Differential Role of the Lectin Pathway of Complement Activation in Susceptibility to Neonatal Sepsis

Background. The incidence of bacterial sepsis during the neonatal period is high. Mannan-binding lectin (MBL), L-ficolin, and H-ficolin recognize microorganisms and activate the complement system viaMBL-associated serine proteases (MASPs). This study investigated whether cord blood concentrations of the lectin pathway proteins are associated with neonatal sepsis. >Methods. This was a case-control study including 47 infants with culture-proven sepsis during the first month of life and 94 matched controls. MBL, L-ficolin, H-ficolin, MASP-2, and MASP-3 levels were measured in cord blood with use of enzyme-linked immunosorbent assay and time-resolved immunofluorometric assay. Multivariate logistic regression was performed. Results. Infants with gram-positive sepsis had significantly lower H-ficolin cord blood concentrations than controls (multivariate odds ratio [OR], 4.00; 95% confidence interval [CI], 1.51-10.56; P=.005), whereas infants with gram-negative sepsis had lower MBL cord blood concentrations (OR, 2.99; 95% CI, 0.86-10.33; P=.084). When excluding patients with postoperative sepsis, multivariate analysis confirmed that low H-ficolin was associated with a significantly higher risk of gram-positive sepsis (OR, 3.71; 95% CI, 1.26-10.92; P=.017) and late-onset sepsis (OR, 3.14; 95% CI, 1.07-9.21; P=.037). In contrast, low MBL was associated with a significantly higher risk of gram-negative sepsis (OR, 4.39; 95% CI, 1.10-17.45; P=.036) and early-onset sepsis (OR, 3.87; 95% CI, 1.05-14.29; P=.042). The concentrations of all the lectin pathway proteins increased with gestational age (P<.01). Conclusions. These preliminary results indicate that low MBL concentrations are a susceptibility factor for gram-negative sepsis, and low H-ficolin concentrations indicate susceptibility to gram-positive sepsis. The decreased expression of lectin pathway proteins in neonates must be considered to be an additional form of neonatal immunodeficienc

Recommendations for surveillance of pulmonary dysfunction among childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group

\ua9 2024. Childhood, adolescent, and young adult (CAYA) cancer survivors are at risk of pulmonary dysfunction. Current follow-up care guidelines are discordant. Therefore, the International Late Effects of Childhood Cancer Guideline Harmonization Group established and convened a panel of 33 experts to develop evidence-based surveillance guidelines. We critically reviewed available evidence regarding risk factors for pulmonary dysfunction, types of pulmonary function testing, and timings of surveillance, then we formulated our recommendations. We recommend that CAYA cancer survivors and healthcare providers are aware of reduced pulmonary function risks and pay vigilant attention to potential symptoms of pulmonary dysfunction, especially among survivors treated with allogeneic haematopoietic stem cell transplantation, thoracic radiotherapy, and thoracic surgery. Based on existing limited evidence and current lack of interventions, our panel recommends pulmonary function testing only for symptomatic survivors. Since scarce existing evidence informs our recommendation, we highlight the need for prospective collaborative studies to address pulmonary function knowledge gaps among CAYA cancer survivors

Stable Mutated tau441 Transfected SH-SY5Y Cells as Screening Tool for Alzheimer’s Disease Drug Candidates

The role of hyperphosphorylation of the microtubule-associated protein tau in the pathological processes of several neurodegenerative diseases is becoming better understood. Consequently, development of new compounds capable of preventing tau hyperphosphorylation is an increasingly hot topic. For this reason, dependable in vitro and in vivo models that reflect tau hyperphosphorylation in human diseases are needed. In this study, we generated and validated an in vitro model appropriate to test potential curative and preventive compound effects on tau phosphorylation. For this purpose, a stably transfected SH-SY5Y cell line was constructed over-expressing mutant human tau441 (SH-SY5Y-TMHT441). Analyses of expression levels and tau phosphorylation status in untreated cells confirmed relevance to human diseases. Subsequently, the effect of different established kinase inhibitors on tau phosphorylation (e.g., residues Thr231, Thr181, and Ser396) was examined. It was shown with several methods including immunosorbent assays and mass spectrometry that the phosphorylation pattern of tau in SH-SY5Y-TMHT441 cells can be reliably modulated by these compounds, specifically targeting JNK, GSK-3, CDK1/5, and CK1. These four protein kinases are known to be involved in in vivo tau phosphorylation and are therefore authentic indicators for the suitability of this new cell culture model for tauopathies

Rho GTPases as therapeutic targets in Alzheimer’s disease

The progress we have made in understanding Alzheimer’s disease (AD) pathogenesis has led to the identification of several novel pathways and potential therapeutic targets. Rho GTPases have been implicated as critical components in AD pathogenesis, but their various functions and interactions make understanding their complex signaling challenging to study. Recent advancements in both the field of AD and Rho GTPase drug development provide novel tools for the elucidation of Rho GTPases as a viable target for AD. Herein, we summarize the fluctuating activity of Rho GTPases in various stages of AD pathogenesis and in several in vitro and in vivo AD models. We also review the current pharmacological tools such as NSAIDs, RhoA/ROCK, Rac1, and Cdc42 inhibitors used to target Rho GTPases and their use in AD-related studies. Finally, we summarize the behavioral modifications following Rho GTPase modulation in several AD mouse models. As key regulators of several AD-related signals, Rho GTPases have been studied as targets in AD. However, a consensus has yet to be reached regarding the stage at which targeting Rho GTPases would be the most beneficial. The studies discussed herein emphasize the critical role of Rho GTPases and the benefits of their modulation in AD

Cardiovascular and Pulmonary Challenges After Treatment of Childhood Cancer.

