Assessing citizen science data quality for bird monitoring in the Iberian Peninsula.

Citizen science data on biodiversity has experienced significant growth, largely driven by advancements in technology that facilitate data sharing. In recent years, mobile applications have provided a substantial boost to both the collection and sharing of this data. While this accessible information is undoubtedly valuable, we must consider the numerous biases present in this data when used for high-quality research. In this study, we analyse citizen science data for the birds of the Iberian Peninsula, comprising over 23 million unique records after filtering for duplicates (i.e., instances where the same observation was uploaded more than once). Using a 10 × 10 km square grid, we present information on well-surveyed cells (completeness) as well as temporal, taxonomic, geographical, and land use coverages. We found that the completeness of information is generally high, with better coverage around densely populated areas such as major cities and coastal regions, as well as popular birding destinations, which are frequently visited. The Mediterranean ecoregion and wetlands exhibit the highest levels of surveying. Furthermore, we observed an increase in temporal coverage since the 1980s and broad taxonomic coverage across all bird orders in the Iberian region. Our results underscore the utility of citizen science for many locations, as expressed in 10 × 10 km cells. However, they also highlight the inadequate data completeness across part of the territory, particularly in forested or sparsely inhabited areas. These findings not only identify cells suitable for bird diversity or conservation studies but also indicate areas where citizen-driven bird recording efforts should be encouraged.

Chronotype delay and sleep disturbances shaped by the Antarctic polar night.

Chronotype is a reliable biomarker for studying the influence of external zeitgebers on circadian entrainment. Assessment of chronotype variation in participants exposed to extreme photoperiods may be useful to investigate how changes in light-dark cycle modulate the circadian system. This study aimed to examine chronotype and sleep changes during a winter campaign at the Argentine Antarctic station Belgrano II. A sample of 82 men who overwintered in Antarctica completed the Munich Chronotype Questionnaire during March (daylight length: 18.6 h), May (daylight length: 2.8 h), July (daylight length: 0 h), September (daylight length: 14.5 h), November (daylight length: 24 h). The main results showed a decrease in sleep duration and a delay in chronotype and social jetlag during the polar night, highlighting the influence of social cues and the impact of the lack of natural light on circadian rhythms.

Seasonal prevalence of gastrointestinal parasites in desert bighorn sheep (Ovis canadensis) in northern Mexico.

This study aimed to describe the shedding pattern of gastrointestinal parasite eggs by a wild population of desert bighorn sheep (DBS; Ovis canadensis) in northern Mexico. Seventy-five fresh faecal samples were collected from the ground in each season within an hour after being expelled by these animals. The generalized linear mixed model showed that eggs per gram of faeces were highest in winter (577 ± 399) and lowest in summer (260 ± 198). Generalized linear models revealed that Strongyloides spp. predominated during most seasons with a peak in summer (85% of faecal samples analysed) and the absence of this helminth in winter. Nematodirus spp. was another helminth present in three seasons, with the presence of this nematode in 35% of the faecal samples in spring and 0% in summer. Other parasites in DBS faeces included Bunostomun spp., Trichostrongylus spp., Cooperia spp., Mecistocirrus digitatus, Haemonchus contortus, Chabertia ovina and Eimeria ovinoidalis. There were differences among seasons in the percentage of these helminths and coccidia in faecal samples for all these parasites. It was concluded that helminths egg output in DBS in a semi-arid rangeland is lowest in summer and spring and highest in autumn and winter. Furthermore, it was shown that DBS in the study site do not suffer from severe parasite burden. Therefore, this nematode parasite burden is compatible with the conservation and well-being of this particular population.

Two-stage bone and meniscus allograft and autologous chondrocytes implant for unicompartmental osteoarthritis: midterm results.

