, socio-demographic and sexual factors associated with deviant sexual behavior in schizophrenia sex offenders we retrospectively compared a large subgroup of schizophrenia sex offenders with a group of schizophrenia patients incarcerated for other criminal behaviors and a group of sex offenders without schizophrenia. Results indicated significant differences distinguishing schizophrenia sex offenders from schizophrenia non-sex offenders, the former of whom were more likely to be married, employed, non-heterosexual (homosexual and bisexual orientations) and demonstrated less hospitalization, antisocial personality, substance abuse, negative symptoms and overall illness severity. Individuals with schizophrenia had a tendency towards female victims compared to non-schizophrenia sex offenders whose victims tended to be male. Study observations indicate important differences between the 3 subgroups suggesting that the schizophrenia sex offender subpopulation may be a unique subgroup of comorbid conditions.

To investigate the role of genes encoding regulators of G protein signaling in early therapeutic response to antipsychotic drugs and in susceptibility to drug-induced extrapyramidal symptoms. As regulators of G protein signaling and regulators of G protein signaling-like proteins play a pivotal role in dopamine receptor signaling, genetically based, functional variation could contribute to interindividual variability in therapeutic and adverse effects.Consecutively hospitalized, psychotic patients with Diagnostic and Statistical Manual of Mental Disorder-IV schizophrenia (n=121) were included in the study if they received treatment with typical antipsychotic medication (n=72) or typical antipsychotic drugs and risperidone (n=49) for at least 2 weeks. Clinical state and adverse effects were rated at baseline and after 2 weeks. Twenty-four single nucleotide polymorphisms were genotyped in five regulators of G protein signaling genes.None of the single nucleotide polymorphisms were related to clinical response to antipsychotic treatment at 2 weeks. Five out of six single nucleotide polymorphisms within or flanking the RGS2 gene were nominally associated with development or worsening of parkinsonian symptoms (PARK+) as measured by the Simpson Angus Scale, one of them after correction for multiple testing (rs4606, P=0.002). A GCCTG haplotype encompassing tagging single nucleotide polymorphisms within and flanking RGS2 was significantly overrepresented among PARK+ compared with PARK--patients (0.23 vs. 0.08, P=0.003). A second, 'protective', GTGCA haplotype was significantly overrepresented in PARK--patients (0.13 vs. 0.30, P=0.009). Both haplotype associations survive correction for multiple testing.Subject to replication, these findings suggest that genetic variation in the RGS2 gene is associated with susceptibility to extrapyramidal symptoms induced by antipsychotic drugs.

Human immunodeficiency virus 1 (HIV-1) Rev and integrase (IN) proteins are required within the nuclei of infected cells in the late and early phases of the viral replication cycle, respectively. Here we show using various biochemical methods, that these two proteins interact with each other in vitro and in vivo. Peptide mapping and fluorescence anisotropy showed that IN binds residues 1-30 and 49-74 of Rev. Following this observation, we identified two short Rev-derived peptides that inhibit the 3′-end processing and strand-transfer enzymatic activities of IN in vitro. The peptides bound IN in vitro, penetrated into cultured cells, and significantly inhibited HIV-1 in multinuclear activation of a galactosidase indicator (MAGI) and lymphoid cultured cells. Real time PCR analysis revealed that the inhibition of HIV-1 multiplication is due to inhibition of the catalytic activity of the viral IN. The present work describes novel anti-HIV-1 lead peptides that inhibit viral replication in cultured cells by blocking DNA integration in vivo.

Affective disorders are a major cause of morbidity and disability among middle-aged and older people. Thus, the prophylaxis of both unipolar depression and bipolar disorder in this patient subpopulation is an important task of psychiatrists and other physicians. Although lithium remains an effective prophylactic and treatment agent in younger individuals with bipolar disorder, its prophylactic efficacy and tolerability has not been thoroughly investigated among middle aged and older people with unipolar depression and bipolar disorder. Our study is based on a mirror-image design that compared the clinical course with lithium treatment and the clinical course prior to lithium treatment based on a retrospective chart review. We examined the results obtained with long-term lithium maintenance in a group of 60 middle-aged and older adult patients (age >60 years) with unipolar depression and bipolar disorder. More specifically, we analyzed changes of frequency, severity, and duration of depressive or manic relapses, rate and duration of hospitalizations and suicidal behavior (thoughts or attempts), and various assessments of outcome. A significant reduction was found on all indices during lithium therapy compared to before lithium treatment, attesting to the prophylactic efficacy of long-term lithium in unipolar depression and bipolar disorder. The range of side effects in our sample was similar to that found in other reports in this age group. The probability of relapse and recurrence in patients with bipolar disorder and with unipolar depression can be significantly decreased by lithium prophylaxis. Further investigation is mandated to confirm these findings under double-blind conditions.

