Differential plasticity and fate of brain-resident and recruited macrophages during the onset and resolution of neuroinflammation.

Microglia and border-associated macrophages (BAMs) are brain-resident self-renewing cells. Here, we examined the fate of microglia, BAMs, and recruited macrophages upon neuroinflammation and through resolution. Upon infection, Trypanosoma brucei parasites invaded the brain via its border regions, triggering brain barrier disruption and monocyte infiltration. Fate mapping combined with single-cell sequencing revealed microglia accumulation around the ventricles and expansion of epiplexus cells. Depletion experiments using genetic targeting revealed that resident macrophages promoted initial parasite defense and subsequently facilitated monocyte infiltration across brain barriers. These recruited monocyte-derived macrophages outnumbered resident macrophages and exhibited more transcriptional plasticity, adopting antimicrobial gene expression profiles. Recruited macrophages were rapidly removed upon disease resolution, leaving no engrafted monocyte-derived cells in the parenchyma, while resident macrophages progressively reverted toward a homeostatic state. Long-term transcriptional alterations were limited for microglia but more pronounced in BAMs. Thus, brain-resident and recruited macrophages exhibit diverging responses and dynamics during infection and resolution.

In vitro production of cat-restricted Toxoplasma pre-sexual stages.

Sexual reproduction of Toxoplasma gondii, confined to the felid gut, remains largely uncharted owing to ethical concerns regarding the use of cats as model organisms. Chromatin modifiers dictate the developmental fate of the parasite during its multistage life cycle, but their targeting to stage-specific cistromes is poorly described1,2. Here we found that the transcription factors AP2XII-1 and AP2XI-2 operate during the tachyzoite stage, a hallmark of acute toxoplasmosis, to silence genes necessary for merozoites, a developmental stage critical for subsequent sexual commitment and transmission to the next host, including humans. Their conditional and simultaneous depletion leads to a marked change in the transcriptional program, promoting a full transition from tachyzoites to merozoites. These in vitro-cultured pre-gametes have unique protein markers and undergo typical asexual endopolygenic division cycles. In tachyzoites, AP2XII-1 and AP2XI-2 bind DNA as heterodimers at merozoite promoters and recruit MORC and HDAC3 (ref. 1), thereby limiting chromatin accessibility and transcription. Consequently, the commitment to merogony stems from a profound epigenetic rewiring orchestrated by AP2XII-1 and AP2XI-2. Successful production of merozoites in vitro paves the way for future studies on Toxoplasma sexual development without the need for cat infections and holds promise for the development of therapies to prevent parasite transmission.

Dimensions of Arachnoid Bulk Ratio: A Superior Optic Nerve Sheath Index for Intracranial Pressure.

Background Discrepancies in the literature regarding optimal optic nerve sheath diameter (ONSD) cutoffs for intracranial pressure (ICP) necessitate alternative neuroimaging parameters to improve clinical management. Purpose To evaluate the diagnostic accuracy of the dimensions of the perineural subarachnoid space to the optic nerve sheath ratio, measured using US, in predicting increased ICP. Materials and Methods In a prospective cohort study from April 2022 to December 2023, patients with suspected increased ICP underwent optic nerve US to determine the dimensions of arachnoid bulk (DAB) ratio and ONSD before invasive ICP measurement. Correlation between the parameters and ICP, as well as diagnostic accuracy, was assessed using area under the receiver operating characteristic curve (AUC) analysis. Results A total of 30 participants were included (mean age, 39 years ± 14 [SD]; 24 female). The DAB ratio and ONSD were significantly larger in participants with increased ICP (38% [0.16 of 0.42] and 14% [0.82 of 6.04 mm], respectively; P < .001). The DAB ratio showed a stronger correlation with ICP than ONSD (rs = 0.87 [P < .001] vs rs = 0.61 [P < .001]). The DAB ratio and ONSD optimal cutoffs for increased ICP were 0.5 and 6.5 mm, respectively, and the ratio had higher sensitivity (100% vs 92%) and specificity (94% vs 83%) compared with ONSD. Moreover, the DAB ratio better predicted increased ICP than ONSD, with a higher AUC (0.98 [95% CI: 0.95, 1.00] vs 0.86 [95% CI: 0.71, 0.95], P = .047). Conclusion An imaging ratio was proposed to predict ICP based on the relative anatomy of the cerebrospinal fluid space, demonstrating more accurate diagnosis of increased ICP and a strong correlation with ICP values, suggesting its potential utility as a neuroimaging marker in clinical settings. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Shepherd in this issue.

