Effects of intubation timing in patients with COVID-19 throughout the four waves of the pandemic: a matched analysis.

BACKGROUND: The primary aim of our study was to investigate the association between intubation timing and hospital mortality in critically ill patients with coronavirus disease 2019 (COVID-19)-associated respiratory failure. We also analysed both the impact of such timing throughout the first four pandemic waves and the influence of prior noninvasive respiratory support on outcomes. METHODS: This is a secondary analysis of a multicentre, observational and prospective cohort study that included all consecutive patients undergoing invasive mechanical ventilation due to COVID-19 from across 58 Spanish intensive care units (ICUs) participating in the CIBERESUCICOVID project. The study period was between 29 February 2020 and 31 August 2021. Early intubation was defined as that occurring within the first 24 h of ICU admission. Propensity score matching was used to achieve a balance across baseline variables between the early intubation cohort and those patients who were intubated after the first 24 h of ICU admission. Differences in outcomes between early and delayed intubation were also assessed. We performed sensitivity analyses to consider a different time-point (48 h from ICU admission) for early and delayed intubation. RESULTS: Of the 2725 patients who received invasive mechanical ventilation, a total of 614 matched patients were included in the analysis (307 for each group). In the unmatched population, there were no differences in mortality between the early and delayed groups. After propensity score matching, patients with delayed intubation presented higher hospital mortality (27.3% versus 37.1%; p=0.01), ICU mortality (25.7% versus 36.1%; p=0.007) and 90-day mortality (30.9% versus 40.2%; p=0.02) compared with the early intubation group. Very similar findings were observed when we used a 48-h time-point for early or delayed intubation. The use of early intubation decreased after the first wave of the pandemic (72%, 49%, 46% and 45% in the first, second, third and fourth waves, respectively; first versus second, third and fourth waves p<0.001). In both the main and sensitivity analyses, hospital mortality was lower in patients receiving high-flow nasal cannula (HFNC) (n=294) who were intubated earlier. The subgroup of patients undergoing noninvasive ventilation (n=214) before intubation showed higher mortality when delayed intubation was set as that occurring after 48 h from ICU admission, but not when after 24 h. CONCLUSIONS: In patients with COVID-19 requiring invasive mechanical ventilation, delayed intubation was associated with a higher risk of hospital mortality. The use of early intubation significantly decreased throughout the course of the pandemic. Benefits of such an approach occurred more notably in patients who had received HFNC.

Screening sourdough samples for gliadin-degrading activity revealed Lactobacillus casei strains able to individually metabolize the coeliac-disease-related 33-mer peptide.

A selective culture medium containing acid-hydrolyzed gliadins as the sole nitrogen source was used in the search for sourdough-indigenous lactic acid bacteria (LAB) with gliadin-metabolizing activity. Twenty gliadin-degrading LAB strains were isolated from 10 sourdoughs made in different ways and from different geographical regions. Fifteen of the 20 isolated strains were identified as Lactobacillus casei, a species usually reported as subdominant in sourdough populations. The other 5 gliadin-degrading strains belonged to the more commonly encountered sourdough species Leuconostoc mesenteroides and Lactobacillus plantarum. All these strains were shown to be safe in terms of their resistance to antimicrobial agents. When individually incubated with the α2-gliadin-derived immunotoxic 33-mer peptide (97.5 ppm), half of the L. casei strains metabolized at least 50% of it within 24 h. One strain metabolized 82% of the 33-mer peptide within 8 h and made it fully disappear within 12 h. These results reveal for the first time the presence in sourdough of proteolytic L. casei strains with the capacity to individually metabolize the coeliac-disease-related 33-mer peptide.

Tyramine biosynthesis is transcriptionally induced at low pH and improves the fitness of Enterococcus faecalis in acidic environments.

Enterococcus faecalis is a commensal bacterium of the human gut that requires the ability to pass through the stomach and therefore cope with low pH. E. faecalis has also been identified as one of the major tyramine producers in fermented food products, where they also encounter acidic environments. In the present work, we have constructed a non-tyramine-producing mutant to study the role of the tyramine biosynthetic pathway, which converts tyrosine to tyramine via amino acid decarboxylation. Wild-type strain showed higher survival in a system that mimics gastrointestinal stress, indicating that the tyramine biosynthetic pathway has a role in acid resistance. Transcriptional analyses of the E. faecalis V583 tyrosine decarboxylase cluster showed that an acidic pH, together with substrate availability, induces its expression and therefore the production of tyramine. The protective role of the tyramine pathway under acidic conditions appears to be exerted through the maintenance of the cytosolic pH. Tyramine production should be considered important in the adaptability of E. faecalis to acidic environments, such as fermented dairy foods, and to survive passage through the human gastrointestinal tract.

