A moral trade-off system produces intuitive judgments that are rational and coherent and strike a balance between conflicting moral values.

How does the mind make moral judgments when the only way to satisfy one moral value is to neglect another? Moral dilemmas posed a recurrent adaptive problem for ancestral hominins, whose cooperative social life created multiple responsibilities to others. For many dilemmas, striking a balance between two conflicting values (a compromise judgment) would have promoted fitness better than neglecting one value to fully satisfy the other (an extreme judgment). We propose that natural selection favored the evolution of a cognitive system designed for making trade-offs between conflicting moral values. Its nonconscious computations respond to dilemmas by constructing "rightness functions": temporary representations specific to the situation at hand. A rightness function represents, in compact form, an ordering of all the solutions that the mind can conceive of (whether feasible or not) in terms of moral rightness. An optimizing algorithm selects, among the feasible solutions, one with the highest level of rightness. The moral trade-off system hypothesis makes various novel predictions: People make compromise judgments, judgments respond to incentives, judgments respect the axioms of rational choice, and judgments respond coherently to morally relevant variables (such as willingness, fairness, and reciprocity). We successfully tested these predictions using a new trolley-like dilemma. This dilemma has two original features: It admits both extreme and compromise judgments, and it allows incentives-in this case, the human cost of saving lives-to be varied systematically. No other existing model predicts the experimental results, which contradict an influential dual-process model.

Experimental and cross-cultural evidence that parenthood and parental care motives increase social conservatism.

Differences in attitudes on social issues such as abortion, immigration and sex are hugely divisive, and understanding their origins is among the most important tasks facing human behavioural sciences. Despite the clear psychological importance of parenthood and the motivation to provide care for children, researchers have only recently begun investigating their influence on social and political attitudes. Because socially conservative values ostensibly prioritize safety, stability and family values, we hypothesized that being more invested in parental care might make socially conservative policies more appealing. Studies 1 (preregistered; n = 376) and 2 (n = 1924) find novel evidence of conditional experimental effects of a parenthood prime, such that people who engaged strongly with a childcare manipulation showed an increase in social conservatism. Studies 3 (n = 2610, novel data from 10 countries) and 4 (n = 426 444, World Values Survey data) find evidence that both parenthood and parental care motivation are associated with increased social conservatism around the globe. Further, most of the positive association globally between age and social conservatism is accounted for by parenthood. These findings support the hypothesis that parenthood and parental care motivation increase social conservatism.

Mitochondrial dysfunction in down syndrome: molecular mechanisms and therapeutic targets.

Trisomy of chromosome 21 (TS21) is the most common autosomal aneuploidy compatible with postnatal survival with a prevalence of 1 in 700 newborns. Its phenotype is highly complex with constant features, such as mental retardation, dysmorphic traits and hypotonia, and variable features including heart defects, susceptibility to Alzheimer's disease (AD), type 2 diabetes, obesity and immune disorders. Overexpression of genes on chromosome-21 (Hsa21) is responsible for the pathogenesis of Down syndrome (DS) phenotypic features either in a direct or in an indirect manner since many Hsa21 genes can affect the expression of other genes mapping to different chromosomes. Many of these genes are involved in mitochondrial function and energy conversion, and play a central role in the mitochondrial dysfunction and chronic oxidative stress, consistently observed in DS subjects.Recent studies highlight the deep interconnections between mitochondrial dysfunction and DS phenotype. In this short review we first provide a basic overview of mitochondrial phenotype in DS cells and tissues. We then discuss how specific Hsa21 genes may be involved in determining the disruption of mitochondrial DS phenotype and biogenesis. Finally we briefly focus on drugs that affect mitochondrial function and mitochondrial network suggesting possible therapeutic approaches to improve and/or prevent some aspects of the DS phenotype.

Introduction of gluten, HLA status, and the risk of celiac disease in children.