Estimating excess mortality and economic burden of Clostridioides difficile infections and recurrences during 2015-2019: the RECUR Germany study.

BACKGROUND: Clostridioides difficile infections (CDIs) and recurrences (rCDIs) remain a major public health challenge due to substantial mortality and associated costs. This study aims to generate real-world evidence on the mortality and economic burden of CDI in Germany using claims data between 2015 and 2019. METHODS: A longitudinal and matched cohort study using retrospective data from Statutory Health Insurance (SHI) was conducted in Germany with the BKK database. Adults diagnosed with CDI in hospital and community settings between 2015 and 2018 were included in the study. Patients had a minimum follow-up of 12-months. All-cause mortality was described at 6-, 12-, and 24-months. Healthcare resource usage (HCRU) and associated costs were assessed at 12-months of follow-up. A cohort of non-CDI patients matched by demographic and clinical characteristics was used to assess excess mortality and incremental costs of HCRU. Up to three non-CDI patients were matched to each CDI patient. RESULTS: A total of 9,977 CDI patients were included in the longitudinal cohort. All-cause mortality was 32%, 39% and 48% at 6-, 12-, and 24-months, respectively, with minor variations by number of rCDIs. When comparing matched CDI (n = 5,618) and non-CDI patients (n = 16,845), CDI patients had an excess mortality of 2.17, 1.35, and 0.94 deaths per 100 patient-months, respectively. HCRU and associated costs were consistently higher in CDI patients compared to non-CDI patients and increased with recurrences. Total mean and median HCRU cost per patient during follow-up was €12,893.56 and €6,050 in CDI patients, respectively, with hospitalisations representing the highest proportion of costs. A total mean incremental cost per patient of €4,101 was estimated in CDI patients compared to non-CDI patients, increasing to €13,291 in patients with ≥ 3 rCDIs. CONCLUSIONS: In this real-world study conducted in Germany, CDI was associated with increased risk of death and substantial costs to health systems due to higher HCRU, especially hospitalisations. HCRU and associated costs were exacerbated by rCDIs.

Epidemiological and clinical burden of Clostridioides difficile infections and recurrences between 2015 - 2019: the RECUR Germany study.

BACKGROUND: This real-world study assessed the epidemiology and clinical complications of Clostridioides difficile infections (CDIs) and recurrences (rCDIs) in hospital and community settings in Germany from 2015 - 2019. METHODS: An observational retrospective cohort study was conducted among adult patients diagnosed with CDI in hospital and community settings using statutory health insurance claims data from the BKK database. A cross-sectional approach was used to estimate the annual incidence rate of CDI and rCDI episodes per 100,000 insurants. Patients' demographic and clinical characteristics were described at the time of first CDI episode. Kaplan-Meier method was used to estimate the time to rCDIs and time to complications (colonic perforation, colectomy, loop ileostomy, toxic megacolon, ulcerative colitis, peritonitis, and sepsis). A Cox model was used to assess the risk of developing complications, with the number of rCDIs as a time-dependent covariate. RESULTS: A total of 15,402 CDI episodes were recorded among 11,884 patients. The overall incidence of CDI episodes declined by 38% from 2015 to 2019. Most patients (77%) were aged ≥ 65 years. Around 19% of CDI patients experienced at least one rCDI. The median time between index CDI episode to a rCDI was 20 days. The most frequent complication within 12-months of follow-up after the index CDI episode was sepsis (7.57%), followed by colectomy (3.20%). The rate of complications increased with the number of rCDIs. The risk of any complication increased by 31% with each subsequent rCDI (adjusted hazard ratio [HR]: 1.31, 95% confidence interval: 1.17;1.46). CONCLUSIONS: CDI remains a public health concern in Germany despite a decline in the incidence over recent years. A substantial proportion of CDI patients experience rCDIs, which increase the risk of severe clinical complications. The results highlight an increasing need of improved therapeutic management of CDI, particularly efforts to prevent rCDI.

The Protective Effect of Juçara Fruit (Euterpe edulis Martius) Extracts on LPS-Activated J774 Macrophages.