Putrescine production via the agmatine deiminase pathway increases the growth of Lactococcus lactis and causes the alkalinization of the culture medium.

Lactococcus lactis is the most important starter culture organism used in the dairy industry. Although L. lactis species have been awarded Qualified Presumption of Safety status by the European Food Safety Authority, and Generally Regarded as Safe status by the US Food and Drug Administration, some strains can produce the biogenic amine putrescine. One such strain is L. lactis subsp. cremoris CECT 8666 (formerly L. lactis subsp. cremoris GE2-14), which was isolated from Genestoso cheese. This strain catabolizes agmatine to putrescine via the agmatine deiminase (AGDI) pathway, which involves the production of ATP and two ammonium ions. The present work shows that the availability of agmatine and its metabolization to putrescine allows for greater bacterial growth (in a biphasic pattern) and causes the alkalinization of the culture medium in a dose-dependent manner. The construction of a mutant lacking the AGDI cluster (L. lactis CECT 8666 Δagdi) confirmed the latter's direct role in putrescine production, growth, and medium alkalinization. Alkalinization did not affect the putrescine production pattern and was not essential for increased bacterial growth.

IS256 abolishes gelatinase activity and biofilm formation in a mutant of the nosocomial pathogen Enterococcus faecalis V583.

Enterococcus faecalis is one of the most controversial species of lactic acid bacteria. Some strains are used as probiotics, while others are associated with severe and life-threatening nosocomial infections. Their pathogenicity depends on the acquisition of multidrug resistance and virulence factors. Gelatinase, which is required in the first steps of biofilm formation, is an important virulence determinant involved in E. faecalis pathogenesis, including endocarditis and peritonitis. The gene that codes for gelatinase (gelE) is controlled by the Fsr quorum-sensing system, whose encoding genes (fsrA, fsrB, fsrC, and fsrD) are located immediately upstream of gelE. The integration of a DNA fragment into the fsr locus of a derived mutant of E. faecalis V583 suppressed the gelatinase activity and prevented biofilm formation. Sequence analysis indicated the presence of IS256 integrated into the fsrC gene at nucleotide position 321. Interestingly, IS256 is also associated with biofilm formation in Staphylococcus epidermidis and Staphylococcus aureus. This is the first description of an insertion sequence that prevents biofilm formation in E. faecalis.

Lactose-mediated carbon catabolite repression of putrescine production in dairy Lactococcus lactis is strain dependent.

Lactococcus lactis is the lactic acid bacterial (LAB) species most widely used as a primary starter in the dairy industry. However, several strains of L. lactis produce the biogenic amine putrescine via the agmatine deiminase (AGDI) pathway. We previously reported the putrescine biosynthesis pathway in L. lactis subsp. cremoris GE2-14 to be regulated by carbon catabolic repression (CCR) via glucose but not lactose (Linares et al., 2013). The present study shows that both these sugars repress putrescine biosynthesis in L. lactis subsp. lactis T3/33, a strain isolated from a Spanish artisanal cheese. Furthermore, we demonstrated that both glucose and lactose repressed the transcriptional activity of the aguBDAC catabolic genes of the AGDI route. Finally, a screening performed in putrescine-producing dairy L. lactis strains determined that putrescine biosynthesis was repressed by lactose in all the L. lactis subsp. lactis strains tested, but in only one L. lactis subsp. cremoris strain. Given the obvious importance of the lactose-repression in cheese putrescine accumulation, it is advisable to consider the diversity of L. lactis in this sense and characterize consequently the starter cultures to select the safest strains.

Generation of food-grade recombinant Lactobacillus casei delivering Myxococcus xanthus prolyl endopeptidase.

Prolyl endopeptidases (PEP) (EC 3.4.21.26), a family of serine proteases with the ability to hydrolyze the peptide bond on the carboxyl side of an internal proline residue, are able to degrade immunotoxic peptides responsible for celiac disease (CD), such as a 33-residue gluten peptide (33-mer). Oral administration of PEP has been suggested as a potential therapeutic approach for CD, although delivery of the enzyme to the small intestine requires intrinsic gastric stability or advanced formulation technologies. We have engineered two food-grade Lactobacillus casei strains to deliver PEP in an in vitro model of small intestine environment. One strain secretes PEP into the extracellular medium, whereas the other retains PEP in the intracellular environment. The strain that secretes PEP into the extracellular medium is the most effective to degrade the 33-mer and is resistant to simulated gastrointestinal stress. Our results suggest that in the future, after more studies and clinical trials, an engineered food-grade Lactobacillus strain may be useful as a vector for in situ production of PEP in the upper small intestine of CD patients.

