Causal Pathways from Enteropathogens to Environmental Enteropathy: Findings from the MAL-ED Birth Cohort Study

Background Environmental enteropathy (EE), the adverse impact of frequent and numerous enteric infections on the gut resulting in a state of persistent immune activation and altered permeability, has been proposed as a key determinant of growth failure in children in low- and middle-income populations. A theory-driven systems model to critically evaluate pathways through which enteropathogens, gut permeability, and intestinal and systemic inflammation affect child growth was conducted within the framework of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) birth cohort study that included children from eight countries. Methods Non-diarrheal stool samples (N = 22,846) from 1253 children from multiple sites were evaluated for a panel of 40 enteropathogens and fecal concentrations of myeloperoxidase, alpha-1-antitrypsin, and neopterin. Among these same children, urinary lactulose:mannitol (L:M) (N = 6363) and plasma alpha-1-acid glycoprotein (AGP) (N = 2797) were also measured. The temporal sampling design was used to create a directed acyclic graph of proposed mechanistic pathways between enteropathogen detection in non-diarrheal stools, biomarkers of intestinal permeability and inflammation, systemic inflammation and change in length- and weight- for age in children 0–2 years of age. Findings Children in these populations had frequent enteric infections and high levels of both intestinal and systemic inflammation. Higher burdens of enteropathogens, especially those categorized as being enteroinvasive or causing mucosal disruption, were associated with elevated biomarker concentrations of gut and systemic inflammation and, via these associations, indirectly associated with both reduced linear and ponderal growth. Evidence for the association with reduced linear growth was stronger for systemic inflammation than for gut inflammation; the opposite was true of reduced ponderal growth. Although Giardia was associated with reduced growth, the association was not mediated by any of the biomarkers evaluated. Interpretation The large quantity of empirical evidence contributing to this analysis supports the conceptual model of EE. The effects of EE on growth faltering in young children were small, but multiple mechanistic pathways underlying the attribution of growth failure to asymptomatic enteric infections had statistical support in the analysis. The strongest evidence for EE was the association between enteropathogens and linear growth mediated through systemic inflammation

Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

BACKGROUND Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and inter-leukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn’s disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn’s Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P = 0.005 and P = 0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS Among patients with moderately to severely active Crohn’s disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355.

Assessment of motor functioning in the preschool period

The assessment of motor functioning in young children has become increasingly important in recent years with the acknowledgement that motor impairment is linked with cognitive, language, social and emotional difficulties. However, there is no one gold standard assessment tool to investigate motor ability in children. The aim of the current paper was to discuss the issues related to the assessment of motor ability in young pre-school children and to provide guidelines on the best approach for motor assessment. The paper discusses the maturational changes in brain development at the preschool level in relation to motor ability. Other issues include sex differences in motor ability at this young age, and evidence for this in relation to sociological versus biological influences. From the previous literature it is unclear what needs to be assessed in relation to motor functioning. Should the focus be underlying motor processes or movement skill assessment? Several key assessment tools are discussed that produce a general measure of motor performance followed by a description of tools that assess specific skills, such as fine and gross motor, ball and graphomotor skills. The paper concludes with recommendations on the best approach in assessing motor function in pre-school children

Approaches in biotechnological applications of natural polymers

Natural polymers, such as gums and mucilage, are biocompatible, cheap, easily available and non-toxic materials of native origin. These polymers are increasingly preferred over synthetic materials for industrial applications due to their intrinsic properties, as well as they are considered alternative sources of raw materials since they present characteristics of sustainability, biodegradability and biosafety. As definition, gums and mucilages are polysaccharides or complex carbohydrates consisting of one or more monosaccharides or their derivatives linked in bewildering variety of linkages and structures. Natural gums are considered polysaccharides naturally occurring in varieties of plant seeds and exudates, tree or shrub exudates, seaweed extracts, fungi, bacteria, and animal sources. Water-soluble gums, also known as hydrocolloids, are considered exudates and are pathological products; therefore, they do not form a part of cell wall. On the other hand, mucilages are part of cell and physiological products. It is important to highlight that gums represent the largest amounts of polymer materials derived from plants. Gums have enormously large and broad applications in both food and non-food industries, being commonly used as thickening, binding, emulsifying, suspending, stabilizing agents and matrices for drug release in pharmaceutical and cosmetic industries. In the food industry, their gelling properties and the ability to mold edible films and coatings are extensively studied. The use of gums depends on the intrinsic properties that they provide, often at costs below those of synthetic polymers. For upgrading the value of gums, they are being processed into various forms, including the most recent nanomaterials, for various biotechnological applications. Thus, the main natural polymers including galactomannans, cellulose, chitin, agar, carrageenan, alginate, cashew gum, pectin and starch, in addition to the current researches about them are reviewed in this article.. }To the Conselho Nacional de Desenvolvimento Cientfíico e Tecnológico (CNPq) for fellowships (LCBBC and MGCC) and the Coordenação de Aperfeiçoamento de Pessoal de Nvíel Superior (CAPES) (PBSA). This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit, the Project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462) and COMPETE 2020 (POCI-01-0145-FEDER-006684) (JAT)

