Balancing porosity and mechanical properties of titanium samples to favor cellular growth against bacteria

Two main problems limit the success of titanium implants: bacterial infection, which restricts their osseointegration capacity; and the stiffness mismatch between the implant and the host cortical bone, which promotes bone resorption and risk of fracture. Porosity incorporation may reduce this difference in stiffness but compromise biomechanical behavior. In this work, the relationship between the microstructure (content, size, and shape of pores) and the antibacterial and cellular behavior of samples fabricated by the space-holder technique (50 vol % NH4HCO3 and three ranges of particle sizes) is established. Results are discussed in terms of the best biomechanical properties and biofunctional activity balance (cell biocompatibility and antibacterial behavior). All substrates achieved suitable cell biocompatibility of premioblast and osteoblast in adhesion and proliferation processes. It is worth to highlighting that samples fabricated with the 100–200 μm space-holder present better mechanical behavior—in terms of stiffness, microhardness, and yield strength—which make them a very suitable material to replace cortical bone tissues. Those results exposed the relationship between the surface properties and the race of bacteria and mammalian cells for the surface with the aim to promote cellular growth over bacteria.University of Seville (Spain) VI Plan Propio de Investigación y Transferencia—US 2018, I.3A

Effect of disinfectants used in clinical facilities on the induction of the SOS response and mutation frequency in Escherichia coli

Motivation: The development of antibiotic resistance is one of the mechanism used to study adaptive evolution. Antibiotics not only select for preexisting resistant strains in a population, but they can also promote the appearance of resistant strains (1, 2). Antibiotics at high concentrations can be lethal to bacteria, but it has been shown that sub-inhibitory concentrations of some antibiotics can stimulate horizontal transfer of DNA and mutation in different chromosomal loci (1, 3). These antibiotics can increase the mutation rate through several mechanisms, such as oxidative stress and the SOS response, which is triggered by DNA damage (2, 3). In this context, we wanted to determine if commonly-used disinfectants also promote mutation. Methods: The disinfectants used were ethanol, sodium hypochlorite, chlorhexidine, silver nitrate, benzalkonium chloride, triclosan and povidone-iodine complex. The E.coli strain used was IBDS1, which includes a tetracycline gene regulated by the cI (Ind-) repressor gene, that allows us to measure the mutation rate.To study the effect of these disinfectants, the strain IBDS1 was tested with a window of concentrations very close to the minimum inhibitory concentration (MIC) by evaluating the appearance of mutants resistant to rifampicin or tetracycline (3). To determine if this effect could be linked to the induction of the SOS system, we used a plasmid which expresses the "Green Fluorescence Protein" (GFP) under the control of the promoter of the recA gene to detect when the SOS system is activated by measuring fluorescence.Results: Three of the disinfectants tested increased mutation frequency. Concentrations of 0.013 μg/ml and 0.026 μg/ml of NaClO (1/4x CMI y 1/2x MIC) increased the mutation frequency approximatly 4 fold and 0.5 μg/ml of clorhexidine (1/4x MIC) and 0.125 μg/ml of triclosan (1/4x MIC) 3 fold, approximately. In relation to the SOS system, none of the concentrations tested induced the SOS response. Conclusions: These results show that certain concentrations of sodium hypochlorite, chlorhexidine and triclosan increase the mutation frequency and therefore may facilitate the appearance of resistant strains, although it appears that this mutagenic effect is not related to the induction of the SOS system. Therefore, it would be interesting to study whether this mutagenic effects is due to the reactive oxygen species (ROS) produced by disinfectants.