This study investigated the anti-inflammatory effect of hydrophilic and lipophilic extracts from juçara fruits (Euterpe edulis Martius) through measurement of nitric oxide (NOx) and cytokines (IL-12p70, TNF-α, INF-γ, MCP-1, IL-6, and IL-10). J774 macrophages were stimulated with lipopolysaccharides (1 µg/mL) and treated with various concentrations (1-100 µg/mL) of juçara fruits extracts from crude extracts, and hexane, dichloromethane, ethyl acetate, and butanol fractions. Potential relationships between the phenolic composition of the extracts determined by LC-ESI-MS/MS and their anti-inflammatory capacity were also evaluated. Hexane and dichloromethane fractions inhibited NOx and IL-12p70 while increased IL-10. Hexane fractions also decreased IL-6 and IFN-γ production. Hexane and dichloromethane fractions showed a higher number of phenolic compounds (32 and 34, respectively) than the other extracts tested and were also the only ones that presented benzoic acid and pinocembrin. These results suggest juçara fruits compounds as potential anti-inflammatory agents, especially those of a more apolar nature.

Height benefit of GnRH agonists after age 8 in a Portuguese cohort of central precocious puberty.

OBJECTIVE: Idiopathic central precocious puberty (iCPP) is common in paediatric endocrinology. Gonadotropin-releasing hormone agonists (GnRHa) are safe, but the effect on final height and the ideal timing for treatment remains controversial. This study aims to assess the effectiveness of GnRHa on growth outcomes in girls with iCPP treated before and after the age of 8 years old. DESIGN AND PATIENTS: This retrospective longitudinal study evaluated data from Portuguese girls with iCPP who completed treatment between 2010 and 2021. MEASUREMENTS: Auxological and clinical characteristics were compared according to age at treatment onset. RESULTS: A cohort of 134 girls with iCPP, was divided into early treatment (ET) (<8 years, n = 48) and later treatment (LT) groups (≥8 years, n = 86). In both groups, most children presented with Tanner II and III. Tanner IV was more frequent in LT group (p = .003). At the end of treatment, predicted adult height increased in both groups (ET p = .032; LT p = .04) and bone age significantly slowed down in all participants (p = .008, p = .034). The height gain was greater in the ET group, but without significant differences (p = .065). CONCLUSIONS: Treatment with GnRHa improved final height in all girls with iCPP, even when initiated after 8 years. To achieve better outcomes, treatment should be provided promptly after diagnosis.

Measuring subjective aspects of participation in adults with disabilities: A systematic review of the coverage, content validity and internal structure of standardised instruments.

OBJECTIVE: To systematically review evidence on the coverage, content validity and internal structure of self-report measures capturing subjective aspects of participation for adults with disabilities. DATA SOURCES: EMBASE, MEDLINE and reference lists were searched until July 10th, 2022 for articles on measurement properties of instruments measuring participation as defined in the International Classification of Functioning, Disability and Health, from a subjective perspective. METHOD: Each instrument was assessed for its coverage of subjective aspects of participation. The Consensus-based Standards for the Selection of Health Measurement Instruments were used to assess the quality of each study. Content validity and internal structure (structural validity, internal consistency and cross-cultural validity) were rated against published standards and qualified by the adapted Grading of Recommendations Assessment, Development and Evaluation. RESULTS: Thirty-eight studies regarding 10 instruments were analysed. Most instruments mix activity and participation items. Only the Measure of Experiential Aspects of Participation (with high-quality evidence of sufficient structural validity and generally sufficient internal consistency), the Participation Enfranchisement and the Community Integration Measure showed adequate coverage. For all instruments, evidence of content validity is of low- to very low quality. There is high-quality evidence that the Participation Scale is not unidimensional. CONCLUSION: In general, the coverage and the evidence for content validity and internal structure of measures capturing experiential aspects of participation are limited. The Measure of Experiential Aspects of Participation has the best level of evidence in support of its use. The score of the Participation Scale cannot be considered an adequate reflection of participation.

Barriers to mental health services utilisation in Portugal - results from the National Mental Health Survey.

