Coronavirus disease 2019, allergic diseases, and allergen immunotherapy: Possible favorable mechanisms of interaction.

Background: Both, allergen immunotherapy (AIT) and SARS-COV-2 infection cause a set of immunologic changes that respectively vary during the course of the treatment or the disease. Objective: To review immune changes brought along by each of these entities and how they might interrelate. Methods: We start presenting a brief review of the structure of the new coronavirus and how it alters the functioning of the human immune system. Subsequently, we describe the immune changes induced by AIT and how these changes could be favorable or unfavorable in the allergic patient infected with SARS-CoV-2 at a particular point of time during the evolving infection. Results: We describe how a healthy immune response against SARS-CoV-2 develops, versus an immune response that is initially suppressed by the virus, but ultimately overactivated, leading to an excessive production of cytokines (cytokine-storm-like). These changes are then linked to the clinical manifestations and outcomes of the patient. Reviewing the immune changes secondary to AIT, it becomes clear how AIT is capable of restoring a healthy innate immunity. Investigators have previously shown that the frequency of respiratory infections is reduced in allergic patients treated with AIT. On the other hand it also increases immunoregulation. Conclusion: As there are many variables involved, it is hard to predict how AIT could influence the allergic patient's reaction to a SARS-CoV-2 infection. In any case, AIT is likely to be beneficial for the patient with allergic rhinitis and/or allergic asthma in the context of the SARS-CoV-2 pandemic as controlling allergic diseases leads to a reduced need for contact with healthcare professionals. The authors remind the reader that everything in this article is still theoretical, since at the moment, there are no published clinical trials on the outcome of COVID-19 in allergic patients under AIT.

Universal influenza vaccination: a Mexican Expert Position Paper.

OBJECTIVE: Influenza is a costly disease for the population. It is a cause of seasonal morbidity and mortality, epidemics and pandemics or syndemics. Given the variability of the virus, surveillance systems are implemented in order to update the strains and include them in the annual influenza vaccine. This vaccine is currently recommended in some high-risk groups. However, universal vaccination remains controversial. To evaluate the evidence and describe the position of a panel of experts on the relevance of universal vaccination against influenza virus. MATERIAL AND METHODS: Five clinical questions were asked, whereby a systematic search of the literature in electronic sources and a Delphi panel were carried out. The evidence was analyzed, and recommendations were issued by the experts. RESULTS: The group of experts recommends vaccinating the population starting at six months of age and include people who live with egg protein allergy, with comorbidities (diabetes, obesity, cancer), health workers and pregnant women. CONCLUSIONS: Vaccination, starting with vulnerable groups, is a necessary, ethical and cost-effective strategy. However, expanding the coverage to achieve universal vaccination could reduce the transmission of the disease and its consequences in the population.

OBJETIVO: La influenza es una enfermedad costosa para la población. Es causa de morbimortalidad estacional, epidemias y pandemias o sindemias. Debido a la variabilidad del virus, se implementan sistemas de vigilancia para actualizar las cepas e incluirlas en la vacuna antiinfluenza anual. Actualmente se recomienda esta vacuna en algunos grupos de alto riesgo. Sin embargo, la vacunación universal es aún controvertida. Evaluar la evidencia y describir la posición de un panel de expertos sobre la pertinencia de la vacunación universal contra el virus de influenza. MATERIAL Y MÉTODOS: Se realizaron cinco preguntas clínicas, con las que se realizó una búsqueda sistemática de la literatura en fuentes electrónicas y un panel Delphi. Se analizó la evidencia y se emitieron recomendaciones por los expertos. RESULTADOS: El grupo de expertos recomienda vacunar a la población desde los seis meses de edad e incluir a personas que viven con alergia a la proteína del huevo, con comorbilidades (diabetes, obesidad, cáncer), trabajadores de la salud y embarazadas. CONCLUSIONES: La vacunación, iniciando con los grupos vulnerables, es una estrategia necesaria, ética y costo-efectiva. Sin embargo, extender la cobertura para lograr la vacunación universal podría disminuir la transmisión de la enfermedad y sus consecuencias en la población.

Genetic, Immunological, and Clinical Features of the First Mexican Cohort of Patients with Chronic Granulomatous Disease.

