Epidemiological assessment of Anaplasma marginale, Babesia bigemina, and Babesia bovis infections in Colombian creole cattle breeds: A molecular survey in northeastern Colombia.

Anaplasmosis and babesiosis are globally distributed arthropod-borne diseases known for causing substantial economic losses due to their high morbidity and mortality rates. This study aims to assess the frequency and epidemiological features associated with the infection of Anaplasma marginale, Babesia bigemina, and Babesia bovis in three Creole cattle breeds (Chino Santandereano (Chino), Casanareño (CAS), and Sanmartinero (SM)) in northeastern Colombia. Between June 2019 and March 2020, a total of 252 Creole cattle were sampled, with Chino, CAS, and SM accounting for 42.8%, 29.5%, and 29.5% of the samples, respectively. Blood samples were subjected to molecular analysis to detect the DNA of A. marginale, B. bigemina, and B. bovis, using species-specific primers. Additionally, Packed Cell Volume (PCV), total serum proteins, and body condition were evaluated. Molecular analyses revealed the presence of B. bigemina, A. marginale, and B. bovis in 83.7% (211/252; 95% CI = 79.1%-88.3%), 59.9% (151/252; 95% CI = 53.8%-66.1%), and 40.9% (103/252; 95% CI = 34.7%-46.9%) of the samples, respectively, with 69% (174/252; 95% CI = 57.8%-80.3%) exhibiting coinfections. Notably, in infected animals, no significant alterations in PCV, total serum proteins, or body condition were observed. Multivariate analyses indicated a statistically significant association between the frequency of A. marginale infection and the breed and season, with a higher frequency in SM during the rainy season (P < 0.05). To our knowledge, this is the first molecular survey that evaluates multiple arthropod-borne pathogens in Colombian Creole breeds. The results revel a high frequency of B. bigemina and A. marginale infections, coupled with a notable frequency of coinfections, all without significant alteration in the PCV, total serum proteins and body conditions. Our findings enhance the understanding of the epidemiological aspects of arthropod-borne pathogens in Colombian Creole breed and contribute to the improvement of sanitary programs for these animals.

Assessing the electrochemical degradation of reactive orange 84 with Ti/IrO2-SnO2-Sb2O5 anode using electrochemical oxidation, electro-Fenton, and photoelectro-Fenton under UVA irradiation.

Today, water shortage problems around the world have forced the search for new treatment alternatives, in this context, electrochemical oxidation technology is a hopeful process for wastewater treatment, although it is still needed exploration of new efficient and economically viable electrode materials. In this way, mixed metal oxide anodes look like promising alternatives but their preparation is still a significant point to study, searching for finding low-cost materials to improve electrocatalytic efficiencies. In an exploration of this kind of highly efficient materials, this work presents the results obtained using an MMO Ti/IrO2-SnO2-Sb2O5 anode. All the prepared anodes exhibited excellent physical and electrochemical properties. The electrochemical oxidation of 100 mL and 200 mg L-1 Reactive Orange 84 (RO 84) diazo dye was studied using 3 cm2 of such synthesized anodes by applying current densities of 25, 50, and 100 mA cm-2. Faster and more efficient electrochemical oxidation occurred at 100 mA cm-2 with 50 mM of Na2SO4 + 10 mM NaCl as supporting electrolyte at pH 3.0. The degradation and mineralization processes of the above solution were enhanced with the electro-Fenton process with 0.05 mM Fe2+ and upgraded using photoelectron-Fenton with UVA light. This process yielded 91% COD decay with a low energy consumption of 0.1137 kWh (g COD)-1 at 60 min. The evolution of a final carboxylic acid like oxalic was followed by HPLC analysis. The Ti/IrO2-SnO2-Sb2O5 is then an efficient and low-cost anode for the photoelectro-Fenton treatment of RO 84 in a chloride and sulfate media.

Mechanical Properties, Corrosion Behavior, and In Vitro Cell Studies of the New Ti-25Ta-25Nb-5Sn Alloy.