BACKGROUND: We analyzed the clinical and radiographic evolution of patients with knee unicompartmental osteoarthritis and axis alteration and osteochondral lesions in the femoral condyle, treated with tibial plateau and meniscus allograft and cultured autologous chondrocyte implantation in the femur in two steps. PURPOSE: To analyze the clinical results with the first patients treated with this two-stage technique to avoid knee prosthesis in patients with unicompartmental osteoarthritis. MATERIAL AND METHODOLOGY: Sixteen patients, average age 56 years, were included in a cohort study. We performed an osteotomy with tibia plateau allograft, including the meniscus. In a second surgery, the chondrocyte fibrin scaffold was placed in the femur. Clinical symptoms and function were measured using KSSR and KOOS scores. Wilcoxon's test was performed to compare the results over the 2-year follow-up period. RESULTS: Mean KSSR before surgery was 35.69 (SD: 3.75) points, rising to 67 (SD: 15.42) at 3 months, 95.88 at 12 months (SD: 2.68) and 96.31 at 24 months (SD: 2.24). The KOOS before surgery was 65.14 (SD: 16.34), rising to 72.68 after 3 months (SD: 19.15), 76.68 at 12 months (SD: 18.92) and 64.28 at 24 months (SD: 11.79). Four of 5 patients returned to engaging in the activity that they had stopped practicing. Three patients experienced collapse of the tibia allograft, and they needed later a prosthesis. CONCLUSIONS: Simultaneous tibia plateau allograft and autologous chondrocyte implantation in the femur, after correction of the angular deformity, were performed, restoring the anatomy of the medial compartment and knee function in 82% of the patients 2 years after the operation. LEVEL OF EVIDENCE: IV.

Environmental status of marine plastic pollution in Spain.

The excessive use of plastic in our society is causing a massive accumulation, since it is a non-biodegradable product and with still poor recycling rates. This effect can be observed in the seas, which more and more plastic waste are accumulating. The present work is a critical review, based on all currently available literature, that reports environmental status of marine plastic pollution, especially microplastic pollution, in Spain. The three Spanish water areas with the highest presence of plastics are the Alboran Sea, the Gulf of Alicante and the vicinity of Barcelona probably related to fishing and industrial activities and high population densities. With regard to microplastic contamination on beaches in Spain, annual monitoring by the Spanish government shows contamination along the entire coast of the country, with particularly high concentrations in the Canary Islands (between 800 and 8800 particles/m2 in spring). Between 40 and 50% of the particles analyzed were pellets and the main factors postulated for the distribution of these particles are marine currents and the geomorphological characteristics. With regards to biota, ingestion of microplastics by fish has been intensely confirmed and, important differences were observed between the locations of the sampling, being bogues (Boops boops) one of the fish species more studied in Spain. Finally, the work includes a revision of European and Spanish legislation about plastics and marine pollution and some strategies to reduce this kind of contamination in Spain.

Metagenomic Profiling and Microbial Metabolic Potential of Perdido Fold Belt (NW) and Campeche Knolls (SE) in the Gulf of Mexico.

The Gulf of Mexico (GoM) is a particular environment that is continuously exposed to hydrocarbon compounds that may influence the microbial community composition. We carried out a metagenomic assessment of the bacterial community to get an overall view of this geographical zone. We analyzed both taxonomic and metabolic markers profiles to explain how the indigenous GoM microorganims participate in the biogeochemical cycling. Two geographically distant regions in the GoM, one in the north-west (NW) and one in the south-east (SE) of the GoM were analyzed and showed differences in their microbial composition and metabolic potential. These differences provide evidence the delicate equilibrium that sustains microbial communities and biogeochemical cycles. Based on the taxonomy and gene groups, the NW are more oxic sediments than SE ones, which have anaerobic conditions. Both water and sediments show the expected sulfur, nitrogen, and hydrocarbon metabolism genes, with particularly high diversity of the hydrocarbon-degrading ones. Accordingly, many of the assigned genera were associated with hydrocarbon degradation processes, Nitrospira and Sva0081 were the most abundant in sediments, while Vibrio, Alteromonas, and Alcanivorax were mostly detected in water samples. This basal-state analysis presents the GoM as a potential source of aerobic and anaerobic hydrocarbon degradation genes important for the ecological dynamics of hydrocarbons and the potential use for water and sediment bioremediation processes.

