Association between chronic irritability and depressive symptoms in children and adolescents.

Association between chronic irritability and depressive symptoms in children and adolescents. Busto-Garrido, M.; Gutierrez-Castillo, D; Navas- Gonzalez, JR; Gutierrez-Bedmar, M; Gutierrez-Casares, JR; Martin-Lunar, MT; Rodríguez-Rosado, A; Pena-Andreu, JM. European Psychiatry 415(2017) 5221.Chronic irritability is the most frequently reported symptom in child and adolescent depression. The association of both has been linked with high rates of chronicity, comorbility and impairment. Objectives To study the association between chronic irritability and depressive symptoms in children and adolescents. Methods We have studied 857 participants recruited from the only Child and Adolescent Mental Health Clinic in a catchment area of 122968 people under 18 (2004-2010). A sample of 677 participants (57 controls and 620 patients) was included to carry out a cross-sectional study. Chronic irritability was measured by a Visual Analog Scale (VAS irritability) -scored from 0 to 10-, and depressive symptoms by the Children's Depression Inventory (CDI). The participants were categorized into controls and patients, and according to their chronic irritability (≤4 [I],5 [II] and ≥6 [III]). The mean of CDI score was calculated for each of the groups, adjusted by sex and age, and analyzed by ANCOVA. Results The following means were obtained from the controls: 13,71 (group I), 9,82 (group II) and 17,45 (group III). Regarding to the patients: 13,92 (group I), 11,54 (group II) and 15,64 (group III). A quadratic association (p <0,0015) was found between VAS irritability score and CDI score. Conclussions There is not a lineal association between chronic irritability and depressive symptoms in children and adolescent. High rates of depressive symptoms were associated both with high and low rates of irritability. Several questions remain unexplained about the status of irritability in psychiatry as Stringaris group has been pointed out. Disclosure statement I have no potential conflict of interest to discloseUniversidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Lentiviral Vector Production Titer Is Not Limited in HEK293T by Induced Intracellular Innate Immunity

Most gene therapy lentiviral vector (LV) production platforms employ HEK293T cells expressing the oncogenic SV40 large T-antigen (TAg) that is thought to promote plasmid-mediated gene expression. Studies on other viral oncogenes suggest that TAg may also inhibit the intracellular autonomous innate immune system that triggers defensive antiviral responses upon detection of viral components by cytosolic sensors. Here we show that an innate response can be generated after HIV-1-derived LV transfection in HEK293T cells, particularly by the transgene, yet, remarkably, this had no effect on LV titer. Further, overexpression of DNA sensing pathway components led to expression of inflammatory cytokine and interferon (IFN) stimulated genes but did not result in detectable IFN or CXCL10 and had no impact on LV titer. Exogenous IFN-β also did not affect LV production or transduction efficiency in primary T cells. Additionally, manipulation of TAg did not affect innate antiviral responses, but stable expression of TAg boosted vector production in HEK293 cells. Our findings demonstrate a measure of innate immune competence in HEK293T cells but, crucially, show that activation of inflammatory signaling is uncoupled from cytokine secretion in these cells. This provides new mechanistic insight into the unique suitability of HEK293T cells for LV manufacture

Use of aequorin-based indicators for monitoring Ca2+ in acidic organelles

Over the last years, there is accumulating evidence that acidic organelles can accumulate and release Ca2+ upon cell activation. Hence, reliable recording of Ca2+ dynamics in these compartments is essential for understanding the physiopathological aspects of acidic organelles. Genetically encoded Ca2+ indicators (GECIs) are valuable tools to monitor Ca2+ in specific locations, although their use in acidic compartments is challenging due to the pH sensitivity of most available fluorescent GECIs. By contrast, bioluminescent GECIs have a combination of features (marginal pH sensitivity, low background, no phototoxicity, no photobleaching, high dynamic range and tunable affinity) that render them advantageous to achieve an enhanced signal-to-noise ratio in acidic compartments. This article reviews the use of bioluminescent aequorin-based GECIs targeted to acidic compartments. A need for more measurements in highly acidic compartments is identified