This study aims to characterize a new Ti-25Ta-25Nb-5Sn alloy for biomedical application. Microstructure, phase formation, mechanical and corrosion properties, along with the cell culture study of the Ti-25Ta-25Nb alloy with Sn content 5 mass% are presented in this article. The experimental alloy was processed in an arc melting furnace, cold worked, and heat treated. For characterization, optical microscopy, X-ray diffraction, microhardness, and Young's modulus measurements were employed. Corrosion behavior was also evaluated using open-circuit potential (OCP) and potentiodynamic polarization. In vitro studies with human ADSCs were performed to investigate cell viability, adhesion, proliferation, and differentiation. Comparison among the mechanical properties observed in other metal alloy systems, including CP Ti, Ti-25Ta-25Nb, and Ti-25Ta-25-Nb-3Sn showed an increase in microhardness and a decrease in the Young's modulus when compared to CP Ti. The potentiodynamic polarization tests indicated that the corrosion resistance of the Ti-25Ta-25Nb-5Sn alloy was similar to CP Ti and the experiments in vitro demonstrated great interactions between the alloy surface and cells in terms of adhesion, proliferation, and differentiation. Therefore, this alloy presents potential for biomedical applications with properties required for good performance.

Influence of TiO2 nanoparticles content as reinforce material to enhance the mechanical and corrosion resistance properties of Sn and Sn-Ag alloy for dental applications.

This study evaluated the influence of the TiO2 nanoparticles (NPs) on the mechanical and chemical performance of Sn and Sn-Ag alloys. The XRD (X-ray diffraction) and HR-TEM (high resolution-transmission electron microscopy) methods were used to characterize the NPs synthesized by the sol-gel microwave process. The chemical composition of the alloys was Sn, Sn+3TiO2 NPs, Sn-5Ag+1.5TiO2 NPs, Sn-10Ag, and Sn-10Ag+3TiO2 NPs, obtained from an experimental factorial design (EFD). A statistical model was used to determine the mechanical and chemical properties, showing the Vickers hardness response surface, tensile strength, wear, and corrosion resistance. The wear and corrosion tests for the various alloy compositions were performed using human artificial saliva solution. The results indicated that the Sn-10Ag+3TiO2 NPs exhibited the highest mechanical performance due to their increased hardness (380 HV), tensile strength (370 N), and wear resistance (0.34 × 10-3 mm3 Nm-1); in all the cases, the inclusion of TiO2 NPs enhanced the corrosion resistance of the alloys. According to the American Dental Association (ADA), Sn-10Ag+3TiO2 NPs alloy could be classified as a possible type IV restorative material.

Critical Pronociceptive Role of Family 2 Voltage-Gated Calcium Channels in a Novel Mouse Model of HIV-Associated Sensory Neuropathy.

Some people living with HIV present painful sensory neuropathy (HIV-SN) that is pharmacoresistant, sex-associated, and a major source of morbidity. Since the specific mechanisms underlying HIV-SN are not well understood, the aim of our study was to characterize a novel model of painful HIV-SN by combining the HIV-1 gp120 protein and the antiretroviral stavudine (d4T) in mice and to investigate the pronociceptive role of the family 2 voltage-gated calcium channel (VGCC) α1 subunit (Cav2.X channels) in such a model. HIV-SN was induced in male and female C57BL/6 mice by administration of gp120 and/or d4T and detected by a battery of behavior tests and by immunohistochemistry. The role of Cav2.X channels was assessed by the treatment with selective blockers and agonists as well as by mRNA detection. Repeated administration with gp120 and/or d4T produced long-lasting touch-evoked painful-like behaviors (starting at 6 days, reaching a maximum on day 13, and lasting up to 28 days after treatment started), with a greater intensity in female mice treated with the combination of gp120 + d4T. Moreover, gp120 + d4T treatment reduced the intraepidermal nerve fibers and well-being of female mice, without altering other behaviors. Mechanistically, gp120 + d4T treatment induced Cav2.1, 2.2, and 2.3 transcriptional increases in the dorsal root ganglion and the Cav2.X agonist-induced nociception. Accordingly, intrathecal selective Cav2.2 blockade presented longer and better efficacy in reversing the hyperalgesia induced by gp120 + d4T treatment compared with Cav2.1 or Cav2.3, but also presented the worst safety (inducing side effects at effective doses). We conclude that the family 2 calcium channels (Cav2.X) exert a critical pronociceptive role in a novel mouse model of HIV-SN.

