Direct oral challenge for immediate and non-immediate beta-lactam allergy in children: A real-world multicenter study.

BACKGROUND: Allergy to beta-lactam antibiotics (BLA) is frequently suspected in children, but a drug provocation test (DPT) rules it out in over 90% of cases. Direct oral DPT (DODPT), without skin or other previous tests, is increasingly been used to delabel non-immediate BLA reactions. This real-world study aimed to assess the safety and effectiveness of DODPT in children with immediate and non-immediate reactions to BLAs. METHODS: Ambispective registry study in children (<15 years), attended between 2016 and 2023 for suspected BLA allergy in 15 hospitals in Spain that routinely perform DODPT. RESULTS: The study included 2133 patients with generally mild reactions (anaphylaxis 0.7%). Drug provocation test with the implicated BLA was performed in 2014 patients (94.4%): 1854 underwent DODPT (86.9%, including 172 patients with immediate reactions). One hundred forty-five (7.2%) had symptoms associated with DPT, although only four reactions were severe: two episodes of anaphylaxis and two of drug-induced enterocolitis syndrome, which resolved rapidly with treatment. Of the 141 patients with mild reactions in the first DPT, a second DPT was considered in 87 and performed in 57, with 52 tolerating it without symptoms. Finally, BLA allergy was ruled out in 90.9% of the sample, confirmed in 3.4%, and remained unverified, usually due to loss to follow-up, in 5.8%. CONCLUSIONS: Direct oral DPT is a safe, effective procedure even in immediate mild reactions to BLA. Many reactions observed in DPT are doubtful and require confirmation. Severe reactions are exceptional and amenable to treatment. Direct oral DPT can be considered for BLA allergy delabeling in pediatric primary care.

Exposure to secondhand aerosol from electronic cigarettes at homes: A real-life study in four European countries.

Electronic cigarette (e-cigarette) use emits potentially hazardous compounds and deteriorates indoor air quality. Home is a place where e-cigarettes may frequently be used amid its increasing prohibition in public places. This study assessed the real-life scenario of bystanders' exposure to secondhand e-cigarette aerosol (SHA) at home. A one-week observational study was conducted within the TackSHS project in four countries (Greece, Italy, Spain, and the United Kingdom) in 2019 including: 1) homes of e-cigarette users living together with a non-user/non-smoker; and 2) control homes with no smokers nor e-cigarette users. Indoor airborne nicotine, PM2.5, and PM1.0 concentrations were measured as environmental markers of SHA. Biomarkers, including nicotine and its metabolites, tobacco-specific nitrosamines, propanediol, glycerol, and metals were measured in participants' saliva and urine samples. E-cigarette use characteristics, such as e-cigarette refill liquid's nicotine concentration, e-cigarette type, place of e-cigarette use at home, and frequency of ventilation, were also collected. A total of 29 e-cigarette users' homes and 21 control homes were included. The results showed that the seven-day concentrations of airborne nicotine were quantifiable in 21 (72.4 %) out of 29 e-cigarette users' homes; overall, they were quite low (geometric mean: 0.01 µg/m3; 95 % CI: 0.01-0.02 µg/m3) and were all below the limit of quantification in control homes. Seven-day concentrations of PM2.5 and PM1.0 in e-cigarette and control homes were similar. Airborne nicotine and PM concentrations did not differ according to different e-cigarette use characteristics. Non-users residing with e-cigarette users had low but significantly higher levels of cotinine, 3'-OH-cotinine and 1,2-propanediol in saliva, and cobalt in urine than non-users living in control homes. In conclusion, e-cigarette use at home created bystanders' exposure to SHA regardless of the e-cigarette use characteristics. Further studies are warranted to assess the implications of SHA exposure for smoke-free policy.

Environmental and individual exposure to secondhand aerosol of electronic cigarettes in confined spaces: Results from the TackSHS Project†.

