Two-stage targeted maximum likelihood estimation for mixed aggregate and individual participant data analysis with an application to multidrug resistant tuberculosis.

In this study, we develop a new method for the meta-analysis of mixed aggregate data (AD) and individual participant data (IPD). The method is an adaptation of inverse probability weighted targeted maximum likelihood estimation (IPW-TMLE), which was initially proposed for two-stage sampled data. Our methods are motivated by a systematic review investigating treatment effectiveness for multidrug resistant tuberculosis (MDR-TB) where the available data include IPD from some studies but only AD from others. One complication in this application is that participants with MDR-TB are typically treated with multiple antimicrobial agents where many such medications were not observed in all studies considered in the meta-analysis. We focus here on the estimation of the expected potential outcome while intervening on a specific medication but not intervening on any others. Our method involves the implementation of a TMLE that transports the estimation from studies where the treatment is observed to the full target population. A second weighting component adjusts for the studies with missing (inaccessible) IPD. We demonstrate the properties of the proposed method and contrast it with alternative approaches in a simulation study. We finally apply this method to estimate treatment effectiveness in the MDR-TB case study.

Mesenchymal stem cells attenuate the proinflammatory cytokine pattern in a guinea pig model of chronic cigarette smoke exposure.

AIMS: Cigarette smoke often induces pulmonary and systemic inflammation. In animal models, mesenchymal stem cells (MSC) tend to ameliorate these effects. We aimed to explore the local and systemic expression of cytokines in guinea pigs chronically exposed to cigarette smoke, and their modifications by MSC. MAIN METHODS: Concentrations of IL-1ß, IL-6, IL-8, IL-12, TNF-α, INF-É£, TSG-6, MMP-9, TIMP-1, and/or TIMP-2 in serum and bronchoalveolar lavage (BALF) from animals exposed to tobacco smoke (20 cigarettes/day, 5 days/week for 10 weeks) were determined, and mRNA expression of some of them was measured in lung tissue. Intratracheal instillation of allogeneic bone marrow MSC (5x106 cells in 1 ml) was done at week 2. KEY FINDINGS: After cigarette smoke, IL-6 and IFN-γ increased in serum and BALF, while IL-1ß and IL-12 decreased in serum, and TSG-6 and TIMP-2 increased in BALF. IL-1ß had a paradoxical increase in BALF. MSC had an almost null effect in unexposed animals. The intratracheal administration of MSC in guinea pigs exposed to cigarette smoke was associated with a statistically significant decrease of IL-12 and TSG-6 in serum, as well as a decrease of IL-1ß and IFN-γ and an increase in TIMP-1 in BALF. Concerning mRNA expression in lung tissue, cigarette smoke did not modify the relative amount of the studied transcripts, but even so, MSC decreased the IL-12 mRNA and increased the TIMP-1 mRNA. SIGNIFICANCE: A single intratracheal instillation of MSC reduces the pulmonary and systemic proinflammatory pattern induced by chronic exposure to cigarette smoke in guinea pigs. TRIAL REGISTRATION: Not applicable.

Salivary concentrations of cytokines and other analytes in healthy children.

BACKGROUND: Blood has been the usual biological fluid for measuring analytes, but there is mounting evidence that saliva may be also useful for detecting cytokines in a noninvasive way. Thus, in this study we aimed to determine concentration of cytokines and other analytes in saliva from a population of healthy children. METHODS: We collected un-stimulated whole saliva samples from clinically healthy children, and concentration of 17 cytokines and 12 other analytes were measured in supernatants. All values were adjusted by albumin content and were log-transformed before multivariate statistical analysis. RESULTS: We included 114 children (53.5% females) between 6.0 and 11.9 years old. The highest concentrations (medians, pg/µg albumin) were seen for visfatin (183.70) and adiponectin (162.26) and the lowest for IL-13 and IL-2 (~0.003). Albumin concentration was associated with age (rS = 0.39, p < 0.001). In the multivariate analysis, five analytes (C peptide, ghrelin, GLP-1, glucagon, leptin) inversely correlated with age and positively with height-for-age. Age was also positively associated with PAI-1, while height-for-age was also positively associated with insulin and visfatin. Finally, BMI-for-age had a positive correlation with GM-CSF and insulin. CONCLUSIONS: Herein, we provided concentration values for 29 analytes in saliva from healthy children that may be useful as preliminary reference framework in the clinical research setting.