Targeted Therapy for Locally Advanced or Metastatic Urothelial Cancer (mUC): Therapeutic Potential of Sacituzumab Govitecan.

Urothelial carcinoma is the second most frequent genitourinary malignancy. Despite the poor prognosis, new treatment options have emerged and have expanded the therapeutic landscape for the disease. Although major improvements have been achieved, many patients experience rapid disease progression and low responses in subsequent lines of therapy. Sacituzumab govitecan is an ADC that targets Trop-2, which is highly expressed in urothelial cancers. Promising results in early clinical trials have led to further drug development which confirmed encouraging efficacy. Sacituzumab govitecan has been given accelerated approval in 2021 for patients with locally advanced and metastatic urothelial cancer who previously received a platinum containing chemotherapy and either a programmed death receptor-1 or programmed death ligand inhibitor. The results are promising, with encouraging efficacy and safety, however responses are not universal. There is a growing comprehension of mechanisms of resistance and predictive biomarkers that are crucial to improving outcomes. In this review, we summarize the current knowledge on antibody-drug conjugates and the clinical findings that led to the approval of Sacituzumab govitecan and discuss the therapeutic potential of new combinations, mechanisms of resistance and predictive biomarkers.

MicroRNA-375 inhibits laryngeal squamous cell carcinoma progression via targeting CST1

Abstract Objective: This study aims to explore the effect and mechanism of miR-375 in Laryngeal Squamous Cell Carcinoma (LSCC) cell progression. Methods: LSCC cells (LSC-1 and TU177) were transfected with miR-375-mimic, miR-375-inhibitor or miR-375-mimic + oe-CST1. The expression of miR-375, CST1, MMP-2, and MMP-9 was measured. The effect of miR-375-mimic, miR-375-inhibitor or miR-375-mimic + oe-CST1 on cell biological functions, including cell proliferation, migration, invasion, and apoptosis, was also assessed. The potential relationship between CST1 and miR-375 was predicted by Jefferson software and validated by dual luciferase reporter gene assay. Results: Downregulated miR-375 expression was found in LSCC cells. Overexpression of miR-375 inhibited the viability and migration and promoted apoptosis of LSCC cells. Jefferson database and dual luciferase reporter gene assay confirmed that miR-375 directly targeted CST1. Over-expression of CST1 could reverse the anti-cancer effect of miR-375 overexpression in LSCC cells. Conclusion: Collected evidence showed that miR-375/CST1 axis was implicated in LSCC progression. Level of evidence: Level 3

MicroRNA-375 inhibits laryngeal squamous cell carcinoma progression via targeting CST1.

OBJECTIVE: This study aims to explore the effect and mechanism of miR-375 in Laryngeal Squamous Cell Carcinoma (LSCC) cell progression. METHODS: LSCC cells (LSC-1 and TU177) were transfected with miR-375-mimic, miR-375-inhibitor or miR-375-mimic+oe-CST1. The expression of miR-375, CST1, MMP-2, and MMP-9 was measured. The effect of miR-375-mimic, miR-375-inhibitor or miR-375-mimic+oe-CST1 on cell biological functions, including cell proliferation, migration, invasion, and apoptosis, was also assessed. The potential relationship between CST1 and miR-375 was predicted by Jefferson software and validated by dual luciferase reporter gene assay. RESULTS: Downregulated miR-375 expression was found in LSCC cells. Overexpression of miR-375 inhibited the viability and migration and promoted apoptosis of LSCC cells. Jefferson database and dual luciferase reporter gene assay confirmed that miR-375 directly targeted CST1. Overexpression of CST1 could reverse the anti-cancer effect of miR-375 overexpression in LSCC cells. CONCLUSION: Collected evidence showed that miR-375/CST1 axis was implicated in LSCC progression. LEVEL OF EVIDENCE: Level 3.

