Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency.

A molecular and functional link between neurotrophin signaling and cerebellar foliation is lacking. Here we show that constitutive knockout of two homologous genes encoding the RNA binding protein RBM4 results in foliation defects at cerebellar lobules VI-VII and delayed motor learning in mice. Moreover, the features of Rbm4 double knockout (dKO), including impaired differentiation of cerebellar granule cells and dendritic arborization of Purkinje cells, are reminiscent of neurotrophin deficiency. Loss of RBM4 indeed reduced brain-derived neurotrophic factor (BDNF). RBM4 promoted the expression of BDNF and full-length TrkB, implicating RBM4 in efficient BDNF-TrkB signaling. Finally, prenatal supplementation with 7,8-dihydroxyflavone, a TrkB agonist, restored granule cell differentiation, Purkinje cell dendritic complexity and foliation-the intercrural fissure in particular-in the neonatal cerebellum of Rbm4dKO mice, which also showed improved motor learning in adulthood. This study provides evidence that prenatal activation of TrkB signaling ameliorates cerebellar malformation caused by BDNF deficiency.

Occlusion-Based Three-Dimensional Craniofacial Anthropometric and Symmetric Evaluation in Preadolescences: A Comparative COHORT Study.

BACKGROUND: The importance of early diagnosis of pediatric malocclusion and early intervention has been emphasized. Without use of radiation, 3D imaging holds the potential to be an alternative for evaluating facial features in school-aged populations. METHODS: Students aged 9 and 10 years were recruited. We performed annual 3D stereophotogrammetry of the participants' heads. A total of 37 recognizable anatomical landmarks were identified for linear, angular, and asymmetric analyses using the MATLAB program. RESULTS: This study included 139 healthy Taiwanese children with a mean age of 9.13, of whom 74 had class I occlusion, 50 had class II malocclusion, and 15 had class III malocclusion. The class III group had lower soft-tissue convexity (p = 0.01) than the class II group. The boys with class II malocclusion had greater dimensions in the anteroposterior position of the mid-face (p = 0.024) at age 10. Overall asymmetry showed no significance (p > 0.05). Heat maps of the 3D models exhibited asymmetry in the mid-face of the class II group and in the lower face of the class III group. CONCLUSION: Various types of malocclusion exhibited distinct facial traits in preadolescents. Those with class II malocclusion had a protruded maxilla and convex facial profile, whereas those with class III malocclusion had a less convex facial profile. Asymmetry was noted in facial areas with relatively prominent soft-tissue features among different malocclusion types.

The Src-ZNRF1 axis controls TLR3 trafficking and interferon responses to limit lung barrier damage.

Type I interferons are important antiviral cytokines, but prolonged interferon production is detrimental to the host. The TLR3-driven immune response is crucial for mammalian antiviral immunity, and its intracellular localization determines induction of type I interferons; however, the mechanism terminating TLR3 signaling remains obscure. Here, we show that the E3 ubiquitin ligase ZNRF1 controls TLR3 sorting into multivesicular bodies/lysosomes to terminate signaling and type I interferon production. Mechanistically, c-Src kinase activated by TLR3 engagement phosphorylates ZNRF1 at tyrosine 103, which mediates K63-linked ubiquitination of TLR3 at lysine 813 and promotes TLR3 lysosomal trafficking and degradation. ZNRF1-deficient mice and cells are resistant to infection by encephalomyocarditis virus and SARS-CoV-2 because of enhanced type I interferon production. However, Znrf1-/- mice have exacerbated lung barrier damage triggered by antiviral immunity, leading to enhanced susceptibility to respiratory bacterial superinfections. Our study highlights the c-Src-ZNRF1 axis as a negative feedback mechanism controlling TLR3 trafficking and the termination of TLR3 signaling.

Evolution of estimated glomerular filtration rate in HIV/HCV-coinfected patients who received direct-acting antivirals: A multicenter retrospective study.