Secondhand electronic cigarette (e-cigarette) aerosol (SHA) might impair indoor air quality and expose bystanders. This study aims to investigate exposure to SHA in controlled conditions of enclosed settings simulating real-world scenario. An experiment was performed in a car and in a room, in which SHA was generated during a 30-minute ad libitum use of an e-cigarette. The experiment was replicated on five consecutive days in each setting. We measured PM2.5 , airborne nicotine concentrations, and biomarkers of exposure to SHA, such as nicotine metabolites, tobacco-specific nitrosamines, propylene glycol, and glycerol in bystanders' saliva samples before, during, and after the exposure period. Self-reported health symptoms related to exposure to SHA were also recorded. The results showed that the highest median PM2.5 concentration was recorded during the exposure period, being 21 µg/m3 in the room setting and 16 µg/m3 in the car setting-about twofold increase compared to the baseline. Most concentrations of the airborne nicotine and all biomarkers were below the limit of quantification in both settings. Bystanders in both settings experienced some short-term irritation symptoms, expressed as dry throat, nose, eyes, and phlegm. In conclusion, short-term use of an e-cigarette in confined spaces increased indoor PM2.5 level and caused some irritation symptoms in bystanders.

Exposure to second-hand tobacco smoke in waterpipe cafés in Barcelona, Spain: An assessment of airborne nicotine and PM2.5.

BACKGROUND: Waterpipe tobacco smoking has grown in popularity worldwide, with the prevalence of use increasing in Spain from 6.2% to 10.8% in the last decade, despite the smoking ban enacted in 2010 for all hospitality premises. OBJECTIVE: To assess exposure to second-hand smoke from waterpipes based on the concentrations of airborne nicotine and particulate matter ≤2.5 µm in diameter (PM2.5) in a sample of waterpipe cafés in the city of Barcelona (Spain). METHODS: This cross-sectional study included a sample of 20 waterpipe cafés. Airborne nicotine and PM2.5 were sampled for 30 min in each venue using a nicotine sampling device connected by a tube to a pump and a TSI SidePak Personal Aerosol Monitor. Five outdoor control locations were also measured. We computed medians, interquartile ranges (IQRs), and maximum values and compared them according to venues' and sampling characteristics using the Kruskall-Wallis and U-Mann Whitney tests. Nicotine and PM2.5 were correlated by calculating the Spearman-rank correlation coefficient. RESULTS: The median concentration of nicotine and PM2.5 were 1.15 and 230.50 µg/m3 in waterpipe cafés and 0.03 and 10.00 µg/m3 in control locations (p<0.05 in both cases). The Spearman correlation coefficient between both markers was 0.61 (95% confidence interval: 0.18-0.84). No differences were found in nicotine or PM2.5 concentration according to the venues' and sampling characteristics studied, with the exception of area. After stratifying for area, venues >100 m2, located in a tourist area, with >15 lit waterpipes, >8 waterpipes/100 m2, and a ratio of 2 users per waterpipe or less had significantly higher nicotine concentration. DISCUSSION: Despite the current smoking ban, which includes hospitality venues, we found nicotine and PM2.5 levels in Barcelona waterpipe cafés that exceeded the threshold recommended by the World Health Organization. This exposure poses serious risks to the health of both workers and customers and constitutes a non-compliance of the legislation.

Poisoning after Ingestion of Spartium junceum Seeds: Dose-Dependent Effects in Three Boys.

BACKGROUND: Spanish broom (Spartium junceum L.) is an ornamental, medicinal, and potentially poisonous plant. CASE REPORT: Three children, aged 5-6 years, were accidentally poisoned from ingesting a variable number of seeds of Spanish broom. This plant contains several quinolizidine alkaloids as cytisine, which act as an agonist of nicotinic acetylcholine receptors. The potential danger varies, depending on the dose. After having ingested one to two seeds, one of the boys was asymptomatic. A second boy ingested four to five seeds and presented some digestive problems with favorable clinical evolution. A third boy ingested seven to eight seeds, and presented with digestive and neurologic symptoms, as well as minor metabolic acidosis. In this case there was vomiting with remains of the seeds. He responded well to a gastric lavage and activated charcoal. He was discharged 24 h post ingestion. The intake within one to eight seeds was accompanied by moderate symptoms, with good response to treatment. Children poisoned by plants with nicotine-like symptomatology usually fully recover, but some fatal cases have been reported. Prevention is always a key aspect to consider so as to reduce the risk of poisoning. There is a lack of legislative measures, based on lists provided by experts, to regulate real or potentially poisonous plants in children's areas. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case serves as an example of accidental plant poisoning. For emergency physicians, it is usually complicated to identify the specific plant involved, so initial treatment often starts with basic measures (airway, breathing, and circulation).