Modulating the lipid profile of blastocyst cell membrane with DPPC multilamellar vesicles.

The aim of this study was to evaluate the effect of multilamellar vesicles (MLVs) of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) in co-culture with in vitro-produced bovine embryos (IVPEs). The stability of five concentrations of MLVs (1.0, 1.25, 1.5, 1.75, and 2.0 mM) produced using ultrapure water or embryonic culture medium with 24 or 48 h of incubation at 38.5 °C with 5% CO2 was assessed. In addition, the toxicity of MLVs and their modulation of the lipid profile of the plasma membrane of IVPEs were evaluated after 48 h of co-culture. Both media allowed the production of MLVs. Incubation (24 and 48 h) did not impair the MLV structure but affected the average diameter. The rate of blastocyst production was not reduced, demonstrating the nontoxicity of the MLVs even at 2.0 mmol/L. The lipid profile of the embryos was different depending on the MLV concentration. In comparison with control embryos, embryos cultured with MLVs at 2.0 mmol/L had a higher relative abundance of six lipid ions (m/z 720.6, 754.9, 759.0, 779.1, 781.2, and 797.3). This study sheds light on a new culture system in which the MLV concentration could change the lipid profile of the embryonic cell membrane in a dose-dependent manner.

Design of new lipids from bovine milk fat for baby nutrition.

The lipid phase of infant formulas is generally composed of plant-based lipids structured with a high concentration of palmitic acid (C16:0) esterified at the sn-2 position of triacylglycerol since this structure favors the absorption and metabolism of fatty acids. Palm oil is commonly used to make up the lipid phase of infant formulas due to its high concentration of palmitic acid and solids profile and melting point similar to human milk fat. However, the addition of palm oil to infant formulas has been associated with the presence of 3-monochloropropane-1,2-diol (3-MCPD) esters, a group of glycerol-derived chemical contaminants (1,2,3-propanotriol), potentially toxic, formed during the refining process of vegetable oil. Bovine milk fat obtained from the complex biosynthesis in the mammary gland has potential as a technological alternative to replace palm oil and its fractions for the production of structured lipids to be used in infant formulas. Its application as a substitute is due to its composition and structure, which resembles breast milk fat, and essentially to the preferential distribution pattern of palmitic acids (C16:0) with approximately 85% distributed at the sn-1 and sn-2 position of triacylglycerol. This review will address the relationship between the chemical composition and structure of lipids in infant nutrition, as well as the potential of bovine milk fat as a basis for the production of structured lipids in substitution for the lipid phase of vegetable origin currently used in infant formulas.

Recent High-Resolution Structures of Amyloids Involved in Neurodegenerative Diseases.

Amyloids are highly ordered aggregates composed of proteins or peptides. They are involved in several pathologies, including hallmark neurodegenerative disorders such as Alzheimer's (AD) and Parkinson's (PD). Individuals affected by these diseases accumulate in their brains amyloids inclusions composed of misfolded forms of a peptide (Aß) and a protein (Tau) in AD and α-synuclein protein (α-Sn) in PD. Tau and α-Sn aggregates are also present in other neurodegenerative diseases. The insoluble nature and heterogeneity of amyloids have hampered their study at the molecular level. However, the use of solid state NMR and Cryogenic-electron microscopy along with fine-tuned modulation of the aggregation in vitro and improved isolation methods of brain-derived amyloids has allowed the elucidation of these elusive conformations at high resolution. In this work, we review the latest progress on the recent amyloid structures reported for Aß, Tau, and α-Sn. The two-fold symmetry emerges as a convergent feature in the tridimensional arrangement of the protofilaments in the fibrillary structure of these pathological amyloids, with many of them exhibiting a Greek-key topology as part of their overall architecture. These specific features can serve as novel guides to seek potential molecular targets in drug design efforts.

Synthesis of EPA- and DHA-Enriched Structured Acylglycerols at the sn-2 Position Starting from Commercial Salmon Oil by Enzymatic Lipase Catalysis under Supercritical Conditions.