BACKGROUND: The treatment gap for mental disorders remains a challenge worldwide. Identifying reasons for nontreatment may contribute to reducing this gap. AIMS: To evaluate sociodemographic and clinical factors associated with use and barriers to treatment in Portugal. METHOD: Data from the 2009 National Mental Health Survey were used. Participants reported 12-month treatment and reasons for nontreatment. Logistic regression models analysed the association between sociodemographic (education; employment; income; marital status) and clinical variables (mental disorder diagnosis; disability) with treatment and type of barriers (low perceived need; structural; attitudinal). RESULTS: The majority of participants with a mental disorder was not treated. Treatment was more common among participants with mood disorders (OR = 4.19; 95% CI: 2.72-6.46), and disability (OR = 2.43; 95% CI: 1.33-4.46), and less common among single participants (OR = 0.38; 95% CI: 0.20-0.70) and those with basic/secondary education (OR = 0.42; 95% CI: 0.24-0.73). Attitudinal barriers were more likely among participants with none/primary (OR = 2.90; 95% CI: 1.42-5.90) and basic/secondary education (OR = 1.70; 95% CI: 1.01-2.85), and less likely among those with substance use disorders (OR = 0.27; 95% CI: 0.10-0.70). Low perceived need was higher among single people (OR = 1.77; 95% CI: 1.01-3.08), and lower among those with anxiety (OR = 0.50; 95% CI: 0.28-0.90) and mood disorders (OR = 0.16; 95% CI: 0.09-0.30). Unemployed participants had higher odds of reporting structural barriers (OR = 3.76; 95% CI: 1.29-10.92). CONCLUSIONS: This study identifies factors associated with nontreatment, providing useful evidence to develop policies and effective interventions.

Identifying the variables that drive tamoxifen-independent CreERT2 recombination: Implications for microglial fate mapping and gene deletions.

Ligand-dependent Cre recombinases such as the CreERT2 system allow for tamoxifen-inducible Cre recombination. Important examples are the Cx3cr1-CreERT2 and Sall1-CreERT2 lines that are widely used for fate mapping and gene deletion studies of brain macrophages. Our results now show that both CreERT2 lines can exhibit a high rate of tamoxifen-independent "leaky" excision with some reporter strains, while this is not observed with others. We suggest that this disparity is determined by the length of the floxed transcriptional STOP cassette that is incorporated in the various reporter lines. In addition, the rate of spontaneous recombination was also determined by the CreERT2 expression levels and the longevity of the CreERT2-expressing cells. The implications of these results are discussed in the context of fate mapping and inducible gene deletion studies in macrophages and microglia.

The experience of school-aged children with hospitalisation.

AIMS AND OBJECTIVES: This study intended to contribute to the improvement of nursing care for both children and their parents and aimed to identify the best and worst experiences of school-aged children during hospitalisation. BACKGROUND: Child hospitalisation has traditionally been studied from the parent's perspective, but studies in which the child is the subject are scarce and mainly focus on to the hospitalisation experiences. DESIGN: A cross-sectional, observational and descriptive exploratory design was used, and STROBE reporting guidelines were followed. METHODS: A paper survey was applied by the primary researcher within a 3 months period to 252 children. It presented two open-ended statements: 'In my opinion the best thing about the hospital is …' and 'In my opinion the worst thing about the hospital is…'. The study was submitted and approved by the national data protection commission and also by the ethics committees of each of the six institutions where the study was undertaken. Informed consent was also obtained from children and parents. RESULTS: Answers were analysed through content analysis. Five categories were identified for each of the open-ended statements. Children identified 'people', 'physical environment', 'activities', 'outcomes' and 'food' as best experiences. The worst experiences included: 'feelings', 'activities', 'food', 'environment' and 'outcomes'. CONCLUSIONS: The results allowed the identification of the children's most valued aspects of hospitalisation. RELEVANCE TO CLINICAL PRACTICE: The results should be considered by healthcare professionals in order to make the hospitalisation experience more positive from the perspective of the school-aged children.

How did the use of psychotropic drugs change during the Great Recession in Portugal? A follow-up to the National Mental Health Survey.