Musculoskeletal evaluation in severe haemophilia A patients from Latin America

There is a paucity of literature on haemophilia treatment in Latin American countries, a region characterized by rapidly improving systems of care, but with substantial disparities in treatment between countries. The aim of this study was to evaluate the musculoskeletal status of haemophilia patients from Latin America and to examine the relationship between musculoskeletal status and treatment practices across countries. The Committee of Latin America on the Therapeutics of Inhibitor Groups conducted a survey of its member country representatives on key aspects of haemophilia treatment in 10 countries. Musculoskeletal status of patients was obtained during routine comprehensive evaluations between March 2009 and March 2011. Eligible patients had severe haemophilia A (factor VIII <1%) without inhibitors (<0.6 BU mL−1) and were ≥5 years of age. Musculoskeletal status was compared between three groups of countries, based primarily on differences in the availability of long‐term prophylaxis. Overall, 143 patients (5–66 years of age) were enrolled from nine countries. In countries where long‐term prophylaxis had been available for at least 10 years (Group A), patients aged 5–10 years had significantly better mean World Federation of Hemophilia clinical scores, fewer target joints and fewer affected joints than patients from countries where long‐term prophylaxis has been available for about 5 years (Group B) or was not available (Group C). In Latin America, the musculoskeletal status of patients with severe haemophilia without inhibitors has improved significantly in association with the provision of long‐term prophylaxis. As more countries in Latin America institute this practice, further improvements are anticipated

Exploring a new generation of bimetallic magnetic ionic liquids with ultra-low viscosity in microextraction that enable direct coupling with high-performance liquid-chromatography

Background: The incorporation of bimetallic magnetic ionic liquids (MILs) in microextraction methods is an emerging trend due to the improved magnetic susceptibility offered by these solvents, which relies on the presence of metallic components in both the cation and the anion. This feature favors easy magnetic separation of these solvents in analytical sample preparation strategies. However, reported liquid-phase microextraction methods based on bimetallic MILs still present an important drawback in that the MILs are highly viscous, making a dispersive solvent during the microextraction procedure necessary, while also requiring a tedious back-extraction step prior to the chromatographic analysis. Results: We propose for the first time a new generation of ultra-low viscosity bimetallic MILs composed of two paramagnetic Mn(II) complexes characterized by their easy usage in dispersive liquid-liquid microextraction (DLLME). The approach does not require dispersive solvent and the MIL-DLLME setup was directly combined with high-performance liquid chromatography (HPLC) and fluorescence detection (FD), without any back-extraction step. The approach was evaluated for the determination of five monohydroxylated polycyclic aromatic hydrocarbons, as carcinogenic biomarkers, in human urine. Optimum conditions of the MIL-DLLME method included the use of a low MIL volume (75 μL), a short extraction time (5 min), and no need of any dispersive solvent neither NaCl. The method presented limits of detection down to 7.50 ng L−1, enrichment factors higher than 17, and provided inter-day relative standard deviation lower than 11%. Analysis of urine samples was successfully performed, with biomarker content found at levels between 0.24 and 7.8 ng mL−1. Significance: This study represents the first liquid-phase microextraction method using the new generation of low-viscous bimetallic MILs. The proposed MIL-DLLME approach represents 2 important advances with respect to previous methods employing bimetallic MILs: 1) no dispersive solvent is required, and 2) direct injection of the MIL in the HPLC is possible after minor dilution (no back extraction steps are required). Therefore, the microextraction strategy is simple, rapid, and consumes very small amounts of energy.This article is published as González-Martín, Raúl, Sirintorn Jullakan, María J. Trujillo-Rodríguez, Nabeel Mujtaba Abbasi, Shashini De Silva, Jared L. Anderson, and Verónica Pino. "Exploring a new generation of bimetallic magnetic ionic liquids with ultra-low viscosity in microextraction that enable direct coupling with high-performance liquid-chromatography." Analytica Chimica Acta (2024): 342448. doi: https://doi.org/10.1016/j.aca.2024.342448. © 2024 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

ESRETNET Study Group, The ERDC Study Group, The Associated Clinical Study Group.Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations.This work was supported by the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Health (FIS; PI16/00425 and PI19/00321), Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER, 06/07/0036), IIS-FJD BioBank (PT13/0010/0012), Comunidad de Madrid (CAM, RAREGenomics Project, B2017/BMD-3721), European Regional Development Fund (FEDER), the Organización Nacional de Ciegos Españoles (ONCE), Fundación Ramón Areces, Fundación Conchita Rábago and the University Chair UAM-IIS-FJD of Genomic Medicine. Irene Perea-Romero is supported by a PhD fellowship from the predoctoral Program from ISCIII (FI17/00192). Ionut F. Iancu is supported by a grant from the Comunidad de Madrid (CAM, PEJ-2017-AI/BMD7256). Marta del Pozo-Valero is supported by a PhD grant from the Fundación Conchita Rábago. Berta Almoguera is supported by a Juan Rodes program from ISCIII (JR17/00020). Pablo Minguez is supported by a Miguel Servet program from ISCIII (CP16/00116). Marta Corton is supported by a Miguel Servet program from ISCIII (CPII17/00006)