There is consistent evidence that long-chain polyunsaturated fatty acids (LCPUFA) belonging to the n-3 series, i.e., eicosapentaenoic (20:5n-3, EPA) and docosahexaenoic (22:6n-3, DHA) acids, decrease the risk of heart, circulatory and inflammatory diseases. Furthermore, the bioavailability of such fatty acids has been shown to depend on their location in triacylglycerol (TG) molecules at the sn-2 position. Consequently, great attention has been accorded to the synthesis of structured acylglycerols (sAG), which include EPA or DHA at the sn-2 position. The aim of this work was to synthesize sAG starting from deodorized refined commercial salmon oil. For this, immobilized lipase B from Candida antarctica (nonspecific) was used as a catalyst for the intra-interesterification process under CO2 supercritical conditions (CO2SC). According to the CO2SC reaction time, three different fractions including sAG compounds were obtained. The location of EPA and DHA at the sn-2 position in the resulting glycerol backbone was identified by mass spectrometry (MALDI-TOF) analysis. In all fractions obtained, a marked decrease in the starting TG content was observed, while an increase in the DHA content at the sn-2 position was detected. The fraction obtained after the longest reaction time period (2 h) led to the highest yield of sn-2 position DHA in the resulting sAG molecule.

Natural and Enantiopure Alkylglycerols as Antibiofilms Against Clinical Bacterial Isolates and Quorum Sensing Inhibitors of Chromobacterium violaceum ATCC 12472.

Resistance mechanisms occur in almost all clinical bacterial isolates and represent one of the most worrisome health problems worldwide. Bacteria can form biofilms and communicate through quorum sensing (QS), which allow them to develop resistance against conventional antibiotics. Thus, new therapeutic candidates are sought. We focus on alkylglycerols (AKGs) because of their recently discovered quorum sensing inhibition (QSI) ability and antibiofilm potential. Fifteen natural enantiopure AKGs were tested to determine their effect on the biofilm formation of other clinical bacterial isolates, two reference strains and their QSI was determined using Chromobacterium violaceum ATCC 12472. The highest biofilm inhibition rates (%) and minimum QS inhibitory concentration were determined by a microtiter plate assay and ciprofloxacin was used as the standard antibiotic. At subinhibitory concentrations, each AKG reduced biofilm formation in a concentration-dependent manner against seven bacterial isolates, with values up to 97.2%. Each AKG displayed QSI at different levels of ability without affecting the growth of C. violaceum. AKG (2S)-3-O-(cis-13'-docosenyl)-1,2-propanediol was the best QS inhibitor (20 µM), while (2S)-3-O-(cis-9'-hexadecenyl)-1,2-propanediol was the least effective (795 µM). The results showed for the first time the QSI activity of this natural AKG series and suggest that AKGs could be promising candidates for further studies on preventing antimicrobial resistance.

Enantiomeric synthesis of natural alkylglycerols and their antibacterial and antibiofilm activities.

Alkylglycerols (AKGs) are bioactive natural compounds that vary by alkyl chain length and degree of unsaturation, and their absolute configuration is 2S. Three AKGs (5l-5n) were synthesised in enantiomerically pure form, and were characterised for the first time together with 12 other known and naturally occurring AKGs (5a-5k, 5o). Their structures were established using 1H and 13C APT NMR with 2D-NMR, ESI-MS or HRESI-MS and optical rotation data, and they were tested for their antibacterial and antibiofilm activities. AKGs 5a-5m and 5o showed activity against five clinical isolates and P. aeruginosa ATCC 15442, with MIC values in the range of 15-125 µg/mL. In addition, at half of the MIC, most of the AKGs reduced S. aureus biofilm formation in the range of 23%-99% and P. aeruginosa ATCC 15442 biofilm formation in the range of 14%-64%. The antibiofilm activity of the AKGs assessed in this work had not previously been studied.

Small interfering RNA for cancer treatment: overcoming hurdles in delivery.