Analysis of loss to follow-up in 4099 multidrug-resistant pulmonary tuberculosis patients.

Loss to follow-up (LFU) of ≥2 consecutive months contributes to the poor levels of treatment success in multidrug-resistant tuberculosis (MDR-TB) reported by TB programmes. We explored the timing of when LFU occurs by month of MDR-TB treatment and identified patient-level risk factors associated with LFU.We analysed a dataset of individual MDR-TB patient data (4099 patients from 22 countries). We used Kaplan-Meier survival curves to plot time to LFU and a Cox proportional hazards model to explore the association of potential risk factors with LFU.Around one-sixth (n=702) of patients were recorded as LFU. Median (interquartile range) time to LFU was 7 (3-11) months. The majority of LFU occurred in the initial phase of treatment (75% in the first 11 months). Major risk factors associated with LFU were: age 36-50 years (HR 1.3, 95% CI 1.0-1.6; p=0.04) compared with age 0-25 years, being HIV positive (HR 1.8, 95% CI 1.2-2.7; p<0.01) compared with HIV negative, on an individualised treatment regimen (HR 0.7, 95% CI 0.6-1.0; p=0.03) compared with a standardised regimen and a recorded serious adverse event (HR 0.5, 95% CI 0.4-0.6; p<0.01) compared with no serious adverse event.Both patient- and regimen-related factors were associated with LFU, which may guide interventions to improve treatment adherence, particularly in the first 11 months.

Allergic sensitization increases the amount of extracellular ATP hydrolyzed by guinea pig leukocytes.

Increased levels of ATP have been found in the bronchoalveolar lavage of patients with asthma, and subjects with this disease, but not healthy subjects, develop bronchospasm after nebulization with ATP. Because the main mechanism for controlling the noxious effects of extracellular ATP is its enzymatic hydrolysis, we hypothesized that allergic sensitization is accompanied by a decreased functioning of such hydrolysis. In the present study, peripheral blood leukocytes from sensitized and non-sensitized guinea pigs were used for determining the extracellular metabolism (as assessed by inorganic phosphate production) of ATP, ADP, AMP, or adenosine, and for detecting possible changes in the expression (qPCR and Western blot) of major ectonucleotidases (NTPDase1, NTPDase3, and NPP1) and purinoceptors (P2X1, P2X7, P2Y4, and P2Y6). Contrary to our hypothesis, we found that leukocytes from allergic animals produced higher amounts of inorganic phosphate after stimulation with ATP and ADP, as compared with leukocytes from non-sensitized animals. Although at first glance, this result suggested that sensitization caused higher efficiency of ectonucleotidases, their mRNA and protein expressions were unaffected. On the other hand, after sensitization, we found a significant increase in the protein expression of P2X7 and P2Y4, two purinoceptors known to be responsible for ATP release after activation. We concluded that allergic sensitization increased the amount of ATP hydrolyzed by ectonucleotidases, the latter probably not due to the enhanced efficiency of its enzymatic breakdown, but rather due to an increased release of endogenous ATP or other nucleotides, partly mediated by enhanced expression or P2X7 and P2Y4 receptors.

Factors related to changes in the asthma male: female ratio by age in 403 Mexican counties.