BACKGROUND: The relationship between the risk of celiac disease and both the age at which gluten is introduced to a child's diet and a child's early dietary pattern is unclear. METHODS: We randomly assigned 832 newborns who had a first-degree relative with celiac disease to the introduction of dietary gluten at 6 months (group A) or 12 months (group B). The HLA genotype was determined at 15 months of age, and serologic screening for celiac disease was evaluated at 15, 24, and 36 months and at 5, 8, and 10 years. Patients with positive serologic findings underwent intestinal biopsies. The primary outcome was the prevalence of celiac disease autoimmunity and of overt celiac disease among the children at 5 years of age. RESULTS: Of the 707 participants who remained in the trial at 36 months, 553 had a standard-risk or high-risk HLA genotype and completed the study. At 2 years of age, significantly higher proportions of children in group A than in group B had celiac disease autoimmunity (16% vs. 7%, P=0.002) and overt celiac disease (12% vs. 5%, P=0.01). At 5 years of age, the between-group differences were no longer significant for autoimmunity (21% in group A and 20% in group B, P=0.59) or overt disease (16% and 16%, P=0.78 by the log-rank test). At 10 years, the risk of celiac disease autoimmunity was far higher among children with high-risk HLA than among those with standard-risk HLA (38% vs. 19%, P=0.001), as was the risk of overt celiac disease (26% vs. 16%, P=0.05). Other variables, including breast-feeding, were not associated with the development of celiac disease. CONCLUSIONS: Neither the delayed introduction of gluten nor breast-feeding modified the risk of celiac disease among at-risk infants, although the later introduction of gluten was associated with a delayed onset of disease. A high-risk HLA genotype was an important predictor of disease. (Funded by the Fondazione Celiachia of the Italian Society for Celiac Disease; CELIPREV ClinicalTrials.gov number, NCT00639444.).

Are ESPGHAN "biopsy-sparing" guidelines for celiac disease also suitable for asymptomatic patients?

OBJECTIVES: In 2012, European Society of Pediatric Gastroenterology, Hepatology, and Nutrition published novel guidelines on celiac disease (CD) diagnosis. Symptomatic children with serum anti-transglutaminase (anti-tTG) antibody levels ≥10 times upper limit of normal (ULN) could avoid duodenal biopsies after positive HLA test and serum anti-endomysial antibodies (EMAs). So far, both asymptomatic and symptomatic patients with anti-tTG titer <10 times ULN should undergo upper endoscopy with duodenal biopsies to confirm diagnosis. The aim of this study was to assess the accuracy of serological tests to diagnose CD in asymptomatic patients. METHODS: We retrospectively reviewed data of 286 patients (age range: 10 months to 17 years) with CD diagnosis based on elevated titer of anti-tTG, EMA positivity, and histology. All patients were distinguished between symptomatic and asymptomatic; histological lesions were graded according to the Marsh-Oberhuber (MO) criteria. Fisher exact test was applied to analyze both groups in terms of diagnostic reliability of serological markers. RESULTS: A total of 196 patients (68.53%) had anti-tTG titers ≥10 times ULN. Among them, a group of 156 patients (79.59%) also had symptoms suggestive of CD ("high-titer" symptomatic); of these, 142 patients (91.02%) showed severe lesion degree (3a, 3b, 3c MO). Conversely, 40 out of 196 patients (20.40%) were asymptomatic ("high-titer" asymptomatic) and 37 patients (92.5%) of them showed severe lesion degree (3a, 3b, 3c MO). No difference in histological damage was found between "high-titer" symptomatic and "high-titer" asymptomatic children (Fisher exact test, P=1.000). CONCLUSIONS: If confirmed in large multicenter prospective studies, the "biopsy-sparing" protocol seems to be applicable to both symptomatic and asymptomatic patients with anti-tTG titer ≥10 times ULN, positive EMA, and HLA-DQ2/DQ8.

Mapping histologic patchiness of celiac disease by push enteroscopy.