Characterization of a Novel Functional Trimeric Catechol 1,2-Dioxygenase From a Pseudomonas stutzeri Isolated From the Gulf of Mexico.

Catechol 1,2 dioxygenases (C12DOs) have been studied for its ability to cleavage the benzene ring of catechol, the main intermediate in the degradation of aromatic compounds derived from aerobic degradation of hydrocarbons. Here we report the genome sequence of the marine bacterium Pseudomonas stutzeri GOM2, isolated from the southwestern Gulf of Mexico, and the biochemical characterization of its C12DO (PsC12DO). The catA gene, encoding PsC12DO of 312 amino acid residues, was cloned and expressed in Escherichia coli. Many C12DOs have been described as dimeric enzymes including those present in Pseudomonas species. The purified PsC12DO enzyme was found as an active trimer, with a molecular mass of 107 kDa. Increasing NaCl concentration in the enzyme reaction gradually reduced activity; in high salt concentrations (0.7 M NaCl) quaternary structural analysis determined that the enzyme changes to a dimeric arrangement and causes a 51% decrease in specific activity on catechol substrate. In comparison with other C12DOs, our enzyme showed a broad range of action for PsC12DO in solutions with pH values ranging from neutral to alkaline (70%). The enzyme is still active after incubation at 50°C for 30 min and in low temperatures to long term storage after 6 weeks at 4°C (61%). EDTA or Ca2+ inhibitors cause no drastic changes on residual activity; nevertheless, the activity of the enzyme was affected by metal ions Fe3+, Zn2+ and was completely inhibited by Hg2+. Under optimal conditions the k cat and K m values were 16.13 s-1 and 13.2 µM, respectively. To our knowledge, this is the first report describing the characterization of a marine C12DOs from P. stutzeri isolated from the Gulf of Mexico that is active in a trimeric state. We consider that our enzyme has important features to be used in environments in presence of EDTA, metals and salinity conditions.

Molecular signatures of atherosclerotic plaques: An up-dated panel of protein related markers.

Atherosclerosis remains the leading cause of ischemic syndromes such as myocardial infarction or brain stroke, mainly promoted by plaque rupture and subsequent arterial blockade. Identification of vulnerable or high-risk plaques constitutes a major challenge, being necessary to identify patients at risk of occlusive events in order to provide them with appropriate therapies. Clinical imaging tools have allowed the identification of certain structural indicators of prone-rupture plaques, including a necrotic lipidic core, intimal and adventitial inflammation, extracellular matrix dysregulation, and smooth muscle cell depletion and micro-calcification. Additionally, alternative approaches focused on identifying molecular biomarkers of atherosclerosis have also been applied. Among them, proteomics has provided numerous protein markers currently investigated in clinical practice. In this regard, it is quite uncertain that a single molecule can describe plaque rupture, due to the complexity of the process itself. Therefore, it should be more accurate to consider a set of markers to define plaques at risk. Herein, we propose a selection of 76 proteins, from classical inflammatory to recently related markers, all of them identified in at least two proteomic studies analyzing unstable atherosclerotic plaques. Such panel could be used as a prognostic signature of plaque instability.

Clinical-radiological correlations in a de novo cavernous angioma with pseudotumor-like behavior. / Correlato clínico-radiológico de un angioma cavernoso de novo con comportamiento seudotumoral.

Cavernous angiomas are cerebral vascular malformations that are usually congenital. These lesions are characterized as dynamic. The most common phenomenon in the course of these lesions is bleeding, which can result in significant fluctuations in their size and even lead to their disappearance. This article aims to describe the behavior of a cavernous angioma in its natural history, documenting: a) its de novo appearance, a very uncommon observation, and b) its changes on imaging studies, where it grew progressively like an expanding lesion but had no clinical repercussions. On magnetic resonance imaging, atypical signs can orient the etiological diagnosis of cavernous angioma versus other alternatives: de novo appearance, fluid-fluid or air-fluid level, incomplete hypointense ring due to hemosiderin deposition, pseudotumor-like growth, pseudocyst-like or multiloculated shape, vasogenic edema, mass effect, and size greater than 3cm.