BACKGROUND: Asthma is more frequent in males during childhood and in females after adolescence, which has been attributed to changes in sexual hormones levels. OBJECTIVE: We explored changes of the asthma male: female ratio (AMFR) by age group in a large population (nationwide), and its ecological association (at county level) with some medical, geographical, or sociodemographic factors. METHODS: Registries of the largest medical institution in Mexico (∼37.5 million subjects assigned to a family physician) were analyzed and the AMFR calculated using asthma incidences. RESULTS: In boys, asthma incidence peaked at 0 to 4 years and progressively decreased, reaching a plateau in adulthood. In girls, asthma incidence showed a bimodal pattern, with maximal rates at 0 to 4 years old, and again at 50 to 54 years old. In the ecological analysis performed in more than 400 counties, the AMFR in adults (≥15 years old) inversely correlated with population density (r = -0.256) and altitude (r = -0.144), and directly correlated with acute respiratory tract infections (ARTI, r = 0.215), diabetes (r = 0.186), marginalization (r = 0.179), pneumonias (r = 0.166), and mean maximal temperature (r = 0.142), all with P < .01. In the multiple linear regression, only population density (P < .001) and ARTI (P = .006) remained statistically significant in the final model. CONCLUSION: Asthma incidence in males and females did not match the expected sexual hormones variations, and other factors such as population density and ARTI also influenced the AMFR. These findings challenge the traditional belief that sexual hormones are major determinants of the AMFR.

Cystic and pseudocystic pulmonary malformations in children: Clinico-pathological correlation.

Pulmonary malformations are rare disorders, with cystic and pseudocystic pulmonary malformations (CPPM) the most frequent, and constitute the first cause of lobectomy in children <1 year of age. Morphological overlap of congenital cystic pulmonary lesions might correspond to a spectrum of lesions in which bronchial atresia is a common etiopathogenetic mechanism. We aimed to report the frequency of CPPM resected in a tertiary-level hospital and to evaluate the degree of agreement between presurgical and anatomopathological diagnoses. We studied 44 surgical pieces with a diagnosis of CPPM received at the Pathology Service from 2009 to 2014, resected from 39 patients, 51.3 % males, with a median age of 16.8 months. Up to 69.2% of the patients had adenomatoid malformation of pulmonary airway (AMPA), with type 2 the most frequent (55.5%). Pulmonary sequestration was present in 15.4% of patients; in two cases the diagnosis was an incidental finding during surgery for the repair of a diaphragmatic hernia. Congenital lobar hyperinflation (CLH) occurred in 7.6% cases. Bronchogenic cyst (BC) was present in 7.6% cases. Presurgical and anatomopathological diagnoses in all patients coincided in 71.8% of cases. Kappa coefficient was 0.56 for global concordance in patients with AMPA, and 0.72, 0.64, 0.37 and 0.33 for CLH, BC, and types 1 and 2 AMPA, respectively. This relatively low interobserver agreement could reflect the low reproducibility of diagnoses used in the current nomenclature. Thus, the new nomenclature must be promoted in order to allow for better reproducibility and greater clinico-pathological concordance. The anatomopathological analysis must include the intentional search for bronchial atresia.

Characteristic plethysmographic findings in a guinea pig model of COPD.

AIM OF THE STUDY: Long-term exposure to cigarette smoke generates chronic obstructive pulmonary disease (COPD) in guinea pigs, but a comprehensive evaluation of changes in lung function, as assessed by barometric whole body plethysmography (WBP), is lacking. MATERIALS AND METHODS: Female guinea pigs were exposed to the smoke of 20 cigarettes/day, 5 days/week, during 10 weeks (COPD group, n = 8), and were compared with unexposed female guinea pigs of the same age (control group, n = 8). WBP was performed in both groups, followed by lung histology. RESULTS: At the end of the exposure period, guinea pigs in the COPD group had higher respiratory frequency, while duty cycle (Ti/Ttot) was unaffected. There was a trend toward minute ventilation (MV) and expiratory flow at the mid-tidal volume (EF50) to be higher in the COPD group. Enhanced pause (Penh) was lower, while time of braking (TB) and time to PEF relative to Te (Rpef) were higher in the COPD group. All guinea pigs exposed to tobacco smoke developed emphysematous lesions in their lungs and gained less body weight than controls. CONCLUSIONS: In this COPD model, exposure to cigarette smoke produced changes in WBP characterized by a shallow breathing pattern with decreased Penh and a trend toward increasing EF50 (probably due to decreased elastic recoil), increased TB (suggesting dynamic laryngeal narrowing), and a trend of increasing MV (probably due to a higher metabolic rate). Many of these functional changes resemble those observed in patients with COPD and corroborate the suitability of this guinea pig model for the study of COPD.