BACKGROUND: Despite great improvements in serologic testing, duodenal biopsies are still required to diagnose the majority of celiac disease (CD) cases. Nevertheless, the histologic pattern of CD is often patchy, leading to the risk of missing the diagnosis. OBJECTIVE: To evaluate the patchiness of the CD histologic lesions along the small bowel (SB), push enteroscopy has been performed instead of conventional upper GI endoscopy. DESIGN: Prospective, single-center study. SETTING: Tertiary-care referral center. PATIENTS: A total of 41 pediatric patients with suspected CD. INTERVENTION: Prospective evaluation of bulb, duodenal, and jejunal biopsy specimens in the diagnosis of CD. MAIN OUTCOME MEASUREMENTS: Pattern of lesion distribution along the SB (from bulb up to 60 cm beyond the ligament of Treitz) and yield as well accuracy of pediatric CD diagnosis by using push enteroscopy. RESULTS: There was a homogeneous pattern of histologic damage in 17 patients (41.5%), whereas 24 patients (58.5%) had a lesion pattern of patchiness. The second and fourth duodenal regions were involved in 38 children (92.7%) and 37 children (90.2%), respectively; the bulb was involved in 37 patients (90.2%); both distal and proximal jejunal samples showed histologic lesions in 38 children (92.7%). In 1 patient, without lesions in the bulb and duodenum, CD was diagnosed according to proximal and distal jejunal biopsies only (3B and C, respectively). A significant correlation was found between the degree of villous atrophy and the serum anti-transglutaminase titer. LIMITATIONS: Small sample size; academic tertiary-care setting. CONCLUSION: CD histologic lesions often have a discontinuous distribution along the SB, occasionally with an exclusive jejunal involvement. A high degree of villous atrophy correlates with a high anti-transglutaminase titer. When the new ESPGHAN "biopsy-sparing" criteria are not applicable, in case of potential CD, push enteroscopy might be a valuable second-step tool to re-evaluate and identify false "potential" CD hiding exclusive jejunal lesions.

Autoimmune enteropathy in a 13-year-old celiac girl successfully treated with infliximab.

Autoimmune enteropathy (AIE) is a rare cause of small bowel villous atrophy, characterized by malabsorption, unresponsiveness to dietary restriction, circulating autoantibodies to enterocytes, and an overall predisposition to autoimmunity. Albeit mainly regarded as a disease of early childhood, several adult-onset AIE cases have been identified. This report describes for the first time the life-threatening clinical presentation and the management of overlapping AIE in a compliant-to-diet young celiac girl. A 13-year-old celiac girl was admitted because of vomiting, weight loss, diarrhea, hypoproteinemia, and neurological disturbances such as head tremors, vertical nystagmus, and lower limb hyperesthesia. Before this, she had always been compliant on a strict gluten-free diet and her medical history was unremarkable. The diagnosis of AIE was established on histologic findings and on the presence of antienterocyte antibodies. She was initially treated with high-dose Methylprednisolone and Azathioprine. However, only Infliximab proved itself as a highly effective tool for achieving clinical remission and restoring small bowel villous architecture.

Lack of clinical predictors for low mineral density in children with celiac disease.

OBJECTIVES: Metabolic bone disease remains a significant and common complication of celiac disease (CD). Several studies have demonstrated low bone mineral density (BMD) at the time of CD diagnosis in both children and adults. Low BMD in children and adolescents is defined as an areal BMD <2 SD below the age-adjusted mean value (z score <-2 SD). The aim of the study was to evaluate the BMD in a pediatric population with CD at diagnosis and to correlate z score value, anti-tissue transglutaminase type 2 antibody (anti-tTG2) titer, symptoms, and Marsh-Oberhuber (MO) grading. METHODS: We enrolled 99 patients with celiac disease (male 35, female 64) ages 4 to 15 years at the diagnosis. All of the patients had positive test results for anti-tTG2 antibodies and histological lesions graded according to MO classification, and underwent lumbar dual-energy x-ray absorptiometry. BMD was estimated by z score. RESULTS: Low BMD (z score ≤-2 SD) was found in 13 (13.13%) patients; 22 (22.22%) patients with CD showed -2 < z score ≤ -1; -1 < z score < 0 was found in 41 (41.41%) patients. z score ≥ 0 was detected only in 23 (23.23%) patients with CD. Mean BMD value in patients with CD is z score -0.68. No correlations were found between z score value and anti-tTG2 titer (Spearman ρ 0.13), between z score value and MO degree (Spearman ρ -0.17), and between z score and symptoms (Spearman ρ-0.10). CONCLUSIONS: BMD of patients with CD at diagnosis does not seem to correlate with MO degree, anti-tTG2 titer, and symptoms. At the moment, we do not have clinical predictors for low mineral density in children with CD.