PURPOSE: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by an inability of phagocytes to produce reactive oxygen species, impairing their killing of various bacteria and fungi. We summarize here the 93 cases of CGD diagnosed in Mexico from 2011 to 2019. METHODS: Thirteen Mexican hospitals participated in this study. We describe the genetic, immunological, and clinical features of the 93 CGD patients from 78 unrelated kindreds. RESULTS: Eighty-two of the patients (88%) were male. All patients developed bacterial infections and 30% suffered from some kind of fungal infection. Fifty-four BCG-vaccinated patients (58%) presented infectious complications of BCG vaccine. Tuberculosis occurred in 29%. Granulomas were found in 56% of the patients. Autoimmune and inflammatory diseases were present in 15% of patients. A biological diagnosis of CGD was made in 89/93 patients, on the basis of NBT assay (n = 6), DHR (n = 27), and NBT plus DHR (n = 56). The deficiency was complete in all patients. The median age of biological diagnosis was 17 months (range, 0-186 months). A genetic diagnosis was made in 83/93 patients (when material was available), corresponding to CYBB (n = 64), NCF1 (n = 7), NCF2 (n = 7), and CYBA (n = 5) mutations. CONCLUSIONS: The clinical manifestations in these Mexican CGD patients were similar to those in patients elsewhere. This cohort is the largest in Latin America. Mycobacterial infections are an important cause of morbidity in Mexico, as in other countries in which tuberculosis is endemic and infants are vaccinated with BCG. X-linked CGD accounted for most of the cases in Mexico, as in other Latin American countries. However, a significant number of CYBA and NCF2 mutations were identified, expanding the spectrum of known causal mutations.

Clinical Features, Non-Infectious Manifestations and Survival Analysis of 161 Children with Primary Immunodeficiency in Mexico: A Single Center Experience Over two Decades.

PURPOSE: The hallmark of Primary immunodeficiencies (PID) is unusual infection, although other immunological non-infectious manifestations such as autoimmunity, allergy and cancer are often present. Most published reports focus on one disease or defect groups, so that a global prevalence of non-infectious manifestations of PID is hard to find. We aimed to describe the clinical features of our pediatric patients with PID, as well as the frequency and evolution of allergy, cancer and autoimmunity. METHODS: We reviewed all the available charts of patients being followed for PID from 1991 to the spring of 2012 at the National Institute of Pediatrics, Mexico City, to describe their demographic, clinical and laboratory features. Their diagnoses were established by pediatric immunologists in accordance to ESID criteria, including routine immunological workup and specialized diagnostic assays. We divided patients by decade of diagnosis to analyze their survival curves. RESULTS: There were 168 charts available, from which we excluded one duplicate and six equivocal diagnoses. We studied the charts of 161 PID patients (68% male, 86% alive), mostly from the center of the country, with a positive family history in 27% and known consanguinity in 11%. Eighty percent of the patients were diagnosed during the last decade. Current median age was 124 months; median age at onset of infections, 12 months; median age at diagnosis, 52 months; median age at death, 67.5 months. Severe infection and bleeding were the cause of 22 deaths. Eighty-six percent of all patients had at least one infection, while non-infectious manifestations had a global prevalence of 36%, namely: autoimmunity 19%, allergies 17%, and cancer 2.4%. Survival curves were not significantly different when compared by decade of diagnosis. CONCLUSIONS: Compared to other registry reports, we found a lower prevalence of antibody defects, and of associated allergy and cancer. We could only locate two isolated IgA deficiencies and four cases of cancer among our PID patients. Although antibody defects are the most prevalent group (30%), the distribution we found is similar to that reported in Iran, Kuwait, Egypt and Taiwan, with a close 27% share for phagocyte defects, and 26% for the formerly called "well-defined" syndromes. Of note, autoimmune and inflammatory complications are high among our patients with chronic granulomatous disease, as has been reported in both the United States and Japan, but not in Europe.

Primary Immunodeficiency Diseases in Aguascalientes, Mexico: Results from an Educational Program.