Effect of oral glycine on the clinical, spirometric and inflammatory status in subjects with cystic fibrosis: a pilot randomized trial.

BACKGROUND: Patients with cystic fibrosis (CF) have airway inflammation that contributes to symptoms and to pulmonary function derangement. Current drugs used to diminish airway inflammation improve the clinical and spirometric status of patients with CF, but their use is limited due to their undesired side effects, for example, glucose intolerance, growth retardation, and cataracts with corticosteroids, gastrointestinal toxicity with ibuprofen, and macrolide resistance with azythromycin. Glycine is known to decrease activation of inflammatory cells, including alveolar macrophages and neutrophils, and is relatively inexpensive, palatable, and virtually devoid of untoward effects. These features make glycine a good candidate for antiinflammatory treatment of CF. Thus, we aimed to explore whether glycine can exert a beneficial effect in a population of patients with CF. METHODS: This was a randomized, double blinded, cross-over pilot clinical trial. Subjects with CF received, in random order, oral glycine (0.5 g/kg/day, dissolved in any liquid) and placebo (glass sugar), each during 8 weeks with an intermediate 2-week wash-out period. RESULTS: Thirteen subjects aged 6-23 years, 8 females, completed the two arms of the study. As compared with placebo, after glycine intake patients had better symptom questionnaire scores (p = 0.02), mainly regarding sputum features and dyspnea. While spirometric variables tended to decline during placebo intake, they remained stable or even increased during glycine treatment (p = 0.04 to p = 0.003). In this context, FEV1 declined 8.6% after placebo and increased 9.7% at the end of the glycine period. Pulse oximetry improved after glycine intake (p = 0.04 vs. placebo). TNF-α in serum and IL-6 and G-CSF in sputum tended to decline at the end of the glycine period (p = 0.061, p = 0.068 and p = 0.04, respectively, vs placebo). Glycine was remarkably well tolerated. CONCLUSIONS: The clinical, spirometric and inflammatory status of subjects with CF improved after just 8 weeks of glycine intake, suggesting that this amino acid might constitute a novel therapeutic tool for these patients. Thus, further studies are warranted. TRIAL REGISTRATION: www.clinicaltrials.gov , registration number: NCT01417481 , date of registration: March 12, 2012.

Prevalence and Characteristics of Exercise-Induced Bronchoconstriction in High School and College Athletes at 2,240 m Altitude.

BACKGROUND: Athletes practicing strenuous physical activities may develop exercise-induced bronchoconstriction (EIB). We aimed to determine the prevalence and features of this condition in Mexico City (altitude, 2,240 m). METHODS: In the present study, 208 high school and college athletes performed a standardized EIB test on a treadmill. RESULTS: Responses to exercise had large between-subject variability in all physiological parameters (forced expiratory volume in one second [FEV1], heart rate, blood oxygen saturation level [SpO2], blood pressure), with nearly similar proportions of subjects in whom FEV1 increased or decreased. According to the recommended cut-off value of 10% FEV1 decrease, only 15 (7.2%) athletes had a positive EIB test. Weight lifters were more prone to develop EIB (three out of seven athletes; p = 0.01). Subjects with a positive EIB test already had a lower baseline forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio (96.4 vs. 103.2% of predicted, respectively; p = 0.047), and developed more respiratory symptoms after exercise than subjects with a negative test. There were no differences with respect to age, gender, body mass index, history of asthma or atopic diseases, smoking habit, and exposure to potential indoor allergens. CONCLUSIONS: The relatively low prevalence of EIB in athletes from Mexico City raises the possibility that high altitude constitutes a protective factor for EIB. In contrast, weight lifters were especially prone to develop EIB, which suggests that repetitive Valsalva maneuvers could be a novel risk factor for EIB. There was a large between-subject variability of all physiological responses to exercise.