The tyrosyl-tRNA synthetase like gene located in the tyramine biosynthesis cluster of Enterococcus durans is transcriptionally regulated by tyrosine concentration and extracellular pH.

BACKGROUND: The tyramine producer Enterococcus durans IPLA655 contains all the necessary genes for tyramine biosynthesis, grouped in the TDC cluster. This cluster includes tyrS, an aminoacyl-tRNA synthetase like gene. RESULTS: This work shows that tyrS was maximally transcribed in absence of tyrosine at acidic pH, showing a greater than 10-fold induction in mRNA levels over levels occurring in presence of tyrosine. Mapping of the tyrS transcriptional start site revealed an unusually long untranslated leader region of 322 bp, which displays the typical features of the T box transcriptional attenuation mechanism. The tyrosine concentration regulation of tyrS was found to be mediated by a transcription antitermination system, whereas the specific induction at acidic pH was regulated at transcription initiation level. CONCLUSIONS: The expression of the tyrS gene present in the TDC cluster of E. durans is transcriptionally regulated by tyrosine concentration and extracelular pH. The regulation is mediated by both an antitermination system and the promoter itself.

Sequencing and transcriptional analysis of the biosynthesis gene cluster of putrescine-producing Lactococcus lactis.

Lactococcus lactis is a prokaryotic microorganism with great importance as a culture starter and has become the model species among the lactic acid bacteria. The long and safe history of use of L. lactis in dairy fermentations has resulted in the classification of this species as GRAS (General Regarded As Safe) or QPS (Qualified Presumption of Safety). However, our group has identified several strains of L. lactis subsp. lactis and L. lactis subsp. cremoris that are able to produce putrescine from agmatine via the agmatine deiminase (AGDI) pathway. Putrescine is a biogenic amine that confers undesirable flavor characteristics and may even have toxic effects. The AGDI cluster of L. lactis is composed of a putative regulatory gene, aguR, followed by the genes (aguB, aguD, aguA, and aguC) encoding the catabolic enzymes. These genes are transcribed as an operon that is induced in the presence of agmatine. In some strains, an insertion (IS) element interrupts the transcription of the cluster, which results in a non-putrescine-producing phenotype. Based on this knowledge, a PCR-based test was developed in order to differentiate nonproducing L. lactis strains from those with a functional AGDI cluster. The analysis of the AGDI cluster and their flanking regions revealed that the capacity to produce putrescine via the AGDI pathway could be a specific characteristic that was lost during the adaptation to the milk environment by a process of reductive genome evolution.

Conjugative DNA Transfer From E. coli to Transformation-Resistant Lactobacilli.

Lactic acid bacteria (LAB) belonging to the genus classically known as Lactobacillus, recently split into 25 different genera, include many relevant species for the food industry. The well-known properties of lactobacilli as probiotics make them an attractive model also for vaccines and therapeutic proteins delivery in humans. However, scarce tools are available to accomplish genetic modification of these organisms, and most are only suitable for laboratory strains. Here, we test bacterial conjugation as a new tool to introduce genetic modifications into many biotechnologically relevant laboratory and wild type lactobacilli. Using mobilizable shuttle plasmids from a donor Escherichia coli carrying either RP4 or R388 conjugative systems, we were able to get transconjugants to all tested Lactocaseibacillus casei strains, including many natural isolates, and to several other genera, including Lentilactobacillus parabuchneri, for which no transformation protocol has been reported. Transconjugants were confirmed by the presence of the oriT and 16S rRNA gene sequencing. Serendipitously, we also found transconjugants into researcher-contaminant Staphylococcus epidermidis. Conjugative DNA transfer from E. coli to S. aureus was previously described, but at very low frequencies. We have purified this recipient strain and used it in standard conjugation assays, confirming that both R388 and RP4 conjugative systems mediate mobilization of plasmids into S. epidermidis. This protocol could be assayed to introduce DNA into other Gram-positive microorganisms which are resistant to transformation.