PURPOSE: Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders characterized mainly by recurrent infections. Late diagnosis remains as one of the main issues to solve. We aimed to increase PID diagnosis in Aguascalientes, a 1.3 million inhabitants state in the center of Mexico, and to describe the clinical features of such patients. METHODS: We developed an educational program for health personnel and general public; patients with possible PID were referred to a State University clinical center from December 2011 to December 2012. The patients were evaluated at the clinic and their definitive diagnosis pursued through laboratory, molecular and genetic assays. We describe the findings of those patients and analyze the impact of the program in terms of number of referrals. RESULTS: After 41 talks and 12 media appearances 151 patients were referred for evaluation. Fifteen (9.9%) were diagnosed with PID: five (33%) had antibody deficiencies, seven (47%) Well-defined syndromes, two (13%) Severe combined Immunodeficiency (SCID) and one case (7%) of an innate immune deficiency. All of the 15 PID patients had been referred by physicians, as opposed to the public. We estimated a "number needed to teach" of 75 physicians to get one PID patient referral. CONCLUSION: Educational programs are a fundamental part of the global efforts to increase PID diagnosis and care. To be successful, such programs should include public relations, reach for first-contact physicians, and aim to develop an efficient referral network with molecular diagnostic capability. Enhancing medical knowledge on PID is a successful strategy to improve early diagnosis and treatment.

Complex flow dynamics around 3D microbot prototypes.

A new experimental setup for the study of the complex flow dynamics around 3D microbot prototypes in a straight microchannel has been developed and assessed. The ultimate aim of this work is focused on the analysis of the morphology of different microbot prototypes to get a better insight into their efficiency when they swim through the main conduits of the human circulatory system. The setup consists of a fused silica straight microchannel with a 3D microbot prototype fastened in the center of the channel cross-section by an extremely thin support. Four different prototypes were considered: a cube, a sphere and two ellipsoids with aspect ratios of 1 : 2 and 1 : 4, respectively. Flow visualization and micro-particle image velocimetry (µPIV) measurements were performed using Newtonian and viscoelastic blood analogue fluids. An efficiency parameter, ℑ, to discriminate the prototypes in terms of flow disturbance has been proposed.

Gastric adenocarcinoma in the context of X-linked agammaglobulinemia: case report and review of the literature.

The hallmarks of X-linked Agammaglobulinemia (XLA) are panhypogammaglobulinemia, absent B-cells, and recurrent sinopulmonary and gastrointestinal infections starting at an early age, as well as other infections like cellulitis, meningitis, arthritis and sepsis. A number of non-infectious complications have been reported in these patients, including autoimmune diseases and malignancy, especially lymphomas. Here, we report the case of a 30-year old man who developed gastric adenocarcinoma in the context of XLA. Previous reports of, and hypotheses addressing the development of cancer in patients with XLA, are also summarized. Solid cancer in XLA affects mainly the gastrointestinal tract and seems to be related to chronic infection. A natural evolution can be traced back from gastric adenocarcinoma to megaloblastic anemia due to achlorhydria in the context of chronic infection; periodic endoscopy thus seems justified to detect and treat carcinoma in early stages.

Predicting the Adhesive Layer Thickness in Hybrid Joints Involving Pre-Tensioned Bolts.

While most academic studies focus on the properties of cured joints, this research addresses the manufacturing process of hybrid joints in their uncured state. Hybrid joints that combine adhesive bonding with pre-tensioned bolts exhibit superior mechanical performance compared to exclusively bonded or bolted joints. However, the adhesive flow during manufacturing in hybrid joints often results in a nonuniform adhesive thickness, where obtaining an exact thickness is crucial for accurate load capacity predictions. This paper presents experiments involving three different adhesives, providing precise measurements of the adhesive layer thickness distribution, which served as a reference when evaluating and validating the subsequent numerical predictions. The numerical predictions were performed using computational fluid dynamics (CFD) to model the flow behavior of the adhesives during the bonding process and their interactions with the metal substrates. The CFD predictions of the adhesive layer thickness showed good agreement with the experimental data, with the relative differences between the average experimental and numerical thickness values ranging from 4.07% to 27.1%. The results were most accurate for the adhesive with sand particles, whose particles remained intact, ensuring that the adhesive's rheology remained unchanged. The results highlight the importance of the rheological behavior of the adhesive in the final distribution of the adhesive layer thickness, thereby expanding the understanding of these joints.

IL-12Rß1 deficiency: mutation update and description of the IL12RB1 variation database.