Unsuspected Lung Pathology in Autopsies of Children with Cancer.

BACKGROUND: Although pulmonary involvement is common in patients with cancer, its frequency and nature is seldom reported in the medical literature. OBJECTIVE: To determine the frequency and type of lung pathological conditions revealed by autopsy in children with cancer. METHODS: All reports from autopsies performed in children with cancer from 1989 to 2012 in a pediatric hospital were reviewed. RESULTS: In the analyzed period, 118 autopsies (10.2% of all autopsies) corresponded to children who died with cancer; 76 had complete information and were included in the analysis. Children were seen in the Hematology (41 cases) or the Oncology (35 cases) services. Their median age at decease was 7 years (range, 15 days to 16.1 years) and 46.1% were females. Main diagnoses were acute lymphoblastic (31 patients) or myeloblastic (10 patients) leukemias and tumors of the central nervous system (12 patients). A pathological respiratory condition was diagnosed antemortem in 31 (40.8%) patients, and at autopsy in 62 (81.6%) cases. Omitted diagnoses occurred in 58 (76.3%) children, being pneumonia (24 cases) and pulmonary hemorrhage (23 cases) the most frequent omissions. Nine patients had clinically unsuspected tumor infiltration or metastases. CONCLUSIONS: In these children with cancer, more than 80% of autopsies revealed some lung pathology, mainly of infectious or hemorrhagic nature. Thus, pulmonary involvement should be investigated in all children with cancer in a timely and intentional manner.

Oral hygiene and dental status as factors related to asthma in high school and college students.

OBJECTIVE: Considering that oral microbiota might modulate immune responses, we explored if customary oral care procedures might influence immune-driven diseases such as asthma. METHODS: This was a retrospective, cross-sectional analysis of responses to a self-completion medical questionnaire applied to subjects entering into college and high school programs during 2006-2011. RESULTS: Responses from 329 780 students aged 14-24 years (97.6% of the original population) were analyzed. The prevalence of lifetime asthma was 4.01%. Subjects with asthma were slightly older, taller and heavier than subjects without asthma, and these differences were equally present in males and females. Subjects currently having two or more decayed teeth had asthma less frequently than those with one or none decayed tooth, with an odds ratio (OR) = 0.86 and 95% confidence interval (95% CI) 0.83-0.89. In contrast, asthma was reported more frequently among students having two or more missing or filled teeth [OR = 1.1 (95% CI 1.04-1.17) and OR = 1.05 (95% CI 1.01-1.09), respectively]. From 2008 onwards, subjects also responded questions about oral hygiene incorporated into the core questionnaire. In these subjects, the use of toothpaste as well as the frequency and duration of toothbrushing were unrelated to asthma; regular use of mouthwash was associated with asthma in women [OR = 1.16 (95% CI 1.07-1.25)], but not in men [OR = 1.04 (95% CI 0.96-1.13)]. Results of multiple logistic regressions were in line with these findings. CONCLUSIONS: Our results suggested that oral hygiene and dental status could be novel factors influencing asthma development, and thus further studies to confirm and clarify this association are warranted.

Clinical and epidemiological features of extrapulmonary tuberculosis in a high incidence region.