Nanoconjugates as intracorporeal neutralizers of bacterial endotoxins.

Sepsis is a leading cause of mortality that is most often provoked by endotoxins (i.e. lipopolysaccharides; LPS) released by Gram-negative bacteria into the patient's bloodstream during infection. The therapeutic armory currently available for sepsis treatment is poor. We previously identified an LPS-neutralizing small molecule, PTD7. Here we tested the efficacy of novel PTD7-nanoconjugates in a murine model of sepsis. We found that PTD7-based nanoconjugates treated mice had improved survival that it was correlated with a marked decrease in proinflammatory cytokines in the blood. This proves that nanoconjugate-based endotoxin neutralizers can function as intracorporeal neutralizers of bacterial endotoxins.

Study of patients and carriers with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency: difficulties in the diagnosis.

OBJECTIVES: To search for biochemical and molecular markers for the diagnosis of patients and carriers with 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency. DESIGN AND METHODS: Organic acids in urine, MHBD activity in fibroblasts, immunoblotting and molecular studies were performed in seven patients. Seven carriers were also studied. RESULTS: Under low protein diet or poor feeding all the patients showed only a slightly altered organic acid profile. Measurement of 2-methyl-3-hydroxybutyric acid and tiglylglycine after an isoleucine loading test, failed to demonstrate the carrier status of one patient. However, measurement of 2-ethylhydracrylic acid (EHA) was positive in all the carriers tested. MHBD activity was clearly deficient in males and in one female patient. We identified four missense mutations, two of them were novel. CONCLUSIONS: Quantification of EHA may be of help for the diagnosis of the heterozygous condition. The carrier females showed the classical biochemical variability of X-linked diseases due to random X-chromosome inactivation.

Synthesis of a positional scanning library of pentamers of N-alkylglycines assisted by microwave activation and validation via the identification of trypsin inhibitors.

A positional scanning library of 625 N-alkylglycine pentamers has been synthesized on solid-phase, employing a set of 10 commercially available primary amines as a source of chemical diversity. The iterative synthetic steps were carried out in tea bags and accelerated by using microwave assisted organic synthesis (MAOS). The reactivity study of the primary amines used as diversity sources led to determine their relative reactivity values and equireactivity factors, which were applied to the library synthesis to ensure comparable concentrations of all final oligomers in the mixtures. This library was validated by the screening, deconvolution, and identification of trypsin inhibitors. These compounds are of potential interest for controlling the intracellular transport of TRPV1 channel.

Design and synthesis of an optimized positional scanning library of peptoids: identification of novel multidrug resistance reversal agents.

Herein is reported the optimized solid-phase synthesis of a library of 5,120 trimeric N-alkylglycines (peptoids) using the positional scanning format and the submonomer strategy. Diversity at the N-terminal position was generated from 20 commercially available primary amines, whereas 16 primary amines were employed for the middle and C-terminal positions of the trimers. Formation of undesirable side-products observed in a previous library synthesis (Humet, M. et al. J. Comb. Chem. 2003, 5, 597-605) was averted by restricting the use of primary amines functionalized with tertiary amino groups to the third amination step. Screening of the new library for the identification of chemosensitizers yielded two peptoids, compounds 1 and 2, with potent in vitro activity as multidrug resistance (MDR) reversal agents. The structures of the lead peptoids are consistent with a pharmacophore model generated from the interaction of various known inhibitors with the MDR-implicated transmembrane glycoprotein P-gp.

Identification from a positional scanning peptoid library of in vivo active compounds that neutralize bacterial endotoxins.