[Cytoprotective effect of low-dose tacrolimus on islets of Langerhans in cultures subjected to stimulation by acute rejection cytokines]. / Efecto citoprotector del tacrolimus a dosis bajas sobre islotes de Langeerhans en cultivo sometidos a estímulos por citocinas del rechazo agudo.

INTRODUCTION: The improvement in pancreatic islet transplantation results is due to immunosuppression protocols that include, among others, low-dose tacrolimus. Both anti-inflammatory and anti-oxidant effects of tacrolimus could be useful in preventing primary rejection. AIM: To evaluate in vitro islet low-dose tacrolimus response after pro-inflammatory stimulation. MATERIAL AND METHODS: Isolated rat islets were cultured in RPMI medium in the presence of IL-1 (50 UI/mL) plus IF-gamma (1000 UI/mL) and tacrolimus (5 ng/mL). The 24 h production of lipoperoxide (LPO) and nitric oxide (NO) were measured as oxidative stress markers. Determination of apoptosis markers (nucleosome content and Bcl-2) was also performed. RESULTS: Oxidative stress (LPO 10.1+/-1.16 pmol/islet x 24; NO 19.1+/-3.28 pmol/isletx24 h) and apoptosis (nucleosome 0.24+/-0.04 UI/islet; Bcl-2 0.69+/-0.212 UI/islet) markers showed a very significant increase after cytokine stimulation (p<0.01). Both effects improved by adding tacrolimus to the medium. Protective effect was complete when lipoperoxide (1.58 pmol/isletx24 h), nitric oxide (9.81 pmol/isletx24 h) and Bcl-2 (1.37+/-0.23 UI/islet) were determined. CONCLUSION: In vitro cytoprotective effect of low-dose tacrolimus on isolated rat islets decreases both oxidative stress and apoptosis markers after stimulation of pro-inflammatory mediators.

Histamine production in Lactobacillus vaginalis improves cell survival at low pH by counteracting the acidification of the cytosol.

Histamine, one of the most toxic and commonly encountered biogenic amines (BA) in food, is produced by the microbial decarboxylation of histidine. It may accumulate at high concentrations in fish and fermented food. Cheese has some of the highest histamine concentrations, the result of the histidine-decarboxylase activity of certain lactic acid bacteria (LAB). The present work describes the nucleotide sequence and transcriptional organization of the gene cluster responsible for histamine biosynthesis (the HDC cluster) in Lactobacillus vaginalis IPLA 11064 isolated from cheese. The influence of histidine availability and pH on histamine production and the expression of the HDC cluster genes is also examined. As expected, the results suggest that the production of histamine under acidic conditions improves cell survival by maintaining the cytosol at an appropriate pH. However, the transcriptional regulation of the HDC cluster is quite different from that described in other dairy histamine-producing LAB, probably due to the lack of a termination-antitermination system in the histidyl-tRNA synthetase gene (hisS).

Enterococcus faecalis Bacteriophage 156 Is an Effective Biotechnological Tool for Reducing the Presence of Tyramine and Putrescine in an Experimental Cheese Model.

Biogenic amines (BA) - nitrogenous compounds of low molecular weight - are the result of metabolism of certain amino acids. They are biologically present in all living organisms and play essential physiological roles. However, their accumulation in foodstuffs due to the metabolic activity of certain microorganisms represents a toxicological risk. Containing such microorganisms, and with an abundance of precursor substrate amino acids, fermented foods in general, and cheeses in particular, provide an ideal matrix for the accumulation of these toxic compounds. Unfortunately, the main microorganisms responsible for BA accumulation are members of the lactic acid bacteria (LAB) group, which are also essential for the development of the organoleptic characteristics of the final product. The methods used to reduce the BA content of cheese, such as milk pasteurization, commonly fail to do so, and affect desirable non-BA-producing LAB as well. Bacteriophages have been proposed as biotechnological tools for diminishing the presence of undesirable microorganisms in dairy products. Given their specificity, they could be used to target the population of BA-producing bacteria. In this work, we aimed to explore the use of Enterococcus faecalis infecting phages as a tool to reduce the content of BA in dairy products. For this, we proceeded to the isolation and characterization of E. faecalis bacteriophage 156, a member of the family Myoviridae. Its genome was sequenced and compared with that of E. faecalis family Myoviridae phages available in public databases. Its capacity to decrease the accumulation of the BA tyramine and putrescine in an experimental laboratory-scale cheese model was proven.

Multiplex fast real-time PCR for quantitative detection and identification of cos- and pac-type Streptococcus thermophilus bacteriophages.