Chronic granulomatous disease mimicking early-onset Crohn's disease with cutaneous manifestations.

BACKGROUND: Chronic granulomatous disease is a rare inherited disorder of the innate immune system. In patients with a clinical history of recurrent or persistent infections, especially infections caused by uncommon species, chronic granulomatous disease should be considered. CASE PRESENTATION: We report the case of a 5-year-old boy with a presumptive diagnosis of Crohn's disease with extraintestinal manifestations. Chronic granulomatous disease was suspected in this case after Serratia marcescens was isolated from a skin ulcer culture. Granulomas were confirmed on histology and chronic granulomatous disease was diagnosed. CONCLUSION: This case emphasizes the importance of high clinical suspicion of an alternative diagnosis of immune deficiency in patients with presumed inflammatory bowel disease and opportunistic infections, especially when disease occurs in early life.

What's love got to do with jealousy?

Romantic love and jealousy seem antagonistic, but the expression of both emotions have evolutionary functions that can go in the same direction of maintaining a relationship. Considering natural selection designed adaptations to solve the problems surrounding reproduction, then love and romantic jealousy are emotions aimed at staying cooperative for a period of time, where love solves the adaptive challenges of promoting pair bonding, cooperation, and protecting offspring; and jealousy is triggered by a threat or the loss of a valuable cooperative relationship, either on behalf of descendants in need of resources, or a close romantic bond. Consequently, understanding love and romantic jealousy points in the same adaptive functional domain of protecting a romantic pair bond. Specifically, love can be comprehended in two different ways and in regard to jealousy. First, conceiving love as the attachment to significant others one develops throughout lifetime, and secondly, it contemplates affective dependence. Results from a sample of single and committed individuals (n = 332) show the predicted positive correlation between attachment and jealousy as stable traits, consistent with previous literature. In addition, there is a non-significant and low correlation, respectively, between attachment and love as a measure of dependence. Furthermore, in the single participants group, jealousy was associated with love. The discussion emphasizes the need for expanding a functional account of love and jealousy as complementary emotions of our human affective endowment. Finally, it would be informative to study attachment as a relational trait and love as a specific affection for a romantic partner that could be manipulated to elucidate the functional design of jealousy.

Efficacy of molecular and nano-therapies on brain tumor models in microfluidic devices.

The three-dimensional (3D) organization of cells affects their mobility, proliferation, and overall response to treatment. Spheroids, organoids, and microfluidic chips are used in cancer research to reproduce in vitro the complex and dynamic malignant microenvironment. Herein, single- and double-channel microfluidic devices are used to mimic the spatial organization of brain tumors and investigate the therapeutic efficacy of molecular and nano anti-cancer agents. Human glioblastoma multiforme (U87-MG) cells were cultured into a Matrigel matrix embedded within the microfluidic devices and exposed to different doses of free docetaxel (DTXL), docetaxel-loaded spherical polymeric nanoparticles (DTXL-SPN), and the aromatic N-glucoside N-(fluorenylmethoxycarbonyl)-glucosamine-6-phosphate (Fmoc-Glc6P). We observed that in the single-channel microfluidic device, brain tumor cells are more susceptible to DTXL treatment as compared to conventional cell monolayers (50-fold lower IC50 values). In the double-channel device, the cytotoxicity of free DTXL and DTXL-SPN is comparable, but significantly lowered as compared to the single-channel configuration. Finally, the administration of 500 µM Fmoc-Glc6P in the double-channel microfluidic device shows a 50 % U87-MG cell survival after only 24 h, and no deleterious effect on human astrocytes over 72 h. Concluding, the proposed microfluidic chips can be used to reproduce the 3D complex spatial arrangement of solid tumors and to assess the anti-cancer efficacy of therapeutic compounds administrated in situ or systemically.

Greater traditionalism predicts COVID-19 precautionary behaviors across 27 societies.