BACKGROUND: Research suggests that economic recessions might be associated with a higher use of psychotropic drugs, but literature is scarce and contradictory in identifying the most vulnerable groups. This study aims to assess possible changes in the use of psychotropic drugs due to the economic recession in Portugal, by comparing self-reported consumption in 2008/09 and 2015/16. METHODS: Data from the World Mental Health Survey Initiative Portugal (2008/09) and the National Mental Health Survey Follow-Up (2015/16) were used (n = 911). McNemar's tests were performed to estimate changes in consumption of any psychotropic drug and of antidepressants, anxiolytics, and hypnotics/sedatives. Multiple Generalised Estimating Equations models with interaction effects were used to estimate the population odds of consuming psychotropic drugs according to year, gender and age. RESULTS: An increase of 6.74% was estimated in the consumption of psychotropic drugs from 2008/09 to 2015/16. Population odds of consuming any psychotropic drugs in 2015/16 were estimated to be 1.5 times higher than in 2008/09 (OR = 1.50;95%CI:1.13-2.01), particularly for hypnotics/sedatives (OR = 1.60;95%CI:1.14-2.25). Women and older individuals presented higher odds of consuming any psychotropic drugs (OR = 2.79;95%CI:2.03-3.84, and OR = 1.80;95%CI:1.28-2.54), after adjusting for year of assessment and education. However, when evaluating the interaction effect of the year with gender and age, men and younger individuals reported higher odds of consuming any psychotropic drugs in 2015/16, when compared to 2008/09 (OR = 1.85;95%CI:1.08-3.17, and OR = 1.95;95%CI:1.32-2.90, respectively). CONCLUSIONS: The findings indicate that the period of economic recession was associated with an increased risk of psychotropic drugs use in Portugal. Consumption of psychotropic drugs remained higher among women and older individuals, but the results suggest that the economic crisis had a disproportionate impact on men and younger individuals. This identification of the most vulnerable population groups is useful to design effective and targeted public health interventions aimed at alleviating the effects of economic recessions.

Exploring socioeconomic and mental health trajectories during times of economic recession: a qualitative study with primary health care users and professionals.

Background: The 2008 economic recession has been shown to affect populations' mental health due to deterioration of socioeconomic and living conditions. Concurrently, mental health problems may have constituted a vulnerability to wider social inequalities during this period.Aims: To explore perceptions and experiences of primary health care users and professionals regarding the relationship between mental health and socioeconomic position during the economic recession in Portugal.Method: Data were collected in three primary health care centres in Lisbon Metropolitan Area. Focus groups and semi-structured interviews were conducted with users and professionals, respectively. Interviews were audio-recorded, transcribed verbatim and underwent thematic analysis.Results: Two themes were obtained. The first comprised the relationship between changes in socioeconomic conditions (unemployment, precarious work conditions and financial hardship) and poor mental health. The second involved the consequences of experiencing mental health problems during the recession, namely disability, need of sick leave and early retirement.Conclusions: This study provided a comprehensive overview of the bidirectional relationship between socioeconomic conditions and mental health, emphasizing the need to develop policies to address the drivers of poor mental health during times of economic downturn and tackle the barriers faced by people with mental disorders to promote their full social inclusion.

Injury and stress responses of adult neural crest-derived cells.

Multipotent neural crest cells can self-renew and give rise to a plethora of neural and non-neural cell types in the vertebrate embryo. Intriguingly, cells reminiscent of such neural crest stem cells (NCSCs) have also been isolated from various postnatal and adult neural crest (NC)-derived structures. However, it has been debated whether NCSC-like cells in the adult correspond to 'in vitro artefacts' emerging upon isolation or fulfil a physiological role in vivo. Here, we discuss recent findings indicating that in different adult NC derivatives, injury or stress responses induce a NCSC-like state, presumably by reprogramming differentiated cells such as Schwann cells. Thereby, injury or stress appear to endow NC-derived cells with the capacity to generate new cell types during the repair process; in addition, injury can activate a repair program in adult NC-derived cells, which promotes tissue repair or regeneration by paracrine signalling. Thus, there is increasing evidence that NCSC-like cells in NC derivatives represent an in vivo state implicated in distinct physiological functions in the adult organism.

Comparison of time-series models for monitoring temporal trends in endemic diseases sero-prevalence: lessons from porcine reproductive and respiratory syndrome in Danish swine herds.