Racism as a determinant of health: a systematic review and meta-analysis

Despite a growing body of epidemiological evidence in recent years documenting the health impacts of racism, the cumulative evidence base has yet to be synthesized in a comprehensive meta-analysis focused specifically on racism as a determinant of health. This meta-analysis reviewed the literature focusing on the relationship between reported racism and mental and physical health outcomes. Data from 293 studies reported in 333 articles published between 1983 and 2013, and conducted predominately in the U.S., were analysed using random effects models and mean weighted effect sizes. Racism was associated with poorer mental health (negative mental health: r = -.23, 95% CI [-.24,-.21], k = 227; positive mental health: r = -.13, 95% CI [-.16,-.10], k = 113), including depression, anxiety, psychological stress and various other outcomes. Racism was also associated with poorer general health (r = -.13 (95% CI [-.18,-.09], k = 30), and poorer physical health (r = -.09, 95% CI [-.12,-.06], k = 50). Moderation effects were found for some outcomes with regard to study and exposure characteristics. Effect sizes of racism on mental health were stronger in cross-sectional compared with longitudinal data and in non-representative samples compared with representative samples. Age, sex, birthplace and education level did not moderate the effects of racism on health. Ethnicity significantly moderated the effect of racism on negative mental health and physical health: the association between racism and negative mental health was significantly stronger for Asian American and Latino(a) American participants compared with African American participants, and the association between racism and physical health was significantly stronger for Latino(a) American participants compared with African American participants.<br /

Engineering yield and rate of reductive biotransformation in Escherichia coli by partial cyclization of the pentose phosphate pathway and PTS-independent glucose transport

Optimization of yields and productivities in reductive whole-cell biotransformations is an important issue for the industrial application of such processes. In a recent study with Escherichia coli, we analyzed the reduction of the prochiral β-ketoester methyl acetoacetate by an R-specific alcohol dehydrogenase (ADH) to the chiral hydroxy ester (R)-methyl 3-hydroxybutyrate (MHB) using glucose as substrate for the generation of NADPH. Deletion of the phosphofructokinase gene pfkA almost doubled the yield to 4.8 mol MHB per mole of glucose, and it was assumed that this effect was due to a partial cyclization of the pentose phosphate pathway (PPP). Here, this partial cyclization was confirmed by 13C metabolic flux analysis, which revealed a negative net flux from glucose 6-phosphate to fructose 6-phosphate catalyzed by phosphoglucose isomerase. For further process optimization, the genes encoding the glucose facilitator (glf) and glucokinase (glk) of Zymomonas mobilis were overexpressed in recombinant E. coli strains carrying ADH and deletions of either pgi (phosphoglucose isomerase), or pfkA, or pfkA plus pfkB. In all cases, the glucose uptake rate was increased (30–47%), and for strains Δpgi and ΔpfkA also, the specific MHB production rate was increased by 15% and 20%, respectively. The yield of the latter two strains slightly dropped by 11% and 6%, but was still 73% and 132% higher compared to the reference strain with intact pgi and pfkA genes and expressing glf and glk. Thus, metabolic engineering strategies are presented for improving yield and rate of reductive redox biocatalysis by partial cyclization of the PPP and by increasing glucose uptake, respectively

Diffuse idiopathic skeletal hyperostosis (DISH): relation to vertebral fractures and bone density

UnlabelledRadiographs and spinal bone mineral density (BMD) were evaluated from 342 elderly men regarding possible effects of diffuse idiopathic skeletal hyperostosis (DISH) on vertebral fractures and densitometry measurements. Prevalent vertebral fractures were more frequent among men with DISH compared to men with no DISH even after fracture prevalence was adjusted for BMD. Paravertebral calcifications should be considered in patients with DISH when interpreting BMD measurements because both dual X-ray absorptiometry (DXA) and quantitative CT (QCT) densitometry may not be reliable.IntroductionThe purpose of this study is to evaluate the prevalence of DISH in older men and its association with vertebral fractures and with BMD determined by DXA and QCT.MethodsLateral radiographs of the spine were analyzed in a sample of 342 men aged ≥ 65 years participating in the MrOS Study concerning the presence and grade of DISH and vertebral fractures. Lumbar BMD was measured by both DXA (areal, grams per square centimeter) and QCT (volumetric, grams per cubic centimeter). The association between DISH, BMD, and presence of fractures was studied using χ ( 2 ) and t tests.ResultsDISH was present in 52% (178/342) of the men. Men with DISH were older (mean, 75.1 vs 73.3, p &lt; 0.05) and more likely to have prevalent fractures (28% vs 20%, p &lt; p = 0.09). BMD assessed with DXA (1.08 vs 1.00 g/cm(2), p ≤ 0.0001), but not with QCT (0.11 vs 0.11 g/cm3, p = 0.65), was significantly higher in men with DISH compared to men without DISH. Significantly lower BMD of men with both DISH and fractures compared to men with DISH but without fractures was only detected by QCT (-25%, 0.09 vs 0.12, p &lt; 0.05). Both DXA BMD and QCT BMD were significantly higher in severe lumbar DISH (+22% and +31%, p &lt; 0.0001), respectively.ConclusionDISH was associated with a higher prevalence of vertebral fractures in elderly men. Lumbar ossifications related to DISH should be considered when interpreting BMD measurements to predict their fracture risk