Manejo de la inmunosupresión en pacientes trasplantados de riñón con COVID19. Estudio multicéntrico nacional derivado del registro COVID de la Sociedad Española de Nefrología

Introduction: SARS CoV2 infection has had a major impact on renal transplant patients with a high mortality in the first months of the pandemic. Intentional reduction of immunosuppressive therapy has been postulated as one of the cornerstone in the management of the infection in the absence of targeted antiviral treatment. This has been modified according to the patient`s clinical situation and its effect on renal function or anti-HLA antibodies in the medium term has not been evaluated.Objectives: Evaluate the management of immunosuppressive therapy made during SARS-CoV2 infection, as well as renal function and anti-HLA antibodies in kidney transplant patients 6 months after COVID19 diagnosis.Material and methods: Retrospective, national multicentre, retrospective study (30 centres) of kidney transplant recipients with COVID19 from 01/02/20 to 31/12/20. Clinical variables were collected from medical records and included in an anonymised database. SPSS statistical software was used for data analysis.Results: renal transplant recipients with COVID19 were included (62.6% male), with a mean age of 57.5 years. The predominant immunosuppressive treatment prior to COVID19 was triple therapy with prednisone, tacrolimus and mycophenolic acid (54.6%) followed by m-TOR inhibitor regimens (18.6%). After diagnosis of infection, mycophenolic acid was discontinued in 73.8% of patients, m-TOR inhibitor in 41.4%, tacrolimus in 10.5% and cyclosporin A in 10%. In turn, 26.9% received dexamethasone and 50.9% were started on or had their baseline prednisone dose increased. Mean creatinine before diagnosis of COVID19, at diagnosis and at 6 months was: 1.7 +/- 0.8, 2.1 +/- 1.2 and 1.8 +/- 1 mg/dl respectively (p < 0.001). 56.9% of the patients (N = 350) were monitored for anti-HLA antibodies. 94% (N = 329) had no anti-HLA changes, while 6% (N = 21) had positive anti-HLA antibodies. Among the patients with donor-specific antibodies post-COVID19 (N = 9), 7 patients (3.1%) had one immunosuppressant discontinued (5 patients had mycophenolic acid and 2 had tacrolimus), 1 patient had both immunosuppressants discontinued (3.4%) and 1 patient had no change in immunosuppression (1.1%), these differences were not significant.Conclusions: The management of immunosuppressive therapy after diagnosis of COVID19 was primarily based on discontinuation of mycophenolic acid with very discrete reductions or discontinuations of calcineurin inhibitors. This immunosuppression management did not influence renal function or changes in anti-HLA antibodies 6 months after diagnosis

Dendritic cell deficiencies persist seven months after SARS-CoV-2 infection

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection induces an exacerbated inflammation driven by innate immunity components. Dendritic cells (DCs) play a key role in the defense against viral infections, for instance plasmacytoid DCs (pDCs), have the capacity to produce vast amounts of interferon-alpha (IFN-α). In COVID-19 there is a deficit in DC numbers and IFN-α production, which has been associated with disease severity. In this work, we described that in addition to the DC deficiency, several DC activation and homing markers were altered in acute COVID-19 patients, which were associated with multiple inflammatory markers. Remarkably, previously hospitalized and nonhospitalized patients remained with decreased numbers of CD1c+ myeloid DCs and pDCs seven months after SARS-CoV-2 infection. Moreover, the expression of DC markers such as CD86 and CD4 were only restored in previously nonhospitalized patients, while no restoration of integrin β7 and indoleamine 2,3-dyoxigenase (IDO) levels were observed. These findings contribute to a better understanding of the immunological sequelae of COVID-19

Mu-Opioid Receptors Transiently Activate the Akt-nNOS Pathway to Produce Sustained Potentiation of PKC-Mediated NMDAR-CaMKII Signaling