In many ways, cancer cells are different from healthy cells. A lot of tactical nano-based drug delivery systems are based on the difference between cancer and healthy cells. Currently, nanotechnology-based delivery systems are the most promising tool to deliver DNA-based products to cancer cells. This review aims to highlight the latest development in the lipids and polymeric nanocarrier for siRNA delivery to the cancer cells. It also provides the necessary information about siRNA development and its mechanism of action. Overall, this review gives us a clear picture of lipid and polymer-based drug delivery systems, which in the future could form the base to translate the basic siRNA biology into siRNA-based cancer therapies.

Turpentine valorization by its oxyfunctionalization to nopol through heterogeneous catalysis.

Turpentine is a mixture of monoterpene hydrocarbons obtained as a by-product in the paper industry. In this contribution we present its transformation process towards an alcohol named nopol, that is an important household product and fragrance raw material. Reaction conditions were established for the oxyfuntionalization of crude turpentine oil over Sn-MCM-41 catalyst for the selective conversion of ß-pinene to nopol. Synthesized materials were characterized by XRD, N2 adsorption, FT-IR, TEM and chemical absorption. The reaction was tested in 2 mL glass reactor with a sample of commercial turpentine with α-pinene (55.5% w/w) and ß-pinene (39.5% w/w) as main components and scaled up into a 100 mL Parr reactor, getting 92% conversion of ß-pinene and a nopol selectivity of 93%. The reusability tests showed that the catalyst can be reused 4 times without loss of activity. The results showed that 86% less solvent and 37.5% less paraformaldehyde can be used with turpentine, compared to the conditions used with ß-pinene for getting similar catalysts activity.

1H, 29Si and 119Sn double and triple resonance NMR spectroscopy of the small-pore framework sodium stannosilicate Na2SnSi3O9·2H2O.

The small-pore framework sodium stannosilicate AV-10, chemical composition Na2SnSi3O9·2H2O and known crystallographic structure, was synthesized by hydrothermal crystallization. This stannosilicate is built up of a three-dimensional network of corner-shared SiO4 tetrahedra and SnO6 octahedra. The SnO6 sites are linked to six SiO4 tetrahedra (Sn(6Si)) while each of the two crystallographically different SiO4 units are connected to two SnO6 and SiO4 units (Si(2Si,2Sn)). This material was used as model compound for developing a solid-state MAS NMR strategy aimed on the challenges and possibilities for structural studies, particularly considering the short and medium range order to verify the connectivity of SiO4 and SnO6 of such compounds despite the low natural abundances of 4.68% for 29Si and 8.59% for 119Sn nuclei as a real challenge. 29Si{119Sn} and 119Sn{29Si} REDOR (Rotational-Echo Double-Resonance) NMR measurements after 1H cross-polarization (CP) were carried out. The REDOR curves show a significant change after the "normal" quadratic short time evolution from which both (i) the shortest internuclear 29Si - 119Sn distances (and vice versa) and (ii) the number of corner-sharing SiO4 tetrahedra around the SnO6 octahedra (and vice versa) can be obtained. Based on these data, optimized 29Si{119Sn} and 119Sn{29Si} REPT-HMQC (Recoupled Polarization Transfer-Heteronuclear Multiple-Quantum Correlation, again after 1H CP) experiments were implemented, which directly show those heterogroup connectivity as correlation peaks in a 2D spectrum. This information was also obtained using 2D29Si{119Sn}-J-Coupling NMR experiments. Furthermore, 2D29Si INADEQUATE NMR experiments are also feasible, showing the connectivity of SiO4 tetrahedra. The combination of REDOR, REPT-HMQC, J-Coupling and INADEQUATE experiments yielded a complete analysis of the short and medium range structure of this microporous stannosilicate, in agreement with the previously published structure obtained Ab Initio from powder X-Ray diffraction data (XRD).