A review of ureteral injuries after external trauma

<p>Abstract</p> <p>Introduction</p> <p>Ureteral trauma is rare, accounting for less than 1% of all urologic traumas. However, a missed ureteral injury can result in significant morbidity and mortality. The purpose of this article is to review the literature since 1961 with the primary objective to present the largest medical literature review, to date, regarding ureteral trauma. Several anatomic and physiologic considerations are paramount regarding ureteral injuries management.</p> <p>Literature review</p> <p>Eighty-one articles pertaining to traumatic ureteral injuries were reviewed. Data from these studies were compiled and analyzed. The majority of the study population was young males. The proximal ureter was the most frequently injured portion. Associated injuries were present in 90.4% of patients. Admission urinalysis demonstrated hematuria in only 44.4% patients. Intravenous ureterogram (IVU) failed to diagnose ureteral injuries either upon admission or in the operating room in 42.8% of cases. Ureteroureterostomy, with or without indwelling stent, was the surgical procedure of choice for both trauma surgeons and urologists (59%). Complications occurred in 36.2% of cases. The mortality rate was 17%.</p> <p>Conclusion</p> <p>The mechanism for ureteral injuries in adults is more commonly penetrating than blunt. The upper third of the ureter is more often injured than the middle and lower thirds. Associated injuries are frequently present. CT scan and retrograde pyelography accurately identify ureteral injuries when performed together. Ureteroureterostomy, with or without indwelling stent, is the surgical procedure of choice of both trauma surgeons and urologists alike. Delay in diagnosis is correlated with a poor prognosis.</p

Using molecular data for epidemiological inference: assessing the prevalence of Trypanosoma brucei rhodesiense in Tsetse in Serengeti, Tanzania

Background: Measuring the prevalence of transmissible Trypanosoma brucei rhodesiense in tsetse populations is essential for understanding transmission dynamics, assessing human disease risk and monitoring spatio-temporal trends and the impact of control interventions. Although an important epidemiological variable, identifying flies which carry transmissible infections is difficult, with challenges including low prevalence, presence of other trypanosome species in the same fly, and concurrent detection of immature non-transmissible infections. Diagnostic tests to measure the prevalence of T. b. rhodesiense in tsetse are applied and interpreted inconsistently, and discrepancies between studies suggest this value is not consistently estimated even to within an order of magnitude. Methodology/Principal Findings: Three approaches were used to estimate the prevalence of transmissible Trypanosoma brucei s.l. and T. b. rhodesiense in Glossina swynnertoni and G. pallidipes in Serengeti National Park, Tanzania: (i) dissection/microscopy; (ii) PCR on infected tsetse midguts; and (iii) inference from a mathematical model. Using dissection/microscopy the prevalence of transmissible T. brucei s.l. was 0% (95% CI 0–0.085) for G. swynnertoni and 0% (0–0.18) G. pallidipes; using PCR the prevalence of transmissible T. b. rhodesiense was 0.010% (0–0.054) and 0.0089% (0–0.059) respectively, and by model inference 0.0064% and 0.00085% respectively. Conclusions/Significance: The zero prevalence result by dissection/microscopy (likely really greater than zero given the results of other approaches) is not unusual by this technique, often ascribed to poor sensitivity. The application of additional techniques confirmed the very low prevalence of T. brucei suggesting the zero prevalence result was attributable to insufficient sample size (despite examination of 6000 tsetse). Given the prohibitively high sample sizes required to obtain meaningful results by dissection/microscopy, PCR-based approaches offer the current best option for assessing trypanosome prevalence in tsetse but inconsistencies in relating PCR results to transmissibility highlight the need for a consensus approach to generate meaningful and comparable data