Extracellular NK histones promote immune cell anti-tumor activity by inducing cell clusters through binding to CD138 receptor.

BACKGROUND: Natural killer (NK) cells are important anti-tumor cells of our innate immune system. Their anti-cancer activity is mediated through interaction of a wide array of activating and inhibitory receptors with their ligands on tumor cells. After activation, NK cells also secrete a variety of pro-inflammatory molecules that contribute to the final immune response by modulating other innate and adaptive immune cells. In this regard, external proteins from NK cell secretome and the mechanisms by which they mediate these responses are poorly defined. METHODS: TRANS-stable-isotope labeling of amino acids in cell culture (TRANS-SILAC) combined with proteomic was undertaken to identify early materials transferred between cord blood-derived NK cells (CB-NK) and multiple myeloma (MM) cells. Further in vitro and in vivo studies with knock-down of histones and CD138, overexpression of histones and addition of exogenous histones were undertaken to confirm TRANS-SILAC results and to determine functional roles of this material transferred. RESULTS: We describe a novel mechanism by which histones are actively released by NK cells early after contact with MM cells. We show that extracellular histones bind to the heparan sulfate proteoglycan CD138 on the surface of MM cells to promote the creation of immune-tumor cell clusters bringing immune and MM cells into close proximity, and thus facilitating not only NK but also T lymphocyte anti-MM activity. CONCLUSION: This study demonstrates a novel immunoregulatory role of NK cells against MM cells mediated by histones, and an additional role of NK cells modulating T lymphocytes activity that will open up new avenues to design future immunotherapy clinical strategies.

The burn severity and plant recovery relationship affect the biological and chemical soil properties of Pinus halepensis Mill. stands in the short and mid-terms after wildfire.

In the Mediterranean Basin, changes in climate and fire regime (increased recurrence and severity) reduce ecosystem services after wildfires by increasing soil degradation and losses in plant diversity. Our study was a biological approach to relate soil properties to vegetation recovery and burn severity. We focused our study on the natural recovery of the soil-plant interphase in Pinus halepensis Mill. forests located in the SE of Iberian Peninsula, a semiarid climate. We included some chemical properties 3 years after fire (available phosphorus (P) and soil organic carbon (Corg), among others), and biological soil indicators 3 and 5 years after fire (i.e. basal soil respiration (BSR), microbial biomass carbon (Cmic), carbon mineralization coefficient (Cmineral), metabolic quotient (qCO2) and microbial quotient (Cmic:Corg)). We analyzed the activity of three different enzymes: urease (UR), phosphatase (PHP) and ß-glucosidase (GLU). The changes in most chemical properties were ephemeral, but P and Corg showed higher values in burned areas, and the highest were found for low-moderate severity. Plant recovery was the triggering factor for the recovery of Corg and biological soil function. Burn severity and time after fire influenced Cmic and the Cmic:Corg, which were higher for moderate-high severity 3 years later, but were below the unburned values 5 years after fire. The microbial activities of GLU and UR were recovered in burned areas 5 years after fire. The PHP values lowered according to higher burn severity and time after fire. The soil ecological trends obtained by a principal component analysis revealed a relationship linking GLU, BSR and qCO2 that explained soil response to burn severity. PHP, Cmic and Cmic:Corg explained most of the variability related to time after fire. Our results provide insights into how burn severity, in Mediterranean fire-prone Aleppo pine stands, modulated the natural plant recovery linked to soil biochemical and microbiological response to fire. High burn severity limited natural vegetation recovery, and both reduced biological soil functionality. This knowledge can be implemented in post-fire planning to apply post-fire management (for mitigation and restoration) in which the "no intervention" tool should be contemplated. These findings provide information to be applied in adaptive forest management to improve the resilience of vulnerable ecosystems and to reduce burn severity in future fire events.