IL-12Rß1 deficiency is an autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by otherwise poorly pathogenic mycobacteria and salmonella. IL-12Rß1 is a receptor chain of both the IL-12 and the IL-23 receptor and deficiency of IL-12Rß1 thus abolishes both IL-12 and IL-23 signaling. IL-12Rß1 deficiency is caused by bi-allelic mutations in the IL12RB1 gene. Mutations resulting in premature stop codons, such as nonsense, frame shift, and splice site mutations, represent the majority of IL-12Rß1 deficiency causing mutations (66%; 46/70). Also every other morbid mutation completely inactivates the IL-12Rß1 protein. In addition to disease-causing mutations, rare and common variations with unknown functional effect have been reported in IL12RB1. All these variants have been deposited in the online IL12RB1 variation database (www.LOVD.nl/IL12RB1). In this article, we review the function of IL-12Rß1 and molecular genetics of human IL12RB1.

Increased pro-inflammatory cytokine production after lipopolysaccharide stimulation in patients with X-linked agammaglobulinemia.

PURPOSE: To evaluate the lipopolysaccharide (LPS)-induced pro-inflammatory cytokine response by peripheral blood mononuclear cells (PBMCs) from XLA patients. METHODS: Thirteen patients with XLA were included in the study. LPS-induced TNF-α, IL-1ß, IL-6, and IL-10 production was determined in PBMCs from patients and matched healthy controls by ELISA. Cytokine production was correlated with the severity of mutation, affected domain and clinical characteristics. RESULTS: In response to LPS, PBMCs from XLA patients produced significantly higher amounts of pro-inflammatory cytokines and IL-10 compared to controls, and this production was influenced neither by the severity of the mutation nor the affected domain. PBMCs from patients with a history of more hospital admissions before their diagnosis produced higher levels of TNF-α. PBMCs from patients with lower serum IgA levels showed a higher production of TNF-α and IL-1ß. Less severe (punctual) mutations in the Btk gene were associated with higher serum IgG levels at diagnosis. CONCLUSIONS: Our results demonstrate a predominantly inflammatory response in XLA patients after LPS stimulation and suggest a deregulation of TLR signaling in the absence of Btk. This response may be influenced by environmental factors.

Consequences of two naturally occurring missense mutations in the structure and function of Bruton agammaglobulinemia tyrosine kinase.

Bruton agammaglobulinemia tyrosine kinase (BTK) is a key protein in the B-cell receptor (BCR) signaling pathway and plays an essential role in the differentiation of B lymphocytes. X-linked agammaglobulinemia (XLA) is a primary humoral immunodeficiency caused by mutations in the gene encoding BTK. Previously, we identified two novel variations, L111P and E605G, in BTK; these are localized within the pleckstrin homology and Src homology 1 domains, respectively. In the present study, we evaluated the potential effects of these variations on the structural conformation and the function of BTK. Using in silico methods, we found that the L111P and E650G variations are not located directly in protein-protein interfaces but close to them. They distorted the native structural conformation of the BTK protein, affecting not only its geometry and stability but also its ability for protein recognition and in consequence its functionality. To confirm the results of the in silico assays, WT BTK, L111P, and E650G variants were expressed in the BTK-deficient DT40 cell line. The mutant proteins exhibited an absence of catalytic activity, aberrant redistribution after BCR-crosslinking, and deficient intracellular calcium mobilization. This work demonstrates that L111 and E605 residues are fundamental for the activation and function of BTK.

Improved HUMARA for the Detection of X-Linked Agammaglobulinemia Carriers.

Background: Fragment analysis of exon 1 of the human androgen receptor, known as HUMARA, is a polymerase chain reaction (PCR)-based method for detecting X-linked agammaglobulinemia (XLA) carriers. This method takes advantage of X-chromosome inactivation (XCI) in female cells. XLA is caused by mutations in the Bruton tyrosine kinase (BTK) gene, located in Xq22.1. In this study, XCI is nonrandom or skewed in B-cells. B-cells with an active X-chromosome carrying a BTK mutation do not mature. Peripheral B-cells in XLA carriers inactivate the mutated X-chromosome. Methods: HUMARA was performed using DNA from purified B-cells and total leukocytes. DNA was digested using methylation-sensitive HhaI. The PCR of the HUMARA polymorphic marker was performed with the HhaI digested samples. The lengths of the PCR products were determined. If a suspected carrier showed skewed XCI in their B-cells, the marker length that corresponded with the length determined in the index patient indicated their carrier status. Results: HUMARA was conducted on purified B-cells; this allowed easier identification of the mutated or inactive allele, as the active allele was enzymatically digested. Analysis of 30 possible carriers using modified HUMARA corroborated that the carrier status in all samples that were heterozygous for the marker using XCI calculation for leukocytes showed a Gaussian distribution, while the carrier B-cell DNA showed a skewed XCI. Conclusion: Carrier status was successfully determined for most of the analyzed samples. B-cell enrichment resulted in precise carrier determination data, reduced the sample size, and facilitated inactive and active allele identification.