People vary both in their embrace of their society's traditions, and in their perception of hazards as salient and necessitating a response. Over evolutionary time, traditions have offered avenues for addressing hazards, plausibly resulting in linkages between orientations toward tradition and orientations toward danger. Emerging research documents connections between traditionalism and threat responsivity, including pathogen-avoidance motivations. Additionally, because hazard-mitigating behaviors can conflict with competing priorities, associations between traditionalism and pathogen avoidance may hinge on contextually contingent tradeoffs. The COVID-19 pandemic provides a real-world test of the posited relationship between traditionalism and hazard avoidance. Across 27 societies (N = 7844), we find that, in a majority of countries, individuals' endorsement of tradition positively correlates with their adherence to costly COVID-19-avoidance behaviors; accounting for some of the conflicts that arise between public health precautions and other objectives further strengthens this evidence that traditionalism is associated with greater attention to hazards.

Video: argon plasma coagulator in a 2-month-old child with tracheoesophageal fistula.

A 2 month-old boy was admitted to the authors' hospital because of regurgitation and persistent cough during breastfeeding. A chest X-ray examination and a barium esophagogram disclosed small amounts of barium passing in the trachea, suggesting a tracheoesophageal fistula (TEF). Bronchoscopy combined with upper gastrointestinal (GI) endoscopy performed with the patient under general anesthesia confirmed the fistula. The TEF was treated by injection of 1 ml Glubran 2 from the esophageal side. A nasogastric tube was placed for feedings, and 7 days later, a barium esophagogram showed a reduction of caliber but not complete closure of the TEF. Unsuccessful fistula obliteration with Glubran was attributed to technical difficulties in catheterization of the fistula orifice, mainly resulting from its close proximity to the upper esophageal sphincter and to its small caliber. Therefore, an argon plasma coagulator (APC) probe with a circumferentially oriented nozzle was used from the esophageal side as an alternative technique to fulgurate the residual fistula orifice (see video). A nasogastric tube was placed for feedings. Oral feeding was started 7 days later when a barium esophagogram confirmed complete fistula closure. At the 2-year follow-up visit, the boy was asymptomatic, and the barium esophagogram was negative. This report describes a case in which esophagoscopy gave a clear view of the fistula due to its direction from esophagus to trachea. Complete fistula obliteration was not obtained with Glubran. However, APC was successfully used to close the residual fistula orifice. The authors suggest that APC can be used as an alternative endoscopic technique to repair TEF when other techniques fail.

A permeable on-chip microvasculature for assessing the transport of macromolecules and polymeric nanoconstructs.

HYPOTHESIS: The selective permeation of molecules and nanomedicines across the diseased vasculature dictates the success of a therapeutic intervention. Yet, in vitro assays cannot recapitulate relevant differences between the physiological and pathological microvasculature. Here, a double-channel microfluidic device was engineered to comprise vascular and extravascular compartments connected through a micropillar membrane with tunable permeability. EXPERIMENTS: The vascular compartment was coated by endothelial cells to achieve permeability values ranging from ~0.1 µm/sec, following a cyclic adenosine monophosphate (cAMP) pre-treatment (25 µg/mL), up to ~2 µm/sec, upon exposure to Mannitol, Lexiscan or in the absence of cells. Fluorescent microscopy was used to monitor the vascular behavior of 250 kDa Dextran molecules, 200 nm polystyrene nanoparticles (PB), and 1,000 × 400 nm discoidal polymeric nanoconstructs (DPN), under different permeability and flow conditions. FINDINGS: In the proposed on-chip microvasculature, it was confirmed that permeation enhancers could favor the perivascular accumulation of ~200 nm, in a dose and time dependent fashion, while have no effect on larger particles. Moreover, the microfluidic device was used to interrogate the role of particle deformability in vascular dynamics. In the presence of a continuous endothelium, soft DPN attached to the vasculature more avidly at sub-physiological flows (100 µm/sec) than rigid DPN, whose deposition was larger at higher flow rates (1 mm/sec). The proposed double-channel microfluidic device can be efficiently used to systematically analyze the vascular behavior of drug delivery systems to enhance their tissue specific accumulation.

A distinctive 'microbial signature' in celiac pediatric patients.