[Knowledge and attitude among general practitioners in Andalusia (Spain) on the identification of subjects at high risk of breast and colorectal cancer]. / Conocimientos y actitudes de los médicos de Atención Primaria de Andalucía (España) sobre la detección de personas con riesgo elevado de cáncer de mama y colorrectal.

AIMS: To assess the knowledge and attitude among general practitioners in Andalusia on the identification of subjects with elevated risk for breast cancer, colorectal cancer, and hereditary cancers, as well as to detect barriers to accessibility to the screening programs. METHODS: A descriptive, cross-sectional study was conducted based on an online survey of 24 questions. Data are shown as frequencies, and association tests were statistically used. The level of significance was set at<.05. RESULTS: Survey response rate was 32%, of which 224 were valid, and included 56% men, and a mean age±DE of 46±12 years. Established criteria for high risk breast cancer were already known by 71.4% [95% CI 65-76], being worst in those living in big cities (P<.014). Among general practitioners, 86% were allowed to order mammography in women with lumps or at moderate to high risk for breast cancer. As regards colorectal cancer, 87.9% of general practitioners knew the risk factors. Among general practitioners, 58.2% [95% CI 49-62] were allowed to order a colonoscopy if clinical suspicion was present, especially if they lived in large cities (P<.0001). CONCLUSIONS: The screening program for breast cancer is well-known by general practitioners, and the access to mammography is successful. Most of the general practitioners consider the follow-up program for persons at high risk for colorectal cancer appropriate, although half of those surveyed had some barriers to ordering colonoscopy. Knowledge on hereditary cancer is limited, and varies among areas. There is also a general lack of awareness on hereditary cancer and genetic counselling units.

Bacterial Diversity and the Geochemical Landscape in the Southwestern Gulf of Mexico.

Marine sediments are an example of one of the most complex microbial habitats. These bacterial communities play an important role in several biogeochemical cycles in the marine ecosystem. In particular, the Gulf of Mexico has a ubiquitous concentration of hydrocarbons in its sediments, representing a very interesting niche to explore. Additionally, the Mexican government has opened its oil industry, offering several exploration and production blocks in shallow and deep water in the southwestern Gulf of Mexico (swGoM), from which there are no public results of conducted studies. Given the higher risk of large-scale oil spills, the design of contingency plans and mitigation activities before oil exploitation is of growing concern. Therefore, a bacterial taxonomic baseline profile is crucial to understanding the impact of any eventual oil spill. Here, we show a genus level taxonomic profile to elucidate the bacterial baseline, pointing out richness and relative abundance, as well as relationships with 79 abiotic parameters, in an area encompassing ∼150,000 km2, including a region where the exploitation of new oil wells has already been authorized. Our results describe for the first time the bacterial landscape of the swGoM, establishing a bacterial baseline "core" of 450 genera for marine sediments in this region. We can also differentiate bacterial populations from shallow and deep zones of the swGoM based on their community structure. Shallow sediments have been chronically exposed to aromatic hydrocarbons, unlike deep zones. Our results reveal that the bacterial community structure is particularly enriched with hydrocarbon-degrading bacteria in the shallow zone, where a greater aromatic hydrocarbon concentration was determined. Differences in the bacterial communities in the swGoM were also observed through a comprehensive comparative analysis relative to various marine sediment sequencing projects, including sampled sites from the Deep Water Horizon oil spill. This study in the swGoM provides clues to the bacterial population adaptation to the ubiquitous presence of hydrocarbons and reveals organisms such as Thioprofundum bacteria with potential applications in ecological surveillance. This resource will allow us to differentiate between natural conditions and alterations generated by oil extraction activities, which, in turn, enables us to assess the environmental impact of such activities.

Compatibility of Beauveria bassiana and alternative phytosanitary products.