BACKGROUND: The short-term impact of sofosbuvir (SOF)-based direct-acting antivirals (DAAs) combined with antiretroviral therapy (ART) on renal function in patients with HIV/HCV-coinfection remains controversial. METHODS: This multicenter, retrospective study aimed to sequentially record the estimated glomerular filtration rate (eGFR) at baseline, end of therapy (EOT), 12 weeks off-treatment (SVR12), and at time points after SVR12 (post-SVR12) and to identify the factors associated with an eGFR decline to <60 ml/min/1.73 m2 in HIV/HCV-coinfected patients receiving DAAs. The evolution of mean eGFRs between different ART and DAAs combinations among patients of different HIV transmission routes were compared using a generalized linear mixed effects model. The periods between baseline and EOT, between EOT and post-SVR12, and between baseline and post-SVR12 were defined as the on-treatment, post-treatment, and all-course periods, respectively. Acute kidney disease (AKD) was defined as a decline of eGFR to <60 ml/min/1.73 m2. RESULT: A total of 445 patients with baseline eGFRs >60 ml/min/1.73 m2 were included. We found that eGFRs declined during the on-treatment period in the tenofovir-containing ART and SOF-based DAA groups. There were no differences in the slope coefficient during the on-treatment and post-treatment periods among all risk groups except for people who inject drug. Increasing age and plasma HIV RNA >20 copies/ml before DAA treatment were factors independently associated with AKD during the on-treatment period while increasing age was independently associated with AKD during the all-course period. CONCLUSION: Only increasing age was an independent factor associated with AKD among HIV/HCV-coinfected patients during and after DAA treatments.

FAM21 is critical for TLR2/CLEC4E-mediated dendritic cell function against Candida albicans.

FAM21 (family with sequence similarity 21) is a component of the Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) protein complex that mediates actin polymerization at endosomal membranes to facilitate sorting of cargo-containing vesicles out of endosomes. To study the function of FAM21 in vivo, we generated conditional knockout (cKO) mice in the C57BL/6 background in which FAM21 was specifically knocked out of CD11c-positive dendritic cells. BMDCs from those mice displayed enlarged early endosomes, and altered cell migration and morphology relative to WT cells. FAM21-cKO cells were less competent in phagocytosis and protein antigen presentation in vitro, though peptide antigen presentation was not affected. More importantly, we identified the TLR2/CLEC4E signaling pathway as being down-regulated in FAM21-cKO BMDCs when challenged with its specific ligand Candida albicans Moreover, FAM21-cKO mice were more susceptible to C. albicans infection than WT mice. Reconstitution of WT BMDCs in FAM21-cKO mice rescued them from lethal C. albicans infection. Thus, our study highlights the importance of FAM21 in a host immune response against a significant pathogen.

Vaccination with SARS-CoV-2 spike protein lacking glycan shields elicits enhanced protective responses in animal models.

A major challenge to end the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is to develop a broadly protective vaccine that elicits long-term immunity. As the key immunogen, the viral surface spike (S) protein is frequently mutated, and conserved epitopes are shielded by glycans. Here, we revealed that S protein glycosylation has site-differential effects on viral infectivity. We found that S protein generated by lung epithelial cells has glycoforms associated with increased infectivity. Compared to the fully glycosylated S protein, immunization of S protein with N-glycans trimmed to the mono-GlcNAc-decorated state (SMG) elicited stronger immune responses and better protection for human angiotensin-converting enzyme 2 (hACE2) transgenic mice against variants of concern (VOCs). In addition, a broadly neutralizing monoclonal antibody was identified from SMG-immunized mice that could neutralize wild-type SARS-CoV-2 and VOCs with subpicomolar potency. Together, these results demonstrate that removal of glycan shields to better expose the conserved sequences has the potential to be an effective and simple approach for developing a broadly protective SARS-CoV-2 vaccine.

Transcriptomic Analysis and C-Terminal Epitope Tagging Reveal Differential Processing and Signaling of Endogenous TLR3 and TLR7.

Toll-like receptor (TLR) signaling is critical for defense against pathogenic infection, as well as for modulating tissue development. Activation of different TLRs triggers common inflammatory responses such as cytokine induction. Here, we reveal differential impacts of TLR3 and TLR7 signaling on transcriptomic profiles in bone marrow-derived macrophages (BMDMs). Apart from self-regulation, TLR3, but not TLR7, induced expression of other TLRs, suggesting that TLR3 activation globally enhances innate immunity. Moreover, we observed diverse influences of TLR3 and TLR7 signaling on genes involved in methylation, caspase and autophagy pathways. We compared endogenous TLR3 and TLR7 by using CRISPR/Cas9 technology to knock in a dual Myc-HA tag at the 3' ends of mouse Tlr3 and Tlr7. Using anti-HA antibodies to detect endogenous tagged TLR3 and TLR7, we found that both TLRs display differential tissue expression and posttranslational modifications. C-terminal tagging did not impair TLR3 activity. However, it disrupted the interaction between TLR7 and myeloid differentiation primary response 88 (MYD88), the Tir domain-containing adaptor of TLR7, which blocked its downstream signaling necessary to trigger cytokine and chemokine expression. Our study demonstrates different properties for TLR3 and TLR7, and also provides useful mouse models for further investigation of these two RNA-sensing TLRs.