Ecology: a prerequisite for malaria elimination and eradication

* Existing front-line vector control measures, such as insecticide-treated nets and residual sprays, cannot break the transmission cycle of Plasmodium falciparum in the most intensely endemic parts of Africa and the Pacific * The goal of malaria eradication will require urgent strategic investment into understanding the ecology and evolution of the mosquito vectors that transmit malaria * Priority areas will include understanding aspects of the mosquito life cycle beyond the blood feeding processes which directly mediate malaria transmission * Global commitment to malaria eradication necessitates a corresponding long-term commitment to vector ecolog

Non-human TRIM5 variants enhance recognition of HIV-1-infected cells by CD8+ T cells

Tripartite motif-containing protein 5 (TRIM5) restricts human immunodeficiency virus type-1 (HIV-1) in a species-specific manner by uncoating viral particles while activating early innate responses. Although the contribution of TRIM5 proteins to cellular immunity has not yet been studied, their interactions with the incoming viral capsid and the cellular proteasome led us to hypothesize a role for them. Here, we investigate whether the expression of two non-human TRIM5 orthologs, rhesus TRIM5α (RhT5) and TRIM-cyclophilin A (TCyp), both of which are potent restrictors of HIV-1, could enhance immune recognition of infected cells by CD8+ T cells. We illustrate how TRIM5 restriction improves CD8+ T cell-mediated HIV-1 inhibition. Moreover, when TRIM5 activity was blocked by the non-immunosuppressive analog of cyclosporin A, SmBz-CsA, we found a significant reduction in CD107a/MIP1β expression in HIV-1-specific CD8+ T cells. This finding underscores the direct link between TRIM5 restriction and activation of CD8+ T-cell responses. Interestingly, cells expressing RhT5 induced stronger CD8+ T-cell responses through the specific recognition of the HIV-1 capsid by the immune system. The underlying mechanism of this process may involve TRIM5-specific capsid recruitment to cellular proteasomes and increase peptide availability for loading and presentation of HLA class I antigens. In summary, we identified a novel function for non-human TRIM5 variants in cellular immunity. We hypothesise that TRIM5 can couple innate viral sensing and CD8+ T-cell activation to increase species barriers against retrovirus infection. IMPORTANCE: New therapeutics to tackle HIV-1 infection should aim to combine rapid innate viral sensing and cellular immune recognition. Such strategies could prevent seeding of the viral reservoir and the immune damage that occurs during acute infection. The non-human TRIM5 variants, rhesus TRIM5α (RhT5) and TRIM-cyclophilin A (TCyp), are attractive candidates owing to their potency in sensing HIV-1 and blocking its activity. Here, we show that expression of RhT5 and TCyp in HIV-1-infected cells improves CD8+ T cell-mediated inhibition through the direct activation of HIV-1-specific CD8+ T-cell responses. We found that the potency in CD8+ activation was stronger for RhT5 variants and capsid-specific CD8+ T-cells in a mechanism that relies on TRIM5-dependent particle recruitment to cellular proteasomes. This novel mechanism couples innate viral sensing with cellular immunity in a single protein and could be exploited to develop innovative therapeutics for control of HIV-1 infection

Co-evolution of density and topology in a simple model of city formation

We study the influence that population density and the road network have on each others' growth and evolution. We use a simple model of formation and evolution of city roads which reproduces the most important empirical features of street networks in cities. Within this framework, we explicitely introduce the topology of the road network and analyze how it evolves and interact with the evolution of population density. We show that accessibility issues -pushing individuals to get closer to high centrality nodes- lead to high density regions and the appearance of densely populated centers. In particular, this model reproduces the empirical fact that the density profile decreases exponentially from a core district. In this simplified model, the size of the core district depends on the relative importance of transportation and rent costs.Comment: 13 pages, 13 figure

Niemann-Pick disease type C

Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include other lipidoses; idiopathic neonatal hepatitis and other causes of cholestatic icterus should be considered in neonates, and conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults. Symptomatic management of patients is crucial. A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. The prognosis largely correlates with the age at onset of the neurological manifestations