Hemodynamics Challenges for the Navigation of Medical Microbots for the Treatment of CVDs.

Microbots have been considered powerful tools in minimally invasive medicine. In the last few years, the topic has been highly studied by researchers across the globe to further develop the capabilities of microbots in medicine. One of many applications of these devices is performing surgical procedures inside the human circulatory system. It is expected that these microdevices traveling along the microvascular system can remove clots, deliver drugs, or even look for specific cells or regions to diagnose and treat. Although many studies have been published about this subject, the experimental influence of microbot morphology in hemodynamics of specific sites of the human circulatory system is yet to be explored. There are numerical studies already considering some of human physiological conditions, however, experimental validation is vital and demands further investigations. The roles of specific hemodynamic variables, the non-Newtonian behavior of blood and its particulate nature at small scales, the flow disturbances caused by the heart cycle, and the anatomy of certain arteries (i.e., bifurcations and tortuosity of vessels of some regions) in the determination of the dynamic performance of microbots are of paramount importance. This paper presents a critical analysis of the state-of-the-art literature related to pulsatile blood flow around microbots.

Extensional Magnetorheology of Viscoelastic Human Blood Analogues Loaded with Magnetic Particles.

This study represents a pioneering work on the extensional magnetorheological properties of human blood analogue fluids loaded with magnetic microparticles. Dynabeads M-270 particles were dispersed in Newtonian and viscoelastic blood analogue fluids at 5% wt. Capillary breakup experiments were performed, with and without the influence of an external magnetic field aligned with the flow direction. The presence of the particles increased the viscosity of the fluid, and that increment was larger when embedded within a polymeric matrix. The application of an external magnetic field led to an even larger increment of the viscosity of the working fluids, as the formation of small aggregates induced an increment in the effective volume fraction of particles. Regarding the liquid bridge stability, the Newtonian blood analogue fluid remained as a Newtonian liquid exhibiting a pinch-off at the breakup time in any circumstance. However, in the case of the viscoelastic blood analogue fluid, the presence of the particles and the simultaneous application of the magnetic field enhanced the formation of the beads-on-a-string structure, as the Ohnesorge number remained basically unaltered, whereas the time of the experiment increased due to its larger viscosity, which resulted in a decrease in the Deborah Number. This result was confirmed with fluids containing larger concentrations of xanthan gum.

Rheological characterization of polymeric solutions used in spray drying process.

The present works contributes with a rheological characterization of the most commonly used polymers and solvents to formulate amorphous solid dispersions by means of spray drying process: copovidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS) and a copolymer of methacrylic acid and methyl methacrylate (1:1 ratio and commercially known as Eudragit L100). The organic-based solutions are characterized in terms of surface tension, shear viscosity and relaxation time. HPMC and HPMCAS solutions exhibit shear thinning behaviour, i.e. decrease of shear viscosity with the increasing shear rate imposed, while the samples with Eudragit L100 can be considered Boger fluids, showing a constant viscosity but maintaining its viscoelastic character. Under uniaxial extensional flow, these polymers solutions exhibit a viscoelastic behavior with an increasing relaxation time with an increasing concentration, and in some cases showed a 'beads-on-string' effect. In contrast, copovidone showed a Newtonian fluid behavior, with the absence of elasticity. The fundamental understanding and characterization of the present work may be further applied to atomization modelling and support and expedite spray drying process development.

Critical overlap concentration and intrinsic viscosity data of xanthan gum aqueous solutions in dimethyl sulfoxide.

This is the supplementary information of the research paper "Haemodynamics around confined microscopic cylinders" by Rodrigues et al. [1]. The critical overlap concentration of entanglement of polymer coils indicates whether a polymer solution is dilute or semidilute. Here, the reader will find the determination of c * for xanthan gum aqueous solutions in 52 wt.% of dimethyl sulfoxide, often used as non-particulate blood analogues. From the shear flow curves of a dilution series of the polymer the zero-shear viscosities η 0 were obtained, allowing us to estimate the intrinsic viscosity [ η ] based on the xanthan gum concentration of the fluids. Two methodologies for doing so are described: using information from multi-concentration measurements and from a single polymer solution (rough estimate). With the intrinsic viscosity the determination of c * is straightforward.