Teicoplanin versus ß-lactam for febrile patients with Staphylococcus-like bacteremia: focus on methicillin-susceptible Staphylococcus aureus bacteremia.

BACKGROUND: Many studies have shown that vancomycin is inferior to ß-lactam antibiotics in terms of effectiveness in the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. However, limited data are available regarding the comparison of clinical outcomes between patients receiving initial teicoplanin and those receiving ß-lactam antibiotics for MSSA bacteremia. METHODS: Eighty-four adults with MSSA bacteremia were included: initial teicoplanin treatment group (n = 28) and ß-lactam treatment group (n = 56). The two groups were further stratified based on propensity score matching according to the outcome analysis using a logistic regression model. We investigated the clinical outcomes between the groups before and after propensity score matching after treatment completion. RESULTS: Pittsburgh bacteremia score ≥ 4 (odds ratio, 60.6; 95%CI, 7.4-496.8) was an independent risk factor for unfavorable outcome. After propensity score matching, the initial teicoplanin treatment group and the ß-lactam treatment group consisted of 28 patients each. No statistically significant differences were observed in the proportions of patients with favorable outcomes and 30-day overall mortality rates between the groups before and after propensity score matching after the completion of teicoplanin or ß-lactam treatment. The Kaplan-Meier 30-day survival curve also showed no significant difference between the patients receiving initial teicoplanin treatment and those receiving ß-lactam treatment before and after matching (hazard ratio, 1.84, 95%CI, 0.60-5.64; and 3.12, 95%CI, 0.98-9.99, respectively). CONCLUSIONS: There were no significant difference in clinical outcomes between initial teicoplanin treatment and ß-lactam treatment among patients with MSSA bacteremia. Pittsburgh bacteremia score ≥ 4 was a significant risk factor for mortality.

Autism-linked mutations of CTTNBP2 reduce social interaction and impair dendritic spine formation via diverse mechanisms.

Abnormal synaptic formation and signaling is one of the key molecular features of autism spectrum disorders (ASD). Cortactin binding protein 2 (CTTNBP2), an ASD-linked gene, is known to regulate the subcellular distribution of synaptic proteins, such as cortactin, thereby controlling dendritic spine formation and maintenance. However, it remains unclear how ASD-linked mutations of CTTNBP2 influence its function. Here, using cultured hippocampal neurons and knockin mouse models, we screen seven ASD-linked mutations in the short form of the Cttnbp2 gene and identify that M120I, R533* and D570Y mutations impair CTTNBP2 protein-protein interactions via divergent mechanisms to reduce dendritic spine density in neurons. R533* mutation impairs CTTNBP2 interaction with cortactin due to lack of the C-terminal proline-rich domain. Through an N-C terminal interaction, M120I mutation at the N-terminal region of CTTNBP2 also negatively influences cortactin interaction. D570Y mutation increases the association of CTTNBP2 with microtubule, resulting in a dendritic localization of CTTNBP2, consequently reducing the distribution of CTTNBP2 in dendritic spines and impairing the synaptic function of CTTNBP2. Finally, we generated heterozygous M120I knockin mice to mimic the genetic variation of patients and found they exhibit reduced social interaction. Our study elucidates that different ASD-linked mutations of CTTNBP2 result in diverse molecular deficits, but all have the similar consequence of synaptic impairment.

CTTNBP2 Controls Synaptic Expression of Zinc-Related Autism-Associated Proteins and Regulates Synapse Formation and Autism-like Behaviors.