Childhood cancer survivors are at risk for developing cardiovascular disease and pulmonary disease related to cancer treatment. This might not become apparent until many years after treatment and varies from subclinical to life-threatening disease. Important causes are anthracyclines and radiotherapy involving heart, head, or neck for cardiovascular disease, and bleomycin, busulfan, nitrosoureas, radiation to the chest, and lung or chest surgery for pulmonary disease. Most effects are dose dependent, but genetic risk factors have been discovered. Treatment options are limited. Prevention and regular screening are crucial. Survivors should be encouraged to adopt a healthy lifestyle, and modifiable risk factors should be addressed

Molecular epidemiology of hospital-onset methicillin-resistant Staphylococcus aureus infections in Southern Chile

Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogen of public health importance. In Chile, the Cordobes/Chilean clone was the predominant healthcareassociated MRSA (HA-MRSA) clone in 1998. Since then, the molecular epidemiological surveillance of MRSA has not been performed in Southern Chile. We aimed to investigate the molecular epidemiology of HA-MRSA infections in Southern Chile to identify the MRSA clones involved, and their evolutionary relationships with epidemic international MRSA lineages. A total of 303 single inpatient isolates of S. aureus were collected in the Valdivia County Hospital (2007–2008), revealing 33 % (100 MRSA/303) prevalence for HA-MRSA infections. The SCCmec types I and IV were identified in 97 % and 3 % of HA-MRSA, respectively. All isolates lacked the pvl genes. A random sample (n = 29) of all MRSA was studied by pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), SCCmec subtyping, agr and spa typing, and virulence genes profiling. PFGE analysis revealed the predominance (89 %, 26/29) of pulsotype A and three additional pulsotypes, designated H1, I33, and G1. Pulsotype A (ST5-SCCmecI-spa-t149) is clonally related to the Cordobes/Chilean clone. Pulsotype H1 (ST5-SCC mecIVNT-spa-t002) is genetically related to the Pediatric clone (ST5-SCCmecIV). Pulsotype I33 (ST5-SCCmecIVc-spa-t002) is clonally related by PFGE to the community-associated MRSA (CA-MRSA) clone spread in Argentina, I-ST5-IVa-PVL+ . The G1 pulsotype (ST8-SCCmecIVc-spa-t024) is clonally related to the epidemic USA300 CA-MRSA. Here, we demonstrate the stability of the Cordobes/Chilean clone over time as the major HA-MRSA clone in Southern Chile. The identification of two CA-MRSA clones might suggest that these clones have entered into the healthcare setting from the community. These results emphasize the importance of the local surveillance of MRSA infections in the community and hospital settings.Fil: Medina, G.. Universidad Austral de Chile. Facultad de Medicina. Instituto de Microbiología Clínica; ChileFil: Egea, Ana Lía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Otth, C.. Universidad Austral de Chile. Facultad de Medicina. Instituto de Microbiología Clínica; ChileFil: Otth, L.. Universidad Austral de Chile. Facultad de Medicina. Instituto de Microbiología Clínica; ChileFil: Fernández, H.. Universidad Austral de Chile. Facultad de Medicina. Instituto de Microbiología Clínica; ChileFil: Bocco, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Wilson, M.. Universidad Austral de Chile. Facultad de Medicina. Instituto de Microbiología Clínica; ChileFil: Sola, Claudia del Valle. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentin

Synthesis, characterization and initial evaluation of 5-nitro-1-(trifluoromethyl)-3H-1λ3,2-benziodaoxol-3-one

The synthesis of 5-nitro-1-(trifluoromethyl)-3H-1λ3,2-benziodaoxol-3-one (3), a hypervalent-iodine-based electrophilic trifluoromethylating reagent, is described. Whereas considerations based on cyclic voltammetry and X-ray structural properties would predict an inferior reactivity when compared to the non-nitrated derivative 2, 19F NMR kinetic studies showed that this new derivative is almost one order of magnitude more reactive. Furthermore, differential scanning calorimetry measurements indicated that, in addition, it is also safer to handle

Synthesis, characterization and initial evaluation of 5-nitro-1-(trifluoromethyl)-3H-1λ3,2-benziodaoxol-3-one

The synthesis of 5-nitro-1-(trifluoromethyl)-3H-1λ3,2-benziodaoxol-3-one (3), a hypervalent-iodine-based electrophilic trifluoromethylating reagent, is described. Whereas considerations based on cyclic voltammetry and X-ray structural properties would predict an inferior reactivity when compared to the non-nitrated derivative 2, 19F NMR kinetic studies showed that this new derivative is almost one order of magnitude more reactive. Furthermore, differential scanning calorimetry measurements indicated that, in addition, it is also safer to handle.ISSN:1860-539

Deficiency of mannose-binding lectin-associated serine protease-2 associated with increased risk of fever and neutropenia in pediatric cancer patients

BACKGROUND: Mannose-binding lectin-associated serine protease-2 (MASP-2) is an essential component of the lectin pathway of complement activation. MASP-2 deficiency is common because of genetic polymorphisms, but its impact on susceptibility to infection is largely unknown. The aim of the present study was to determine whether children with cancer and MASP-2 deficiency develop more frequent or more severe episodes of fever and severe chemotherapy-induced neutropenia (FN). METHODS: Serum MASP-2 was measured by enzyme-linked immunosorbent assay at the time of diagnosis in children treated with chemotherapy for cancer. Association of FN episodes with MASP-2 concentration was analyzed using Poisson regression accounting for chemotherapy intensity and duration. RESULTS: Median MASP-2 in 94 children was 527 ng/mL (interquartile range, 367-686). Nine (10%) children had MASP-2 deficiency