The Ups and Downs of Mutation Frequencies during Aging Can Account for the Apert Syndrome Paternal Age Effect

Apert syndrome is almost always caused by a spontaneous mutation of paternal origin in one of two nucleotides in the fibroblast growth factor receptor 2 gene (FGFR2). The incidence of this disease increases with the age of the father (paternal age effect), and this increase is greater than what would be expected based on the greater number of germ-line divisions in older men. We use a highly sensitive PCR assay to measure the frequencies of the two causal mutations in the sperm of over 300 normal donors with a wide range of ages. The mutation frequencies increase with the age of the sperm donors, and this increase is consistent with the increase in the incidence rate. In both the sperm data and the birth data, the increase is non-monotonic. Further, after normalizing for age, the two Apert syndrome mutation frequencies are correlated within individual sperm donors. We consider a mathematical model for germ-line mutation which reproduces many of the attributes of the data. This model, with other evidence, suggests that part of the increase in both the sperm data and the birth data is due to selection for mutated premeiotic cells. It is likely that a number of other genetic diseases have similar features

Hypothalamic Neuroendocrine Functions in Rats with Dihydrotestosterone-Induced Polycystic Ovary Syndrome: Effects of Low-Frequency Electro-Acupuncture

Adult female rats continuously exposed to androgens from prepuberty have reproductive and metabolic features of polycystic ovary syndrome (PCOS). We investigated whether such exposure adversely affects estrous cyclicity and the expression and distribution of gonadotropin-releasing hormone (GnRH), GnRH receptors, and corticotrophin-releasing hormone (CRH) in the hypothalamus and whether the effects are mediated by the androgen receptor (AR). We also assessed the effect of low-frequency electro-acupuncture (EA) on those variables. At 21 days of age, rats were randomly divided into three groups (control, PCOS, and PCOS EA; n = 12/group) and implanted subcutaneously with 90-day continuous-release pellets containing vehicle or 5α-dihydrostestosterone (DHT). From age 70 days, PCOS EA rats received 2-Hz EA (evoking muscle twitches) five times/week for 4–5 weeks. Hypothalamic protein expression was measured by immunohistochemistry and western blot. DHT-treated rats were acyclic, but controls had regular estrous cycles. In PCOS rats, hypothalamic medial preoptic AR protein expression and the number of AR- and GnRH-immunoreactive cells were increased, but CRH was not affected; however, GnRH receptor expression was decreased in both the pituitary and hypothalamus. Low-frequency EA restored estrous cyclicity within 1 week and reduced the elevated hypothalamic GnRH and AR expression levels. EA did not affect GnRH receptor or CRH expression. Interestingly, nuclear AR co-localized with GnRH in the hypothalamus. Thus, rats with DHT-induced PCOS have disrupted estrous cyclicity and an increased number of hypothalamic cells expressing GnRH, most likely mediated by AR activation. Repeated low-frequency EA normalized estrous cyclicity and restored GnRH and AR protein expression. These results may help explain the beneficial neuroendocrine effects of low-frequency EA in women with PCOS

Human and mouse neuroinflammation markers in Niemann‐Pick disease, type C1

Niemann‐Pick disease, type C1 (NPC1) is an autosomal recessive lipid storage disorder in which a pathological cascade, including neuroinflammation occurs. While data demonstrating neuroinflammation is prevalent in mouse models, data from NPC1 patients is lacking. The current study focuses on identifying potential markers of neuroinflammation in NPC1 from both the Npc1 mouse model and NPC1 patients. We identified in the mouse model significant changes in expression of genes associated with inflammation and compared these results to the pattern of expression in human cortex and cerebellar tissue. From gene expression array analysis, complement 3 (C3) was increased in mouse and human post‐mortem NPC1 brain tissues. We also characterized protein levels of inflammatory markers in cerebrospinal fluid (CSF) from NPC1 patients and controls. We found increased levels of interleukin 3, chemokine (C‐X‐C motif) ligand 5, interleukin 16 and chemokine ligand 3 (CCL3), and decreased levels of interleukin 4, 10, 13 and 12p40 in CSF from NPC1 patients. CSF markers were evaluated with respect to phenotypic severity. Miglustat treatment in NPC1 patients slightly decreased IL‐3, IL‐10 and IL‐13 CSF levels; however, further studies are needed to establish a strong effect of miglustat on inflammation markers. The identification of inflammatory markers with altered levels in the cerebrospinal fluid of NPC1 patients may provide a means to follow secondary events in NPC1 disease during therapeutic trials.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147148/1/jimd0083.pd