Synaptic dysregulation is a critical feature of autism spectrum disorders (ASDs). Among various autism-associated genes, cortactin binding protein 2 (CTTNBP2) is a cytoskeleton regulator predominantly expressed in neurons and highly enriched at dendritic spines. Here, using Cttnbp2 knockout and ASD-linked mutant mice, we demonstrate that Cttnbp2 deficiency reduces zinc levels in the brain, alters synaptic protein targeting, impairs dendritic spine formation and ultrastructure of postsynaptic density, and influences neuronal activation and autism-like behaviors. A link to autism, the NMDAR-SHANK pathway, and zinc-related regulation are three features shared by CTTNBP2-regulated synaptic proteins. Zinc supplementation rescues the synaptic expression of CTTNBP2-regulated proteins. Moreover, zinc supplementation and administration of D-cycloserine, an NMDAR coagonist, improve the social behaviors of Cttnbp2-deficient mice. We suggest that CTTNBP2 controls the synaptic expression of a set of zinc-regulated autism-associated genes and influences NMDAR function and signaling, providing an example of how genetic and environmental factor crosstalk controls social behaviors.

Clinical Characteristics and Predictors of Mortality in Critically Ill Influenza Adult Patients.

Severe influenza is associated with high morbidity and mortality. The aim of this study was to investigate the factors affecting the clinical outcomes of critically ill influenza patients. In this retrospective study, we enrolled critically ill adult patients with influenza at the Kaohsiung Chang Gung Memorial Hospital in Taiwan. We evaluated the demographic, clinical, and laboratory findings and examined whether any of these measurements correlated with mortality. We then created an event-based algorithm as a simple predictive tool using two variables with statistically significant associations with mortality. Between 2015 and 2018, 102 critically ill influenza patients (median age, 62 years) were assessed; among them, 41 (40.1%) patients died. Of the 94 patients who received oseltamivir therapy, 68 (72.3%) began taking oseltamivir 48 hours after the onset of illness. Of the 102 patients, the major influenza-associated complications were respiratory failure (97%), pneumonia (94.1%), acute kidney injury (65.7%), adult respiratory distress syndrome (ARDS) (51%), gastrointestinal bleeding (35.3%), and bacteremia (16.7%). In the multivariate regression model, high lactate levels, ARDS, acute kidney injury, and gastrointestinal bleeding were independent predictors of mortality in critically ill influenza patients. The optimal lactate level cutoff for predicting mortality was 3.7 mmol/L with an area under curve of 0.728. We constructed an event-associated algorithm that included lactate and ARDS. Fifteen (75%) of 20 patients with lactate levels 3.7 mmol/L and ARDS died, compared with only 1 (7.7%) of 13 patients with normal lactate levels and without ARDS. We identified clinical and laboratory predictors of mortality that could aid in the care of critically ill influenza patients. Identification of these prognostic markers could be improved to prioritize key examinations that might be useful in determining patient outcomes.

Impaired production of immune mediators in dengue virus type 2-infected mononuclear cells of adults with end stage renal disease.

Chronic kidney disease is an epidemiologically identified risk factor for development of severe dengue in dengue-affected patients. However, available data on the immune pathogenesis in end stage renal disease (ESRD) patients affected by dengue is insufficient. We performed an in vitro study to evaluate the sequential immunological reactions and viral load in dengue virus type 2-infected mononuclear cells of patients with ESRD (n = 34) and in healthy controls (n = 30). The concentrations of interleukins (IL)-1 receptor antagonist (Ra), IL-2, IL-6, IL-8, IL-10, IL-12p40, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1b (MIP-1b), vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α and viral load cycle threshold (Ct) were measured in the dengue virus type 2-infected mononuclear cells at 6 h, 24 h, 48 h, and 72 h post-infection. We found in the ESRD group significantly higher GM-CSF and IL-2 levels at 6 h post-infection. However, IL-8, IL-10, IL-12p40, TNF-α, MCP-1, and MIP-1b levels were found significantly lower than in the control group. At 24 h, 48 h, and 72 h post-infection, significantly lower levels of IL-1Ra, IL-6, IL-8, IL-10, IL-12p40, TNF-α, MCP-1, and MIP-1b were detected in ESRD group. Concentration of VEGF at 24 h and 48 h, and of GM-CSF at 48 h and 72 h were also found to be lower in ESRD group than in control group. Compared with controls, the viral load Ct values were significantly lower in ESRD group at 6 h and 24 h post-infection No significant difference in viral load Ct values between two groups was found at 48 h and 72 h post-infection. Our study discloses that the expression of immune mediators of dengue-infected mononuclear cells is impaired in ESRD patients.

The RNA Processing Factor Y14 Participates in DNA Damage Response and Repair.