OBJECTIVE: To describe the clinical features of extrapulmonary tuberculosis (EXPTB) and to evaluate epidemiological data to search for potential explanations for its high frequency in the state of Aguascalientes, Mexico. MATERIALS AND METHODS: Clinical records of all patients with tuberculosis seen in Aguascalientes in 2008 were reviewed, and official databases were analyzed. RESULTS: EXPTB comprised 60.5% of the 86 cases evaluated, being lymph nodes the main site affected. Patients with EXPTB were younger and more obese than subjects with pulmonary tuberculosis (PTB). One third of cases in either group had diabetes, a frequency much higher than expected. Epidemiological analysis showed that PTB incidence, but not EXPTB incidence, decreases as geographical altitude increases, and had a descendent trend from 1997 to 2011. CONCLUSIONS: The lower frequency of PTB (due to its inverse relationship with altitude and its descendent trend in last years) might explain the high frequency of EXPTB. Obesity appeared to protect against developing pulmonary involvement, and diabetes was more frequent than expected among PTB and EXPTB cases.

Glycine by enteral route does not improve major clinical outcomes in severe COVID-19: a randomized clinical pilot trial.

There is a worrying scarcity of drug options for patients with severe COVID-19. Glycine possesses anti-inflammatory, cytoprotective, endothelium-protective, and platelet-antiaggregant properties, so its use in these patients seems promising. In this open label, controlled clinical trial, inpatients with severe COVID-19 requiring mechanical ventilation randomly received usual care (control group) or usual care plus 0.5 g/kg/day glycine by the enteral route (experimental group). Major outcomes included mortality, time to weaning from mechanical ventilation, total time on mechanical ventilation, and time from study recruitment to death. Secondary outcomes included laboratory tests and serum cytokines. Patients from experimental (n = 33) and control groups (n = 23) did not differ in basal characteristics. There were no differences in mortality (glycine group, 63.6% vs control group, 52.2%, p = 0.60) nor in any other major outcome. Glycine intake was associated with lower fibrinogen levels, either evaluated per week of follow-up (p < 0.05 at weeks 1, 2, and 4) or as weighted mean during the whole hospitalization (608.7 ± 17.7 mg/dl vs control 712.2 ± 25.0 mg/dl, p = 0.001), but did not modify any other laboratory test or cytokine concentration. In summary, in severe COVID-19 glycine was unable to modify major clinical outcomes, serum cytokines or most laboratory tests, but was associated with lower serum fibrinogen concentration.Registration: ClinicalTrials.gov NCT04443673, 23/06/2020.

Histamine, carbachol, and serotonin induce hyperresponsiveness to ATP in guinea pig tracheas: involvement of COX-2 pathway.

Extracellular ATP promotes an indirect contraction of airway smooth muscle via the secondary release of thromboxane A2 (TXA2) from airway epithelium. Our aim was to evaluate if common contractile agonists modify this response to ATP. Tracheas from sensitized guinea pigs were used to evaluate ATP-induced contractions before and after a transient contraction produced by histamine, carbachol, or serotonin. Epithelial mRNA for COX-1 and COX-2 was measured by RT-PCR and their expression assessed by immunohistochemistry. Compared with the initial response, ATP-induced contraction was potentiated by pretreatment with histamine, carbachol, or serotonin. Either suramin (antagonist of P2X and P2Y receptors) plus RB2 (antagonist of P2Y receptors) or indomethacin (inhibitor of COX-1 and COX-2) annulled the ATP-induced contraction, suggesting that it was mediated by P2Y receptor stimulation and TXA2 production. When COX-2 was inhibited by SC-58125 or thromboxane receptors were antagonized by SQ-29548, just the potentiation was abolished, leaving the basal response intact. Airway epithelial cells showed increased COX-2 mRNA after stimulation with histamine or carbachol, but not serotonin, while COX-1 mRNA was unaffected. Immunochemistry corroborated this upregulation of COX-2. In conclusion, we showed for the first time that histamine and carbachol cause hyperresponsiveness to ATP by upregulating COX-2 in airway epithelium, which likely increases TXA2 production. Serotonin-mediated hyperresponsiveness seems to be independent of COX-2 upregulation, but nonetheless is TXA2 dependent. Because acetylcholine, histamine, and serotonin can be present during asthmatic exacerbations, their potential interactions with ATP might be relevant in its pathophysiology.