Two peptoids that neutralize the Gram-negative lipopolysaccharide (LPS) were identified from the screening of a positional scanning library. The evaluation of the in vivo activity of these compounds in an endoxemia murine model is also reported. These peptoids did not neutralize lipid A, i.e., the hydrophobic toxic component of LPS. This fact suggests that they do not have access to the micellar core and that they should bind to the hydrophilic carbohydrate portion of LPS.

Trimers of N-alkylglycines are potent modulators of the multidrug resistance phenotype.

The multidrug resistance (MDR) phenotype is considered a major cause of the failure of cancer chemotherapy. The acquisition of MDR is usually mediated by the overexpression of drug efflux pumps such as glycoprotein P (P-gp) or multidrug resistance-related protein 1 (MRP1). Thus, the identification, validation, and development of compounds that mitigate the MDR phenotype by modulating the activity of these transport proteins is an important yet elusive target. Here, we have addressed this issue and screened an N-trialkylglycine-based combinatorial library composed of 5120 compounds to search for modulators of the MDR phenotype. The screening identified 20 trimers of N-alkylglycine that increased the intracellular accumulation of daunomycin (DNM) in drug-resistant L1210R tumor cells that overexpressed the P-gp. These compounds seem to act as P-gp antagonists, as evidenced by the augmentation of DNM accumulation in the L1210(P-gp) cell line, a drug-sensitive L1210 cell stably expressing the murine P-gp protein. Similarly, several of the active N-trialkylglycines also produced an increment in DNM uptake in human HL60R cells, which primarily express the MRP1 protein. Trialkylglycines notably sensitized L1210R and HL60R tumor cells to DNM with a potency that rivaled that of verapamil. These findings provide new molecular scaffolds for the development of effective chemosensitizers against the MDR phenotype that, in due turn, could be used as adjuvant drugs in cancer chemotherapy.

La línea de ratas flinders: un modelo animal de depresión / The flinders rat line: an animal model of depression

En las últimas décadas han surgido varias propuestas novedosas de modelos animales para el estudio de la depresion en seres humanos. Algunos de ellos intentan reproducir en animales ciertas características del cuadro depresivo huamno. Otros más intentan simular las anormalidades neuroquímicas que dan origen a la enfermedad. Un tercer grupo de modelos animales pretende ser de utilidad para detectar selectivamente fármacos con acciones antidepresivas. Así, cada propuesta de modelo animal para el estudio de la depresión deberá ponderar su validez en cada uno de estos rubros. En este escrito se revisan las evidencias que recientemente se han generado y que apoyan la validez de las ratas Flinders como un importante modelo animal de depresión. Esta línea de ratas se originó en Australia cruando selectivamente ratas de la cepa Sprague-Dawley que mostraban hipersensibilidad a la estimulación colinérgica y alteraciones en ciertos patrones conductuales, similares a los que se observan en cuadros depresivos en seres humanos. Estas características lograron reproducirse en las generaciones subsecuentes, iniciándose así, una larga serie de estudios de muy diversa índole que han confirmado y ampliado las observaciones originales. La validez de apariencia en las Flinders está sustentada en que muestran una clara disminución de la frecuencia de presentación de las conductas motivadas supuestamente por el placer, lo que se ha interpretado como anhedonia. Junto con esta alteraciones, existen trastornos de la conducta motora, del peso corporal, del acortamiento de la latencia del sueño MOR y del aumento de su duración, respuesta exagerada ante algunos estresores y alteraciones en la ejecución de pruebas conductuales de laboratorio que on indicativas de un estado anímico alterado. Por lo que se refiere a la validez teórica, se mencionan las evidencias que se han obtenico hasta la fecha, confrontándose con al menos dos hipótesis acerca del origen de la depresión: la hipótesis colinérgica y la hipótesis serotoninérgica, ya que en ambos casos, se trata de respuestas exageradas ante la estimulación selectiva de cada uno de estos sistemas y, particularmente, de los receptores muscarínicos en el sistema colinérgico y de los receptores 5-HT-1a en el sistema serotoninérgico