DNA repair deficiency leads to genome instability and hence human disease. Depletion of the RNA processing factor Y14/RBM8A in cultured cells or Rbm8a haplodeficiency in the developing mouse cortex results in the accumulation of DNA damage. Y14 depletion differentially affected the expression of DNA damage response (DDR) factors and induced R-loops, both of which threaten genomic stability. Immunoprecipitation coupled with mass spectrometry revealed DDR factors as potential Y14-interacting partners. Further results confirmed that Y14 interacts with Ku and several DDR factors in an ATM-dependent manner. Y14 co-fractionated with Ku in chromatin-enriched fractions and further accumulated on chromatin upon DNA damage. Y14 knockdown delayed recruitment of DDR factors to DNA damage sites and formation of γH2AX foci and also led to Ku retention on chromatin. Accordingly, Y14 depletion compromised the efficiency of DNA end joining. Therefore Y14 likely plays a direct role in DNA damage repair via its interaction with DDR factors.

Daptomycin versus teicoplanin for bloodstream infection due to methicillin-resistant Staphylococcus aureus with a high teicoplanin minimal inhibitory concentration ≥1.5 mg/L: a propensity score-based analysis.

BACKGROUND: Recent reports have described decreased effectiveness of teicoplanin in the treatment of bacteremia due to methicillin-resistant Staphylococcus aureus (MRSA) with teicoplanin minimal inhibitory concentration (MIC) ≥1.5 mg/L. Consensus guidelines recommend considering use of alternative agents for MRSA infections involving a higher teicoplanin MIC, despite of limited data to support this recommendation. PATIENTS AND METHODS: To compare the clinical outcome among patients with bacteremia due to MRSA with teicoplanin MIC ≥1.5 mg/L, we included patients who received high-dose daptomycin (≥8 mg/kg/day) and those who received standard-dose (6 mg/kg/day) or high-dose (6 mg/kg/12 hours) maintenance teicoplanin. The primary endpoint was a favorable outcome, defined as the resolution of clinical signs and symptoms and a negative culture report at the end of therapy. Adjusted analyses were performed by multivariate analysis and propensity score-based matching. RESULTS: Of 142 patients eligible for inclusion, 28 (19.7%) were treated with high-dose daptomycin, 27 (19.0%) with high-dose teicoplanin, and 87 (61.3%) with standard-dose teicoplanin. In multivariate regression analysis, Pittsburgh bacteremia score ≥4 (OR, 5.3; 95%CI, 1.9-14.5) was independently associated with an unfavorable outcome. After propensity-score matching with age and Pittsburgh bacteremia score ≥4, patients on high-dose daptomycin were more likely to have favorable outcomes than those on standard-dose teicoplanin (74.1% vs 42.6%; P=0.02). However, there was no significant difference in terms of favorable outcomes (P=0.12) between patients receiving high-dose daptomycin and those receiving high-dose teicoplanin after the same propensity-score matching. CONCLUSION: Treatment with high-dose daptomycin resulted in significantly better outcomes than with standard-dose teicoplanin in the treatment of MRSA bacteremia with teicoplanin MIC ≥1.5 mg/L. However, the clinical outcome of the patients receiving high-dose teicoplanin was similar to that of the patients receiving high-dose daptomycin.

Prognostic Factors in Adult Patients with Dengue: Developing Risk Scoring Models and Emphasizing Factors Associated with Death ≤7 Days after Illness Onset and ≤3 Days after Presentation.

Dengue is a mosquito-borne viral disease that is a threat to global health. However, information relating to mortality ≤7 days after dengue onset and ≤3 days after presentation is limited. We retrospectively analyzed 1086 adults with dengue during a 12-year period. Three scoring models were established: model-1 (death ≤3 days after presentation), model-2 (death ≤7 days after illness onset), and model-3 (overall fatality). In total, 39 patients with fatal dengue were identified, of which 17 and 14 patients died ≤7 days after illness onset and ≤3 days after presentation, respectively. In model-1 (range: 0‒4 points), gastrointestinal bleeding ≤72 h after presentation, thrombocytopenia (<50 × 108 cells/L) at presentation, and acute kidney injury after hospitalization, using a cutoff level of 2 points, exhibited good discrimination (area under the receiver curve (AUC): 0.975) between survivors and non-survivors. In model-2, the significant predictors were gastrointestinal bleeding ≤72 h after presentation, and hemoconcentration and leukocytosis after hospitalization. Model-2 (range: 0⁻4 points) showed an AUC of 0.974, with a cutoff value of 2 points. The independent factors in model-2 were the predictors of overall mortality (model-3), which include thrombocytopenia (<50 × 108 cells/L) at presentation. Using a cutoff value of 2 points, model-3 (range: 0⁻7 points) revealed an excellent discrimination between survivors and non-survivors (AUC: 0.963).