AIMS: To assess the compatibility of alternative phytosanitary products (APPs) with the entomopathogenic fungus Beauveria bassiana (Bals.) Vuillemin. METHODS AND RESULTS: The APPs used were Baicao, Orobor® , Topneem, Rotenat and Compostonat at concentrations recommended by the manufacturers (CR), and then half (1/2CR) and double (2CR). To evaluate the compatibility, the following parameters were analysed: germination, colony forming units (CFUs), vegetative growth and conidia production. Compatibility was assessed using rates of toxicity and biological index. The association of APPs and B. bassiana was also evaluated for pathogenicity against larvae of third instar Anagasta kuehniella Zeller (Lepidoptera: Pyralidae) (1·0 × 108 conidia per ml). The germination of conidia of B. bassiana was reduced only by the product Orobor® . The CFUs were not affected by any products. The colony diameter was reduced when in contact with the products Baicao and Orobor® . For conidia production per colony, all products reduced this parameter. None of the products affected the pathogenicity of the fungus on A. kuehniella. CONCLUSIONS: All APPs tested are compatible with B. bassiana. SIGNIFICANCE AND IMPACT OF THE STUDY: The natural products tested and used in the field are considered compatible with B. bassiana under laboratory conditions, making possible new studies and the use of these in insect control.

Action of natural phytosanitary products on Bacillus thuringiensis subsp. kurstaki S-1905.

The objective of this study was to evaluate the effects of natural phytosanitary products (NPs) on spores and crystals of Bacillus thuringiensis subsp. kurstaki S-1905 (Btk S-1905). For the spore assay, NPs and bacteria were applied in combination and individually. For the combined application, Btk S-1905 + NP mixtures were inoculated on nutrient agar (NA), and for the separate applications, the NPs were spread on NA plates, which were later inoculated with the pathogen. The number of colony-forming units (CFU) per milliliter was quantified after 18 h of incubation. For the crystal protein degradation assay, the Btk S-1905 + NP mixtures were added to the diet of Anticarsia gemmatalis (Lepidoptera: Erebidae), and mortality was evaluated at the following time points: 12, 24, 48, and 72 h. Scanning electron microscopy and agarose gel electrophoresis were carried out. Biogermex and Ecolife® reduced the CFU ml-1 in both combined and separate applications. Biogermex, Ecolife®, and Planta Clean were antagonistic to the action of bacterial toxins, and no product affected the morphology or resulted in the degradation of the crystal proteins. The remaining products evaluated did not reduce the CFU ml-1 and had additive effect when combined with the crystal toxin.

Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is an aggressive tumor type affecting cholangiocytes. CCAs frequently arise under certain cholestatic liver conditions. Intrahepatic accumulation of bile acids may facilitate cocarcinogenic effects by triggering an inflammatory response and cholangiocyte proliferation. Here, the role of bile acid receptors FXR and TGR5 in CCA progression was evaluated. METHODS: FXR and TGR5 expression was determined in human CCA tissues and cell lines. An orthotopic model of CCA was established in immunodeficient mice and tumor volume was monitored by magnetic resonance imaging under chronic administration of the specific FXR or TGR5 agonists, obeticholic acid (OCA) or INT-777 (0,03% in chow; Intercept Pharmaceuticals), respectively. Functional effects of FXR or TGR5 activation were evaluated on CCA cells in vitro. RESULTS: FXR was downregulated whereas TGR5 was upregulated in human CCA tissues compared to surrounding normal liver tissue. FXR expression correlated with tumor differentiation and TGR5 correlated with perineural invasion. TGR5 expression was higher in perihilar than in intrahepatic CCAs. In vitro, FXR was downregulated and TGR5 was upregulated in human CCA cells compared to normal human cholangiocytes. OCA halted CCA growth in vivo, whereas INT-777 showed no effect. In vitro, OCA inhibited CCA cell proliferation and migration which was associated with decreased mitochondrial energy metabolism. INT-777, by contrast, stimulated CCA cell proliferation and migration, linked to increased mitochondrial energy metabolism. CONCLUSION: Activation of FXR inhibits, whereas TGR5 activation may promote, CCA progression by regulating proliferation, migration and mitochondrial energy metabolism. Modulation of FXR or TGR5 activities may represent potential therapeutic strategies for CCA.