Modifications of plasma 5-HT concentrations during the allergic bronchoconstriction in guinea pigs.

Several contractile mediators involved in the antigen-induced airway obstruction have been identified, but the role of 5-HT (5-hydroxytryptamine or serotonin) has been scantily investigated. In this work, the potential role of 5-HT in the allergic bronchoconstriction was evaluated through a pharmacological approach and plasma 5-HT measurement in blood samples from the right and left ventricles of anesthetized guinea-pigs. Intravenous 5-HT caused a dose-dependent increase of the lung resistance in anesthetized, nonsensitized guinea pigs. Likewise, in sensitized animals the antigenic challenge with ovalbumin also caused a transient bronchoconstriction (356 ± 60% the basal value), which was largely inhibited by the blockade of serotonergic receptors with methiothepin plus tropisetron (134 ± 10%, P = .007). Sensitized animals tended to have plasma 5-HT concentrations higher than nonsensitized controls, and shortly after the peak of the allergic bronchoconstriction the 5-HT levels in the left ventricle (blood flowing out from lungs) tended to be higher than in the right ventricle (blood entering the lungs), although data dispersion precluded the obtaining of statistical significance. Interestingly, the degree of bronchoconstriction highly correlated with the concentrations of 5-HT found in the left ventricle and measured either in platelet-rich plasma (r = 0.97 P = .007) or platelet-poor plasma (r = 0.97, P = .006). After the obstructive response subsided these correlations were lost, but now the degree of bronchoconstriction turned to be correlated with 5-HT concentration in platelet concentrate (r = 0.76, P = .03). In conclusion, our results suggested that 5-HT is actively released from lungs during the antigenic challenge and that this autacoid is involved in the generation of the airway obstruction.

Passive smoking induces leukotriene production in children: influence of asthma.

BACKGROUND: Passive smoking is associated with poor asthma control in children, but the mechanism is unknown. Leukotrienes are involved in the asthma pathogenesis and their synthesis is increased in adult subjects who actively smoke. OBJECTIVE: To evaluate whether passive smoking, as assessed by urinary cotinine levels, increases leukotriene production in children with or without asthma. METHODS: This was a prospective, cross-sectional study in which children with stable intermittent asthma (without exacerbation) and healthy control children were studied through spirometry and urinary concentrations of cotinine and leukotriene E(4) (LTE(4)). Both groups were balanced to include children with and without passive smoking. RESULTS: Ninety children (49 with asthma and 41 controls, 54.4% females) aged 9 years (range, 5-13 years) were studied. Urinary LTE(4) concentrations were progressively higher as cotinine levels increased (r(S) = 0.23, p = .03). LTE(4) also correlated with body mass index (BMI) (r(S) = 0.30, p = .004), and multiple regression analysis revealed that BMI was even more influential than cotinine for determining LTE(4) levels. LTE(4) concentrations were unrelated with gender, age, or spirometry. In turn, cotinine inversely correlated with forced expiratory volume in one second (FEV(1)) (r(S) = -0.22, p = .04) and forced vital capacity (FVC) (r(S) = -0.25, p = .02), but when analyzed by groups, these relationships were statistically significant only in children with asthma. CONCLUSIONS: Exposure to environmental tobacco smoke, as assessed by urinary cotinine levels, was associated with an increased urinary concentration of LTE(4), although BMI exerted more influence in determining its concentration. Urinary cotinine was associated with decreased lung function, mainly in children with asthma.

[Epidemiological trends 1992-2007 in a neonatal intensive care unit]. / Cambios epidemiológicos de 1992 a 2007 en una unidad de cuidados intensivos neonatales.