Impact of teicoplanin maintenance dose and MIC values on the clinical outcomes of patients treated for methicillin-resistant Staphylococcus aureus bacteremia.

OBJECTIVES: Teicoplanin, a glycopeptide, is regarded as among the drug choices for methicillin-resistant Staphylococcus aureus (MRSA) infections. Few studies have evaluated the relationship between teicoplanin minimal inhibitory concentrations (MICs) and outcomes among patients with serious MRSA infections. SUBJECTS AND METHODS: We investigated the relationship between teicoplanin maintenance dose and clinical outcomes, on the completion of teicoplanin therapy, in bacteremia patients with MRSA infection, with different teicoplanin MICs. A total of 146 adult patients with MRSA bacteremia were enrolled at Kaohsiung Chang Gung Memorial Hospital between September 2012 and September 2015. RESULTS: A higher number of patients in the high-dose regimen group (6 mg/kg/12 h) had favorable outcomes than those in the standard-dose regimen group (6 mg/kg/24 h) (84.1% vs 41.2%; p<0.01), regardless of the teicoplanin MICs. In the multivariate analysis, a Pittsburgh bacteremia score ≥4 (OR, 0.07, 95% CI, 0.03-0.19) was a risk factor for an unfavorable final clinical response, whereas high-dose teicoplanin maintenance therapy for MRSA bacteremia was significantly associated with a favorable final response (OR, 25.3 [95% CI, 4.43-144.03] for isolates with a teicoplanin MIC ≥1.5 mg/L and OR, 5.6 [95% CI, 1.57-19.91] for isolates with a teicoplanin MIC <1.5 mg/L). Survival at 30 days was significantly better for patients receiving high-dose teicoplanin maintenance treatment, regardless of the teicoplanin MICs of the MRSA isolates. Patients were selected using propensity score matching, based on the independent predictors of a favorable final outcome. After appropriate propensity score matching, patients in the high-dose regimen group still had a statistically significant favorable outcome at the end of treatment (84.1% vs 40.9%; p<0.01). CONCLUSION: The results suggested that high-dose teicoplanin maintenance treatment is associated with more favorable outcomes than standard-dose teicoplanin maintenance treatment, for patients with MRSA bacteremia, regardless of the teicoplanin MIC.

NPTX2 is a key component in the regulation of anxiety.

Anxiety disorders significantly impair quality of life. However, limited knowledge of the underlying mechanisms impedes the development of effective therapeutics. Previous studies have suggested that the expression of the Nptx2 gene is associated with anxiety, but the neurobiological processes underlying this association remain unclear. We generated multiple mouse models with knockout or overexpression of Nptx2 in specific brain regions and during different developmental stages to assess anxiety, adult neurogenesis, and glucocorticoid-related gene expression. Our results provide evidence that Nptx2 expression in the adult hippocampus regulates anxiety in mice. Eliminating Nptx2 expression in either the developing mouse brain or in adulthood leads to increased anxiety levels. The increase in anxiety was evident in hippocampus-specific Nptx2 knockout mice, but not in an amygdala specific knockouts. Gene expression analysis revealed increased expression of glucocorticoid receptor target genes in Nptx2 knockout mice after acute stress. Overexpression of Nptx2 in the hippocampus alleviates stress-induced anxious behaviors and reverses the changes in expression of glucocorticoid receptor related genes. In conclusion, we demonstrate that Nptx2 in the hippocampus performs a critical role in modulating anxiety, hippocampal cell proliferation, and glucocorticoid receptor related gene expression. Our results suggest Nptx2 may be a potential target for anxiolytic therapeutics.

Characteristics and predictors for gastrointestinal hemorrhage among adult patients with dengue virus infection: Emphasizing the impact of existing comorbid disease(s).