BACKGROUND: Monitoring systems are essential to detect if the number of cases of a specific disease is rising. Data collected as part of voluntary disease monitoring programs is particularly useful to evaluate if control and eradication programs achieve the target. These data are characterized by random noise which makes harder to interpret temporal changes in the data. Monitoring trends in the data is a possible approach to overcome this issue. The objective of this study was to assess the performance of three time-series models that allows monitoring trends in data in terms of its adaptability when used to monitor changes in disease sero-prevalence at a national scale based on data collected as part of voluntary monitoring programs. We compared two Bayesian forecasting methods and an Exponential smoothing method, specifically a Dynamic Linear Model, a Dynamic Generalized Linear Model and a Holt's linear trend method, respectively. These three different types of time series models were applied to data on weekly sero-prevalence of Porcine Reproductive and Respiratory Syndrome (PRRS) in Danish swine herds. RESULTS: Comparing the linear cross-dependence between the filtered values obtained from the three models and the raw data, we observed that the Holt's linear trend method shows negative linear dependence for roughly half of the time for breeding/nucleus and multiplier herds, having values close to zero for most of the period in finisher herds. CONCLUSIONS: Bayesian forecasting methods adapt faster to changes in the data, compared to the deterministic Holt's linear trend method. The practical implication of this greater flexibility is that the Bayesian methods will provide more reliable values of changes in the data and have potential to be implemented as part of a surveillance system in Denmark.

Untargeted metabolomics of strawberry (Fragaria x ananassa 'Camarosa') fruit from plants grown under osmotic stress conditions.

BACKGROUND: Plants activate defense mechanisms to cope with adverse environmental conditions, leading to the accumulation and / or depletion of general and specialized metabolites. In this study, a multiplatform untargeted metabolomics strategy was employed to evaluate metabolic changes in strawberry fruit of cv. Camarosa grown under osmotic stress conditions. Liquid chromatography-mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-MS) data from strawberries grown under two water-deficit conditions, irrigated at 95% crop evapotranspiration (ETc) and 85% ETc, and one excess salt condition with a 80 mmol L-1 NaCl solution, were analyzed to determine treatment effects on fruit metabolism. RESULTS: Multivariate principal component analysis, orthogonal projections to latent structures - discriminant analysis (OPLS-DA), and univariate statistical analyses were applied to the data set. While multivariate analyses showed group separation by treatment, T-tests and fold change revealed 12 metabolites differentially accumulated in strawberries from different treatments - among them phenolic compounds, glycerophospholipids, phytosterols, carbohydrates, and an aromatic amino acid. CONCLUSION: Untargeted metabolomic analysis allowed for the annotation of compounds differentially accumulated in strawberry fruit from plants grown under osmotic stress and non-stressed plants. The metabolic disturbance in plants under stress involved metabolites associated with the inhibition of reactive oxygen species and cell-wall and membrane lipid biosynthesis, which might serve as osmotic stress biomarkers. © 2019 Society of Chemical Industry.

The effect of socioeconomic position in the experience of disability among people with mental disorders: findings from the World Mental Health Survey Initiative Portugal.

BACKGROUND: Mental disorders are a major cause of disability with impacts on daily functioning and quality of life, which has been associated with socioeconomic disadvantage. The present study aims to assess how socioeconomic position is related to the disability reported by people with mental disorders, using data from the World Mental Health Survey (WMHS) Initiative Portugal. METHODS: Using data from the Portuguese Mental Health Survey, a nationally representative cross-sectional study (n = 3849), several logistic regression models with interaction terms were performed to evaluate the effect of different indicators of socioeconomic position on the disability reported by people with any mental disorder (any 12-month mood or anxiety disorder). Odds ratios were estimated at the specific values of the main effects and interaction terms between the presence of any mental disorder and education, employment status, self-perceived financial deprivation and subjective social status. RESULTS: The prevalence rate of any mood or anxiety disorder was 21.0% (n = 788), among which 14.7% (n = 115) reported disability. The results show that among people with any 12-month mental disorder, those in the employment category of "retired or others" had two times higher odds of reporting disability (OR = 2.19; 95%CI: 1.06-4.48) when compared to participants categorized as "working". Likewise, individuals with financial deprivation had two times higher odds of reporting disability when compared to those non-financially deprived (OR = 2.36; 95%CI: 1.31-4.24). The odds ratios obtained for the specific years of education evaluated were not statistically significant but seem to suggest an educational gradient. CONCLUSIONS: The findings of this study indicate that the disability reported by people with mental disorders varies according to socioeconomic position and draw attention to the need to develop policies to address these inequalities.