Potential Side Effects of the Entomopathogenic Fungus Metarhizium anisopliae on the Egg Parasitoid Trichogramma pretiosum (Hymenoptera: Trichogrammatidae) Under Controlled Conditions.

The purpose was to evaluate the side effects of strains Metarhizium anisopliae (Metsch.) Sorokin sensu lato Unioeste 43 and M. anisopliae sensu stricto ESALQ 1641 on Trichogramma pretiosum Riley (Hymenoptera: Trichogrammatidae) under controlled conditions. A free-choice test for parasitism was performed, with the confinement of T. pretiosum females mated with cards (1 × 5 cm) containing age-standardized Anagasta kuehniella Zeller eggs, either sprayed with a fungal strain (109 conidia/ml) or 0.01% v/v Tween 80 (control). For the no-choice tests, T. pretiosum females mated were confined with cards sprayed with fungal strains before or after parasitism, and cards with fungal applications at different times. The number of parasitized eggs, percentage of emergence, longevity, egg-to-adult period, sex ratio, total and confirmed mortality by the fungus, and longevity of females that parasitized previously sprayed eggs, were assessed. Histological analysis of immature phases was also performed. The fungus was repellent to T. pretiosum in the free-choice test, while in the no-choice test, fungal applications before and after parasitism did not affect the number of eggs parasitized by T. pretiosum or the sex ratio of emerging adults. However, both strains affected adult emergence rates, the egg-to-adult period, and longevity. Overall, both M. anisopliae strains had minor effects on these biological parameters of T. pretiosum under controlled conditions. Hyphae were not detected in histological observations of immature stages of the parasitoid.

Influence of Mitochondrial Genetics on the Mitochondrial Toxicity of Linezolid in Blood Cells and Skin Nerve Fibers.

The antibiotic linezolid is a ribosomal inhibitor with excellent efficacy. Although the administration period has been reduced to 28 days, side effects, usually of hematologic or neuropathic origin, are still reported due to secondary inhibition of mitochondrial protein synthesis. Susceptibility to linezolid toxicity remains unknown. Therefore, the objective of this study was to gain an understanding of clinical heterogeneity in response to identical linezolid exposures through exhaustive examination of the molecular basis of tissue-dependent mitotoxicity, consequent cell dysfunction, and the association of mitochondrial genetics with adverse effects of linezolid administered for the recommended period. Peripheral blood mononuclear cells (PBMC) and skin nerve fibers from 19 and 6 patients, respectively, were evaluated before and after a 28-day linezolid treatment in order to assess toxic effects on mitochondria and cells. Mitochondrial DNA haplotypes and single nucleotide polymorphisms (SNPs) in ribosomal sequences where linezolid binds to mitochondrial ribosomes were also analyzed to investigate their genetic contributions. We found that linezolid reduced mitochondrial protein levels, complex IV activity, and mitochondrial mass in PBMC and was associated with a trend toward an increase in the rate of apoptosis. In skin tissue, mitochondrial mass increased within nerve fibers, accompanied by subclinical axonal swelling. Mitochondrial haplogroup U, mutations in 12S rRNA, and the m.2706A→G, m.3197T→C, and m.3010G→A polymorphisms in 16S rRNA showed a trend toward an association with increased mitochondrial and clinical adverse effects. We conclude that even when linezolid is administered for a shorter time than formerly, adverse effects are reported by 63% of patients. Linezolid exerts tissue-dependent mitotoxicity that is responsible for downstream cellular consequences (blood cell death and nerve fiber swelling), leading to adverse hematologic and peripheral nervous side effects. Multicentric studies should confirm genetic susceptibility in larger cohorts.