BACKGROUND: Celiac Disease (CD) is an autoimmune disorder of the small intestine in which dietary gluten ingestion leads to a chronic enteropathy. Recently, scientific evidence suggested a potential role of gut microbiota in CD. To have a snapshot of dominant duodenal microbiota we analyzed the mucosa-associated microbiota of 20 children with CD, before and after a gluten-free diet (GFD) regimen, and of 10 controls. Total DNA was extracted from duodenal biopsies and amplification products of 16S ribosomal DNA were compared by temporal temperature gradient gel electrophoresis (TTGE). TTGE profiles were analyzed by statistical multivariate analysis. RESULTS: The average number of bands in TTGE profiles was significantly higher (P < 0.0001) in active (n.b. 16.7 +/- 0.7) and inactive states (n.b. 13.2 +/- 0.8) than in controls (n.b. 3.7 +/- 1.3). Mean interindividual similarity index was 54.9% +/- 14.9% for active disease, 55.6% +/- 15.7% for remission state and 21.8% +/- 30.16% for controls. Similarity index between celiac children before and after GFD treatment was 63.9% +/- 15.8%. Differences in microbiota biodiversity were among active and remission state (P = 0.000224) and amid active CD and controls (P < 0.001). Bacteroides vulgatus and Escherichia coli were detected more often in CD patients than in controls (P < 0.0001). CONCLUSIONS: Overall, the results highlighted a peculiar microbial TTGE profile and a significant higher biodiversity in CD pediatric patients' duodenal mucosa. The possible pathophysiological role of these microbial differences needs further characterization.

Gluten-free sourdough wheat baked goods appear safe for young celiac patients: a pilot study.

OBJECTIVES: This study was aimed at showing the safety, for young patients with celiac disease (CD), of sweet baked goods made of wheat flour, which was rendered gluten-free during sourdough fermentation. METHODS AND RESULTS: As shown by R5 antibody-based sandwich and competitive enzyme-linked immunosorbent assay (ELISA), selected lactobacilli and fungal proteases, routinely used in bakeries, degraded gluten to <10 ppm during sourdough fermentation. The resulting flour was mainly a mixture of water-/salt-soluble low-size peptides and free amino acids. Gliadin and glutenin fractions extracted from the pepsin-trypsin (PT) digest of the fermented wheat flour induced the expression of interferon (IFN)-γ at the level comparable with the negative control. After fermentation, the wheat flour was spray dried and used for making sweet baked goods. Eight patients with CD in remission were enrolled for the clinical challenge, and they daily consumed 200 g of sweet baked goods equivalent to 10 g of native gluten. Hematology, serology (total serum IgA, IgG and IgA antigluten, endomysial and tissue transglutaminase IgA antibodies), and intestinal permeability analyses were carried out over time. One patient interrupted the trial after 15 days and another after 30 days only due to difficulties in the compliance of the daily consumption. All of the other patients showed normal values of hematology, serology, and intestinal permeability during 60 days of challenge. CONCLUSIONS: This study showed that a wheat flour-fermented product, having gluten completely degraded, is not toxic for patients with CD. Nevertheless, these foods should not be recommended for patients with celiac disease until a formal trial has been done.

Optimizing the Pharmacological Properties of Discoidal Polymeric Nanoconstructs Against Triple-Negative Breast Cancer Cells.

Fine-tuning loading and release of therapeutic and imaging agents associated with polymeric matrices is a fundamental step in the preclinical development of novel nanomedicines. Here, 1,000 × 400 nm Discoidal Polymeric Nanoconstructs (DPNs) were realized via a top-down, template-based fabrication approach, mixing together poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol)-diacrylate (PEG-DA) chains in a single polymer paste. Two different loading strategies were tested, namely the "direct loading" and the "absorption loading." In the first case, the agent was directly mixed with the polymeric paste to realize DPNs whereas, in the second case, DPNs were first lyophilized and then rehydrated upon exposure to a concentrated aqueous solution of the agent. Under these two loading conditions, the encapsulation efficiencies and release profiles of different agents were systematically assessed. Specifically, six agents were realized by conjugating lipid chains (DSPE) or polymeric chains (PEG) to the near-infrared imaging molecule Cy5 (DSPE-Cy5 A and DSPE-Cy5 B); the chemotherapeutic molecules methotrexate (DSPE-MTX and PEG-MTX) and doxorubicin (LA-DOX and DSPE-DOX). Moderately hydrophobic compounds with low molecular weights (MW) returned encapsulation efficiencies as high as 80% for the absorption loading. In general, direct loading was associated with encapsulation efficiencies lower than 1%. The agent hydrophobicity and MW were shown to be critical also in tailoring the release profiles from DPNs. On triple-negative breast cancer cells (MDA-MB-231), absorption loaded DOX-DPNs showed cytotoxic activities comparable to free DOX but slightly delayed in time. Preliminary in vivo studies demonstrated the high stability of Cy5-DPNs. Collectively, these results demonstrate that the pharmacological properties of DPNs can be finely optimized by changing the loading strategies (direct vs. absorption) and compound attributes (hydrophobicity and molecular weight).