Direct Ink Writing Glass: A Preliminary Step for Optical Application.

In this paper, we present a preliminary study and conceptual idea concerning 3D printing water-sensitive glass, using a borosilicate glass with high alkali and alkaline oxide contents as an example in direct ink writing. The investigated material was prepared in the form of a glass frit, which was further ground in order to obtain a fine powder of desired particle size distribution. In a following step, inks were prepared by mixing the fine glass powder with Pluoronic F-127 hydrogel. The acquired pastes were rheologically characterized and printed using a Robocasting device. Differential scanning calorimetry (DSC) experiments were performed for base materials and the obtained green bodies. After sintering, scanning electron microscope (SEM) and X-ray diffraction (XRD) analyses were carried out in order to examine microstructure and the eventual presence of crystalline phase inclusions. The results confirmed that the as obtained inks exhibit stable rheological properties despite the propensity of glass to undergo hydrolysis and could be adjusted to desirable values for 3D printing. No additional phase was observed, supporting the suitability of the designed technology for the production of water sensitive glass inks. SEM micrographs of the sintered samples revealed the presence of closed porosity, which may be the main reason of light scattering.

Breakup of an electrified viscoelastic liquid bridge.

We study both numerically and experimentally the breakup of a viscoelastic liquid bridge formed between two parallel electrodes. The polymer solutions and applied voltages are those commonly used in electrospinning and near-field electrospinning. We solve the leaky-dielectric finitely extensible nonlinear elastic-Peterlin (FENE-P) model to describe the dynamical response of the liquid bridge under isothermal conditions. The results show that the surface charge screens the inner electric field perpendicular to the free surface over the entire dynamical process. The liquid bridge deformation produces a normal electric field on the outer side of the free surface that is commensurate with the axial one. The surface conduction does not significantly affect the current intensity in the time interval analyzed in the experiments. The force due to the shear electric stress becomes comparable to both the viscoelastic and surface tension forces in the last stage of the filament. However, it does not alter the elastocapillary balance in the filament. As a consequence, the extensional relaxation times measured from the filament exponential thinning approximately coincides with the stress relaxation time prescribed in the FENE-P model. The above results allow us to interpret correctly the experiments. In the experiments, we measure the filament electrical conductivity and extensional relaxation time for polyethylene oxide (PEO) dissolved in deionized water and in a mixture of water and glycerine. We compare the filament electrical conductivity with the value measured in hydrostatic conditions for the same estimated temperature. Good agreement was found for PEO dissolved in water + glycerine, which indicates that the change in the filament microscopic structure due to the presence of stretched polymeric chains does not significantly alter the ion mobility in the stretching direction. Significant deviations are found for PEO dissolved in deionized water. These deviations may be attributed to the heat transferred to the ambient, which is neglected in the calculation of the filament temperature. We measure the extensional relaxation time from the images acquired during the filament thinning. The relaxation times obtained in the first stage of the exponential thinning hardly depend on the applied voltage. Little but measurable influence of the applied voltage is found in the last phase of the filament thinning.

Understanding the role of nutrition in the brain and behavioral development of toddlers and preschool children: identifying and addressing methodological barriers.

The preschool years (i.e. 1-5 years of age) is a time of rapid and dramatic postnatal brain development (i.e. neural plasticity), and of fundamental acquisition of cognitive development (i.e. working memory, attention and inhibitory control). Also, it is a time of transition from a direct maternal mediation/selection of diet-based nutrition to food selection that is more based on self-selection and self-gratification. However, there have been fewer published studies in preschool children than in infants or school-aged children that examined the role of nutrition in brain/mental development (125 studies versus 232 and 303 studies, respectively during the last 28 years). This may arise because of age-related variability, in terms of individual differences in temperament, linguistic ability, and patterns of neural activity that may affect assessment of neural and cognitive development in pre-school children. In this review, we suggest several approaches for assessing brain function in children that can be refined. It would be desirable if the discipline developed some common elements to be included in future studies of diet and brain function, with the idea that they would complement more targeted measures based on time of exposure and understanding of data from animal models. Underlining this approach is the concept of 'window of sensitivity' during which nutrients may affect postnatal neural development: investigators and expert panels need to look specifically for region-specific changes and do so with understanding of the likely time window during which the nutrient was, or was not available.