The fermentation of milk by Streptococcus thermophilus is a widespread industrial process that is susceptible to bacteriophage attack. In this work, a preventive fast real-time PCR method for the detection, quantification, and identification of types of S. thermophilus phages in 30 min is described.

Fast real-time polymerase chain reaction for quantitative detection of Lactobacillus delbrueckii bacteriophages in milk.

One of the main microbiological problems of the dairy industry is the susceptibility of starter bacteria to virus infections. Lactobacillus delbrueckii, a component of thermophilic starter cultures used in the manufacture of several fermented dairy products, including yogurt, is also sensitive to bacteriophage attacks. To avoid the problems associated with these viruses, quick and sensitive detection methods are necessary. In the present study, a fast real-time quantitative polymerase chain reaction assay for the direct detection and quantification of L. delbrueckii phages in milk was developed. A set of primers and a TaqMan MGB probe was designed, based on the lysin gene sequence of different L. delbrueckii phages. The results show the proposed method to be a rapid (total processing time 30 min), specific and highly sensitive technique for detecting L. delbrueckii phages in milk.

Lactobacillus rossiae strain isolated from sourdough produces putrescine from arginine.

This work reports a Lactobacillus rossiae strain (L. rossiae D87) isolated from sourdough that synthesizes putrescine - a biogenic amine that raises food safety and spoilage concerns - from arginine via the ornithine decarboxylase (ODC) pathway. The odc and potE genes were identified and sequenced. These genes respectively encode ornithine decarboxylase (Odc), which participates in the decarboxylation of ornithine to putrescine, and the ornithine/putrescine exchanger (PotE), which exchanges ornithine for putrescine. Transcriptional analysis showed that odc and potE form an operon that is regulated transcriptionally by ornithine in a dose-dependent manner. To explore the possible role of the ODC pathway as an acid stress resistance mechanism for this bacterium, the effect of acidic pHs on its transcriptional regulation and on putrescine biosynthesis was analysed. Acidic pHs induced the transcription of the odc-potE genes and the production of putrescine over that seen at neutral pH. Further, putrescine production via the ODC system improved the survival of L. rossiae D87 by counteracting the acidification of the cytoplasm when the cells were subjected to acidic conditions. These results suggest the ODC pathway of L. rossiae D87 provides a biochemical defence mechanism against acidic environments.

Safety incidents in airway and mechanical ventilation in Spanish ICUs: The IVeMVA study.

PURPOSE: To assess incidence, related factors and characteristics of safety incidents associated with the whole process of airway management and mechanical ventilation (MV) in Spanish ICUs. MATERIALS AND METHODS: Observational, prospective, 7 days cross-sectional multicenter study. Airway and MV related incidents were reported using structured questionnaire. Type, characteristics, severity, avoidability and contributing factors of the incidents were assessed. RESULTS: Participant ICUs: 104. Inclusion of 1267 patients; 745 (59%) suffered one or more incidents. Incidents reported: 2492 (59% non-harm-events, 41% adverse events). Individual risk of suffering at least one incident: 66.6%. Incidence ratio (median) of incidents: 2 per 100 patient-hours. 73.7% of incidents were related to MV process, 9.5% to tracheostomy, 6.2% to non-invasive MV, 5.4% to weaning/extubation, 4.4% to intubation and 0.8% to prone position. Temporary damage was produced in 12% incidents, while 0.8% was related to permanent injuries, risk to the patient's life or contributed to death. Incidents were considered avoidable in 73.5% of cases. 98% of all incidents had 1 or more contributing factors. CONCLUSIONS: MV is a risk process in critical patients. Although most incidents did not harm patients, some caused damage and a few were related to the patient's death or permanent damage. Preventability is high.

Impact of random safety analyses on structure, process and outcome indicators: multicentre study.

BACKGROUND: To assess the impact of a real-time random safety tool on structure, process and outcome indicators. METHODS: Prospective study conducted over a period of 12 months in two adult patient intensive care units. Safety rounds were conducted three days a week ascertaining 37 safety measures (grouped into 10 blocks). In each round, 50% of the patients and 50% of the measures were randomized. The impact of this safety tool was analysed on indicators of structure (safety culture, healthcare protocols), process (improvement proportion related to tool application, IPR) and outcome (mortality, average stay, rate of catheter-related bacteraemias and rate of ventilator-associated pneumonia, VAP). RESULTS: A total of 1214 patient-days were analysed. Structure indicators: the use of the safety tool was associated with an increase in the safety climate and the creation/modification of healthcare protocols (sedation/analgesia and weaning). Process indicators: Twelve of the 37 measures had an IPR > 10%; six showed a progressive decrease in the IPR over the study period. Nursing workloads and patient severity on the day of analysis were independently associated with a higher IPR in half of the blocks of variables. Outcome indicators: A significant decrease in the rate of VAP was observed. CONCLUSIONS: The real-time random safety tool improved the care process and adherence to clinical practice guidelines and was associated with an improvement in structure, process and outcome indicators.