Efficacy of adalimumab in moderate-to-severe pediatric Crohn's disease.

OBJECTIVES: The use of tumor necrosis factor-alpha (TNF-alpha) antagonists has changed the therapeutic strategy for Crohn's disease (CD). Adalimumab (ADA), a fully human anti-TNF-alpha monoclonal antibody, is an effective therapy for patients with CD, both naive patients and those intolerant or refractory to Infliximab (IFX), a chimeric anti-TNF-alpha agent. However, the use of ADA is rarely reported in pediatric CD. We performed an open prospective evaluation of short- and long-term efficacy and safety of ADA in children with moderate-to-severe CD. METHODS: A total of 23 pediatric CD patients (9 naive and 14 intolerant or unresponsive to IFX) received ADA subcutaneously as a loading schedule at weeks 0 and 2, and at every other week (eow) during a 48-week maintenance phase. Loading and maintenance doses were 160/80 and 80 mg eow in 13 cases, 120/80 and 80 mg eow in 2, and 80/40 and 40 mg eow in 8 cases. The primary efficacy outcomes were clinical remission and response at different scheduled visits along the maintenance phase. At baseline, 13 patients also received immunomodulators (IMs). RESULTS: At weeks 2, 4, 12, 24, and 48, remission rates were 36.3, 60.8, 30.5, 50, and 65.2%, respectively, whereas response rates were 87, 88, 70, 86, and 91%, respectively. Four patients at week 24 and 2 at week 48 received IMs; the mean daily corticosteroid dose, disease activity index, C-reactive protein level, and erythrocyte sedimentation rate decreased significantly throughout the trial. No serious adverse events were recorded. CONCLUSIONS: ADA can be an effective and safe biological agent for inducing and maintaining remission in children with moderate-to-severe CD, even in those with previous IFX therapy.

HLA-DQ and risk gradient for celiac disease.

Celiac disease (CD) is a rare example of multifactorial disorder in which a genetic test is of great clinical relevance, as the disease rarely develops in the absence of specific HLA alleles. We typed DR-DQ genes in 437 Italian children with celiac disease, 834 first-degree relatives, and 551 controls. Of patients, 91% carried DQ2 and/or DQ8 heterodimers, 6% only had beta2 chain, 2% was alpha5 positive, and four were DQ2/DQ8/beta2/alpha5 negative. Only the presence of alpha5 resulted negatively associated to disease (p = 2 x 10(-4)), whereas we confirmed the effect of the beta half of DQ2 dimer on CD predisposition (p = 4 x 10(-12)). Considering 1:100 disease prevalence, we obtained a risk gradient ranging from 1:7 for DQ2 and DQ8 individuals down to 1:2518 for subjects lacking all predisposing factors. The DQB1*02 and DQB1*0302 concurrence (p = 9 x 10(-4)), besides the DQB1*02/*02 homozygosity, had an additional role in disease genetic determination. The CD prevalence rose to 17.6% in sisters, 10.8% in brothers, and 3.4% in parents. In the three groups, the subjects carrying high-risk HLA molecules were 57%, 71%, and 58%; among them, 29%, 15%, and 6% respectively had CD. Those siblings and parents with no susceptible factors were not affected. These findings indicate the impact of the HLA test for CD in clinical practice.