Ribosomal Protein Mutations Result in Constitutive p53 Protein Degradation through Impairment of the AKT Pathway.

Mutations in ribosomal protein (RP) genes can result in the loss of erythrocyte progenitor cells and cause severe anemia. This is seen in patients with Diamond-Blackfan anemia (DBA), a pure red cell aplasia and bone marrow failure syndrome that is almost exclusively linked to RP gene haploinsufficiency. While the mechanisms underlying the cytopenia phenotype of patients with these mutations are not completely understood, it is believed that stabilization of the p53 tumor suppressor protein may induce apoptosis in the progenitor cells. In stark contrast, tumor cells from zebrafish with RP gene haploinsufficiency are unable to stabilize p53 even when exposed to acute DNA damage despite transcribing wild type p53 normally. In this work we demonstrate that p53 has a limited role in eliciting the anemia phenotype of zebrafish models of DBA. In fact, we find that RP-deficient embryos exhibit the same normal p53 transcription, absence of p53 protein, and impaired p53 response to DNA damage as RP haploinsufficient tumor cells. Recently we reported that RP mutations suppress activity of the AKT pathway, and we show here that this suppression results in proteasomal degradation of p53. By re-activating the AKT pathway or by inhibiting GSK-3, a downstream modifier that normally represses AKT signaling, we are able to restore the stabilization of p53. Our work indicates that the anemia phenotype of zebrafish models of DBA is dependent on factors other than p53, and may hold clinical significance for both DBA and the increasing number of cancers revealing spontaneous mutations in RP genes.

Reconceptualization innovative moments as a predictor of symptomatology improvement in treatment for depression.

OBJECTIVES: In previous studies, reconceptualization innovative moments were associated with successful psychotherapy. Reconceptualization has two components-(a) a positive temporal contrast between the past self and the present self (contrasting self [CS]) and (b) a description of how and/or why this change has occurred (change process [CP])-from the perspective of the client. The aim of this study is to analyse if CS and CP have the same association with outcomes as reconceptualization. METHOD: Sixteen cases of clients with major depression (305 sessions) were analysed. Longitudinal regression models were used to explore if proportions of CS, CP, and reconceptualization predicted outcome measures and if outcome measures predicted CS, CP, and reconceptualization. RESULTS: Reconceptualization is less frequent than CS and CP taken separately, but reconceptualization was a better predictor of treatment outcomes than were its separate components. Moreover, symptom improvement did not predict reconceptualization. CONCLUSION: The construction of new meanings is important in improving depressive symptomatology. Psychotherapists can elicit these new meanings in their regular practice by posing questions that may help clients to conceptualize what is changing in themselves (CS) and questions of how this change is occurring (CP). The construction of an integrative account of these new meanings is associated with psychotherapeutic gains, and thus, reconceptualizing change could improve symptoms of depression.

The phosphocarrier protein HPr of Neisseria meningitidis interacts with the transcription regulator CrgA and its deletion affects capsule production, cell adhesion, and virulence.

The bacterial phosphotransferase system (PTS) transports and phosphorylates sugars, but also carries out numerous regulatory functions. The ß-proteobacterium Neisseria meningitidis possesses an incomplete PTS unable to transport carbon sources because it lacks a membrane component. Nevertheless, the residual phosphorylation cascade is functional and the meningococcal PTS was therefore expected to carry out regulatory roles. Interestingly, a ΔptsH mutant (lacks the PTS protein HPr) exhibited reduced virulence in mice and after intraperitoneal challenge it was rapidly cleared from the bloodstream of BALB/c mice. The rapid clearance correlates with lower capsular polysaccharide production by the ΔptsH mutant, which is probably also responsible for its increased adhesion to Hec-1-B epithelial cells. In addition, compared to the wild-type strain more apoptotic cells were detected when Hec-1-B cells were infected with the ΔptsH strain. Coimmunoprecipitation revealed an interaction of HPr and P-Ser-HPr with the LysR type transcription regulator CrgA, which among others controls its own expression. Moreover, ptsH deletion caused increased expression of a ΦcrgA-lacZ fusion. Finally, the presence of HPr or phospho-HPr's during electrophoretic mobility shift assays enhanced the affinity of CrgA for its target sites preceding crgA and pilE, but HPr did not promote CrgA binding to the sia and pilC1 promoter regions.