Impact of one year of pandemic on Spanish Intensive Care Units / Impacto de un año de pandemia en las Unidades de Cuidados Intensivos de España

Objective. To measure the impact of the pandemic inSpanish ICUs.Material and methods. On-line survey, conducted inApril 2021, among SEMICYUC members. Participants wereasked about number of patients admitted, increase in thenumber of beds and staff, structures created in the hospitaland self-assessment of the work performed.Results. We received 246 answers from 157 hospitals.67.7% of the ICUs were expanded during the pandemic, overall increase in beds of 58.6%. The ICU medical staff increasedby 6.1% and there has been a nursing shortage in 93.7% ofunits. Patients exceeded 200% the pre-pandemic ICU capacity.In 88% of the hospitals the collaboration of other specialistswas necessary. The predominant collaboration model consisted of the intensive care medicine specialist being responsiblefor triage and coordinating patient management. Despite that53.2% centres offered training for critical care, a deteriorationin the quality of care was perceived. 84.2% hospitals drew upa Contingency Plan and in 77.8% of the hospitals a multidisciplinary committee was set up to agree on decision-making.Self-evaluation of the work performed was outstandingand 91.9% felt proud of what they had achieved, however, upto 15% considered leaving their job.Conclusions. The Spanish ICUs assumed an unprecedented increase in the number of patients. They achieved it withouthardly increasing their staff and, while intensive care medicinetraining was carried out for other specialists who collaborated.The degree of job satisfaction was consistent with pre-pandemic levels. (AU)

Objetivo. Medir el impacto de la pandemia COVID-19 en las UCI españolas. Material y métodos. Cuestionario online, realizado en abril 2021 entre socios de SEMICYUC. Se interrogó acerca delnúmero de pacientes ingresados, incremento en número decamas y personal, estructuras creadas en el hospital y autoevaluación del trabajo realizado.Resultados. Recibimos 246 respuestas de 157 hospitales. El 67.7% de las UCI se expandieron durante la pandemia,con un incremento de camas del 58.6%. El personal médicode las UCI aumentó un 6.1% y hubo escasez de enfermería enel 93.7% de las unidades. Los pacientes excedieron un 200%la capacidad pre-pandemia y en el 88% de los hospitales fuenecesaria la colaboración de otros especialistas, siendo elmodelo predominante aquel en que el especialista en medicina intensiva era responsable del triaje y coordinaba el tratamiento del paciente. A pesar de que en el 53.2% de los centros se ofreció formación en medicina intensiva se detectó undeterioro de la calidad asistencial. El 84.2% de los hospitaleselaboraron un plan de contingencia y el 77.8% conformaronun comité multidisciplinar para consensuar decisiones. Laevaluación del trabajo fue sobresaliente y el 91.9% se sienteorgulloso del resultado, pero hasta el 15% consideró abandonar la especialidad.Conclusiones. Las UCI españolas asumieron un incremento de pacientes sin precedentes, sin apenas aumento delpersonal y mientras formaban a otros especialistas que colaboraron. El grado de satisfacción con el trabajo realizado fuesimilar al pre-pandemia. (AU)

The dietary biogenic amines tyramine and histamine show synergistic toxicity towards intestinal cells in culture.

Tyramine and histamine are the biogenic amines (BA) most commonly found at high concentrations in food; they may even appear together at toxic concentrations. The present work examines, via real-time cell analysis, whether histamine and tyramine show synergistic toxicity towards intestinal cell cultures. Employing a constant equipotency ratio, their interaction was examined via the combination index (CI) method of Chou & Talalay. Co-treatment with tyramine and histamine was associated with a stronger cytotoxic effect than was treatment with either BA or on its own. Indeed, a synergistic interaction (CI<1) was observed in the range of concentrations found in foods. The results also show that histamine, at concentrations below the legal limit, increases the cytotoxicity of tyramine at concentrations frequently reached in some foods. The synergistic cytotoxicity of tyramine and histamine should be taken into account when establishing legal limits designed to ensure consumer safety.