BACKGROUND: Gastrointestinal (GI) bleeding is a leading cause of death in dengue. This study aims to identify predictors for GI bleeding in adult dengue patients, emphasizing the impact of existing comorbid disease(s). METHODS: Of 1300 adults with dengue virus infection, 175 (mean age, 56.5±13.7 years) patients with GI bleeding and 1,125 (mean age, 49.2±15.6 years) without GI bleeding (controls) were retrospectively analyzed. RESULTS: Among 175 patients with GI bleeding, dengue hemorrhagic fever was found in 119 (68%) patients; the median duration from onset dengue illness to GI bleeding was 5 days. Gastric ulcer, erythematous gastritis, duodenal ulcer, erosive gastritis, and hemorrhagic gastritis were found in 52.3%, 33.3%, 28.6%, 28.6%, and 14.3% of 42 patients with GI bleeding who had undergone endoscopic examination, respectively. Overall, nine of the 175 patients with GI bleeding died, giving an in-hospital mortality rate of 5.1%. Multivariate analysis showed age ≥60 years (cases vs. controls: 48% vs. 28.3%) (odds ratio [OR]: 1.663, 95% confidence interval [CI]: 1.128-2.453), end stage renal disease with additional comorbidities (cases vs. controls: 1.7% vs. 0.2%) (OR: 9.405, 95% CI: 1.4-63.198), previous stroke with additional comorbidities (cases vs. controls: 7.4% vs. 0.6%) (OR: 9.772, 95% CI: 3.302-28.918), gum bleeding (cases vs. controls: 27.4% vs. 11.5%) (OR: 1.732, 95% CI: 1.1-2.727), petechiae (cases vs. controls: 56.6% vs. 29.1%) (OR: 2.109, 95% CI: 1.411-3.153), and platelet count <50×109 cells/L (cases vs. controls: 53.1% vs. 25.8%) (OR: 3.419, 95% CI: 2.103-5.558) were independent predictors of GI bleeding in patients with dengue virus infection. CONCLUSIONS: Our study is the first to disclose that end stage renal disease and previous stroke, with additional comorbidities, were strongly significant associated with the risk of GI bleeding in patients with dengue virus infection. Identification of these risk factors can be incorporated into the patient assessment and management protocol of dengue virus infection to reduce its mortality.

Increased Mortality in Seasonal H3N2 Patients Compared with those with Pandemic 2009 H1N1 in Taiwan, 2009-2010.

We conducted a retrospective study to compare clinical and laboratory findings between 1) severe influenza A and mild influenza A and 2) pandemic 2009 H1N1 (pdm09 A/H1) and seasonal H3N2 (A/H3) from 2009 to 2010. A total of 526 (mean age, 13.6 years; 447 pdm09 A/H1, 79 seasonal A/H3) patients were included, 41 (7.8%) with severe influenza (mean age, 28.1 years; 26 pdm09 A/H1, 15 seasonal A/H3). Influenza-associated complications were pneumonia (75.6%), meningoencephalitis (14.6%), acute kidney injury (14.6%), and acute respiratory distress syndrome (12.2%). Patients with seasonal A/H3 were significantly less likely to experience sore throat (P < 0.001), malaise (P < 0.001), and muscle pain (P < 0.001); they were significantly more likely to have hypertension (P < 0.001), diabetes mellitus (P = 0.001), and chronic obstructive pulmonary disease (P < 0.001), delayed hospital presentation (P = 0.001), delayed oseltamivir treatment (P < 0.001), and higher in-hospital mortality (P = 0.02) than patients with pdm09 A/H1. Further comparison between severe pdm09 A/H1 and severe seasonal A/H3 revealed that severe seasonal A/H3 patients (median age, 71 years) were significantly older than patients with severe pdm09 A/H1 (median age, 7 years) (P < 0.001). Comparison between severe influenza and mild influenza, regardless of influenza A subtypes, by multivariate analysis, found that tachypnea (odds ratio [OR] = 44.3, 95% confidence interval [CI] = 15.7-124.6) and delayed oseltamivir therapy ≧ 48 hours after illness onset (OR = 3.7, 95% CI = 1.3-10.5) were independent risk factors for severe influenza. The findings of this study will improve the understanding of the clinical differences between pdm09 A/H1 and seasonal A/H3, and of influenza-associated complications and predictors for severe outcomes that can help to direct clinicians toward the most effective management of influenza patients to reduce the preventable mortality and morbidity.