The cellular cytidine deaminase APOBEC3G (A3G) was first described as an anti-HIV-1 restriction factor, acting by directly deaminating reverse transcripts of the viral genome. HIV-1 Vif neutralizes the activity of A3G, primarily by mediating degradation of A3G to establish effective infection in host target cells. Lymphoma cells, which express high amounts of A3G, can restrict Vif-deficient HIV-1. Interestingly, these cells are more stable in the face of treatments that result in double-stranded DNA damage, such as ionizing radiation and chemotherapies. Previously, we showed that the Vif-derived peptide (Vif25-39) efficiently inhibits A3G deamination, and increases the sensitivity of lymphoma cells to ionizing radiation. In the current study, we show that additional peptides derived from Vif, A3G, and APOBEC3F, which contain the LYYF motif, inhibit deamination activity. Each residue in the Vif25-39 sequence moderately contributes to the inhibitory effect, whereas replacing a single residue in the LYYF motif completely abrogates inhibition of deamination. Treatment of A3G-expressing lymphoma cells exposed to ionizing radiation with the new inhibitory peptides reduces double-strand break repair after irradiation. Incubation of cultured irradiated lymphoma cells with peptides that inhibit double-strand break repair halts their propagation. These results suggest that A3G may be a potential therapeutic target that is amenable to peptide and peptidomimetic inhibition.

Nervous necrosis virus (NNV) is a member of the Betanodavirus genus that causes fatal diseases in over 40 species of fish worldwide. Mortality among NNV-infected fish larvae is almost 100%. In order to elucidate the mechanisms responsible for the susceptibility of fish larvae to NNV, we exposed zebrafish larvae to NNV by bath immersion at 2, 4, 6, and 8 days postfertilization (dpf). Here, we demonstrate that developing zebrafish embryos are resistant to NNV at 2 dpf due to the protection afforded by the egg chorion and, to a lesser extent, by the perivitelline fluid. The zebrafish larvae succumbed to NNV infection during a narrow time window around the 4th dpf, while 6- and 8-day-old larvae were much less sensitive, with mortalities of 24% and 28%, respectively.

Repeated nicotine administration induces neuro-adaptations associated with abnormal dopaminergic activity. These neuronal changes may contribute to impaired inhibitory control and attention deficit. However, it remains unclear whether smokers perform worse than non-smokers on tests that involve attention and control of impulsivity. The present study examined response inhibition and sustained attention capacities in a large sample of smokers and non-smokers.Continuous Performance Test (CPT) and Go/ NoGo computerized tasks were used as a measure of response-inhibition ability and sustained attention. Threeway repeated measures analysis of covariance was used with response time, variability of response time, number of commission errors (inappropriate responses to stimuli) and number of omission errors (missed stimuli) as dependent measures. Main effects were: group (smokers and controls), condition (CPT and Go/NoGo), and block (in each condition); gender, education, and age were used as covariates.Smokers, as compared to the control group, made more errors of commission in the Go/ NoGo task, reflecting impaired inhibition ability. However, we found no significant differences between the groups in our measure of sustained attention. Impaired response inhibition was found to co-occur with heavy smoking and therefore may be a potential target for the development of more effective cessation programs.

Pathological gambling is classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition as an impulse-control disorder. In the International Classification of Diseases of the WHO, pathological gambling is coded under the heading of 'Habit and Impulse Disorders'. Pathological gambling is a chronic, progressive disorder, which has a prevalence of 1-3.4% among western civilizations. The enormous personal and social consequences of this disorder include a high rate of suicide attempts, job loss, marital and family problems, legal problems, and criminal behavior. Recent studies have demonstrated that pathological gambling patients respond well to treatment with selective serotonin reuptake inhibitors, mood stabilizers and opioid antagonists. These findings support the idea that pathological gambling and other disorders of impulse control may be conceptualized as part of the obsessive-compulsive spectrum disorders or addictive disorders. This article will discuss possible treatment strategies according to different behavior patterns in pathological gambling and also remind the physicians who intend to treat this disorder of the possible diagnosis of pathological gambling.