INTRODUCTION: progressive advances in neonatal care are expected to change the epidemiological profile of patients and conditions seen in neonatal intensive care units (NICU). Thus, the objective of this study was to identify such changes in a NICU in Mexico City. METHODS: retrospectively, we analyzed age, gender, weight at admission, hospital stay,diagnoses at discharge and cause of death in 5,192 patients admitted from 1992-2007. RESULTS: in the study period,patients were admitted at a progressively older age (median of 3 days old in 1992 to 9 in 2007; rS = 0.87) and lower weight (2,800-2,343 g; rS = ­0.56), while length of hospital stay was stable (approximately, 9 days). Over 90% patients had cardiological, digestive and/or pulmonary diseases, and most patients (71.4%) had conditions for which a surgical approach is the usual treatment. Cardiological and neurologic problems increased (rS = 0.86 and 0.85, respectively),while pulmonary diseases decreased (rS = ­0.79). Mortality and autopsy rate diminished from 26 to 15% (rS = ­0.80),and from 32.5 to 10.7% (rS = ­0.53), respectively. Conditions more frequently associated with death were urologic/nephrologic and infectious diseases. CONCLUSION: epidemiological patterns in our NICU are clearly changing, and thus searching for similar time trends in other NICU is warranted.

Trends (2007-2019) of major atopic diseases throughout the life span in a large Mexican population.

Background: Major atopic diseases such as atopic dermatitis (AD), allergic rhinitis (AR), and asthma share the same atopic background, but they often show differences in their epidemiological behavior. Objective: We aimed to report the profile of these atopic diseases in a large Mexican population, including their age-related incidences, male:female (M:F) ratios, recent time trends, and association with altitude. Methods: Registries from the largest, nationwide health institution in Mexico (more than 34 million insured subjects), were reviewed. New cases of AD, AR, and asthma diagnosed each year by family physicians from 2007 to 2019 were adjusted by the corresponding insured population to estimate incidence rates. Results: Incidences of the 3 atopic diseases were highest in the 0-4 years age-group and progressively decreased thereafter until adolescence. Asthma and AR, but not AD, were more frequent in males during childhood (M:F ratios of 1.5, 1.3, and 0.95, respectively), but predominated in females during adulthood (M:F ratios of 0.52, 0.68, and 0.73, respectively). Time trends showed an initial increasing trend of annual incidences, with a peak around 2009-2011, and a downward trend afterward. This decreasing trend was seen in all age-groups and was more evident for AD (∼50% drop) and asthma (∼40% drop) than for AR (∼20% drop). Geographical distribution suggested that incidences of asthma and AR, but not of AD, had an inverse association with altitude. Conclusion: Annual incidences of the 3 major atopic diseases have declined in recent years in almost all age groups, and their epidemiological profile during the life span showed contrasting differences according to age, sex, and ecological association with altitude, mainly regarding AD.

Lung function is related to salivary cytokines and hormones in healthy children. An exploratory cross-sectional study.

Pulmonary mechanics has been traditionally viewed as determined by lung size and physical factors such as frictional forces and tissue viscoelastic properties, but few information exists regarding potential influences of cytokines and hormones on lung function. Concentrations of 28 cytokines and hormones were measured in saliva from clinically healthy scholar children, purposely selected to include a wide range of body mass index (BMI). Lung function was assessed by impulse oscillometry, spirometry, and diffusing capacity for carbon monoxide, and expressed as z-score or percent predicted. Ninety-six scholar children (55.2% female) were enrolled. Bivariate analysis showed that almost all lung function variables correlated with one or more cytokine or hormone, mainly in boys, but only some of them remained statistically significant in the multiple regression analyses. Thus, after adjusting by height, age, and BMI, salivary concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF) in boys were associated with zR5-R20 and reactance parameters (zX20, zFres, and zAX), while glucagon inversely correlated with resistances (zR5 and zR20). Thus, in physiological conditions, part of the mechanics of breathing might be influenced by some cytokines and hormones, including glucagon and GM-CSF. This endogenous influence is a novel concept that warrants in-depth characterization.