La vertical verdadera al punto A´(blando), al Pg´(blando), al Labrale superior y al Labrale inferior en posición ideal asistida de la cabeza (PIAC) / The true vertical from point A´(soft), to Pg´ (soft), to superior Labrale and inferior Labrale in Ideal Assisted Head Position (PIAC)

El 81,3% de una encuesta realizada a 96 ortodoncistas y ortopedistas calificados y técnicos radiólogos consultados informan que ubican la cabeza del paciente en una posición ideal, subjetiva del profesional instruido que lo asiste, ya que muchas de sus fotografías y telerradiografías no son posiciones naturales de la cabeza genuinas. Se ha utilizado la vertical verdadera como parámetro para mediciones, todas angulares, para definir la disposición ánteroposterior del punto A´ (de construcción) para el cuerpo del labio superior, el punto Pg´para el mentón, el Labrale superior y el Labrale inferior para el bermellón de cada labio, con la finalidad de planificar correcciones ortopédicas, ortodóncicas u ortodóncicas-quirúrgicas de acuerdo a la anomalía detectada (AU)

Auditory processing disorder evaluations and cognitive profiles of children with specific learning disorder.

OBJECTIVE: This study investigated the auditory sensory-perceptual level of specific learning disorder (SLD) and explored relationships among neuropsychological assessments for SLD, auditory processing, and short and long latencies of auditory event-related potentials (ERPs). METHODS: Fifteen children (7-14 years old) comprised the control group; 34 children comprised the SLD group. Audiologic assessments included tone audiometry, acoustic immittance measurements, acoustic reflex, central auditory processing, brainstem evoked response audiometry, and long latency potentials (P3 and N2). Children's intelligence levels were assessed with 2 intelligence batteries, 1 verbal and 1 non-verbal, as well as with visuomotor skills. RESULTS: Multiple regression showed a significant interaction effect of APE tests and P3/N2 over Wechsler Scale performance in freedom of distractibility indexes and multiple subtests. Errors in the Bender Visual Motor Gestalt Test were predicted by lower parental education, lower performance in APE tests: dichotic digits and pediatric/synthetic sentence identification-ipsilateral, and longer P3/N2 latencies, particularly regarding integration and rotation distortions. CONCLUSIONS: Children with altered auditory processing exhibit a specific cognitive profile, including lower verbal and spatial reasoning performance, that is sensitive to parental education level. SIGNIFICANCE: Children with SLD should undergo a complete multimodal examination to identify their specific difficulties and needs.

SN-38, the active metabolite of irinotecan, inhibits the acute inflammatory response by targeting toll-like receptor 4.

PURPOSE: Anticancer-drug efficacy seems to involve the direct interaction with host immune cells. Although topoisomerase I (Top I) inhibitors have been suggested to block LPS-evoked inflammation, the interaction between these drugs and toll-like receptor 4 (TLR4) is unaddressed. METHODS: SN-38, the active metabolite of the Top I inhibitor irinotecan, and TLR4 interaction was assessed using the in vitro luciferase nuclear factor-κB reporter assay, neutrophil migration to murine air-pouch, in silico simulation, and the thermal shift assay (TSA). Topotecan was used as a positive anti-inflammatory control. RESULTS: Non-cytotoxic concentrations of SN-38 attenuated LPS (a TLR4 agonist)-driven cell activation without affecting peptidoglycan (a TLR2 agonist)-activating response. Similarly, topotecan also prevented LPS-induced inflammation. Conversely, increasing concentrations of LPS reversed the SN-38 inhibitory effect. In addition, SN-38 abrogated LPS-dependent neutrophil migration and reduced TNF-α, IL-6, and keratinocyte chemoattractant levels in the air-pouch model, but failed to inhibit zymosan (a TLR2 agonist)-induced cell migration. A two-step molecular docking analysis indicated two potential binding sites for the SN-38 in the MD-2/TLR4 complex, the hydrophobic MD-2 pocket (binding energy of - 8.1 kcal/mol) and the rim of the same molecule (- 6.9 kcal/mol). The topotecan also bound to the MD-2 pocket. In addition, not only the lactone forms, but also the carboxylate conformations of both Top I inhibitors interacted with the MD-2 molecule. Furthermore, the TSA suggested the interaction of SN-38 with MD-2. CONCLUSIONS: Therefore, SN-38 inhibits acute inflammation by blocking LPS-driven TLR4 signaling. This mechanism seems to be shared by other Top I inhibitors.