BACKGROUND: In periaqueductal grey (PAG) matter, cross-talk between the Mu-opioid receptor (MOR) and the glutamate N-methyl-D-Aspartate receptor (NMDAR)-CaMKII pathway supports the development of analgesic tolerance to morphine. In neurons, histidine triad nucleotide binding protein 1 (HINT1) connects the regulators of G protein signaling RGSZ1 and RGSZ2 to the C terminus of the MOR. In response to morphine, this HINT1-RGSZ complex binds PKCgamma, and afterwards, the interplay between PKCgamma, Src and Gz/Gi proteins leads to sustained potentiation of NMDAR-mediated glutamate responses. METHODOLOGY/PRINCIPAL FINDINGS: Following an intracerebroventricular (icv) injection of 10 nmol morphine, Akt was recruited to the synaptosomal membrane and activated by Thr308 and Ser473 phosphorylation. The Akt activation was immediately transferred to neural Nitric Oxide Synthase (nNOS) Ser1417. Afterwards, nitric oxide (NO)-released zinc ions recruited PKCgamma to the MOR to promote the Src-mediated phosphorylation of the Tyr1325 NMDAR2A subunit. This action increased NMDAR calcium flux and CaMKII was activated in a calcium-calmodulin dependent manner. CaMKII then acted on nNOS Ser847 to produce a sustained reduction in NO levels. The activation of the Akt-nNOS pathway was also reduced by the binding of these proteins to the MOR-HINT1 complex where they remained inactive. Tolerance to acute morphine developed as a result of phosphorylation of MOR cytosolic residues, uncoupling from the regulated G proteins which are transferred to RGSZ2 proteins. The diminished effect of morphine was prevented by LNNA, an inhibitor of nNOS function, and naltrindole, a delta-opioid receptor antagonist that also inhibits Akt. CONCLUSIONS/SIGNIFICANCE: Analysis of the regulatory phosphorylation of the proteins included in the study indicated that morphine produces a transient activation of the Akt/PKB-nNOS pathway. This activation occurs upstream of PKCgamma and Src mediated potentiation of NMDAR activity, ultimately leading to morphine tolerance. In summary, the Akt-nNOS pathway acts as a primer for morphine-triggered events which leads to the sustained potentiation of the NMDAR-CaMKII pathway and MOR inhibition

The ERA Registry Annual Report 2019 : summary and age comparisons

Background Data on renal replacement therapy (RRT) for end-stage renal disease were collected by the European Renal Association (ERA) Registry via national and regional renal registries in Europe and countries bordering the Mediterranean Sea. This article provides a summary of the 2019 ERA Registry Annual Report, including data from 34 countries and additional age comparisons. Methods Individual patient data for 2019 were provided by 35 registries and aggregated data by 17 registries. Using these data, the incidence and prevalence of RRT, the kidney transplantation activity and the survival probabilities were calculated. Results In 2019, a general population of 680.8 million people was covered by the ERA Registry. Overall, the incidence of RRT was 132 per million population (p.m.p.). Of these patients, 62% were men, 54% were >= 65 years of age and 21% had diabetes mellitus as primary renal disease (PRD), and 84% had haemodialysis (HD), 11% had peritoneal dialysis (PD) and 5% had pre-emptive kidney transplantation as an initial treatment modality. The overall prevalence of RRT on 31 December 2019 was 893 p.m.p., with 58% of patients on HD, 5% on PD and 37% living with a kidney transplant. The overall kidney transplant rate was 35 p.m.p. and 29% of the kidney grafts were from a living donor. The unadjusted 5-year survival probability was 42.3% for patients commencing dialysis, 86.6% for recipients of deceased donor grafts and 94.4% for recipients of living donor grafts in the period 2010-14. When comparing age categories, there were substantial differences in the distribution of PRD, treatment modality and kidney donor type, and in the survival probabilities.Peer reviewe

Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism

Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90-day all-cause (odds ratio [OR], 2.81; 95% CI, 2.33-3.38) and PE-related mortality (OR, 2.38; 95% CI, 1.37-4.14) and increased 1-year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10-9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all-cause mortality (OR, 1.91; 95% CI, 1.57-2.32) but not PE-related mortality (OR, 1.50; 95% CI, 0.85-2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR, 2.28; 95% CI, 1.75-2.97) and PE-related (OR, 3.64; 95% CI, 2.01-6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.info:eu-repo/semantics/publishedVersio