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Selenium (Se) is a micronutrient essential for human health. Sub-optimal Se status is common, occurring in a significant proportion of the population across the world including parts of Europe and China. Human and animal studies have shown that Se status is a key determinant of the host response to viral infections. In this review, we address the question whether Se intake is a factor in determining the severity of response to COVID-19. Emphasis is placed on epidemiological and animal studies which suggest that Se affects host response to RNA viruses and on the molecular mechanisms by which Se and selenoproteins modulate the inter-linked redox homeostasis, stress response and inflammatory response. Together these studies indicate that Se status is an important factor in determining the host response to viral infections. Therefore, we conclude that Se status is likely to influence human response to the SARS-CoV-2 infection and that Se status is one (of several) risk factors which may impact on the outcome of SARS-CoV-2 infection, particularly in populations where Se intake is sub-optimal or low. We suggest the use of appropriate markers to assess the Se status of COVID-19 patients and possible supplementation may be beneficial in limiting the severity of symptoms, especially in countries where Se status is regarded as sub-optimal.
Coeliac disease (CD) is a chronic, immune-mediated condition caused by exposure to dietary gluten in genetically susceptible individuals. The prevalence of CD in the general population is estimated at 1%. A gluten-free diet (GFD) is an effective treatment for the vast majority of individuals with CD. Despite advances in serological testing, the duodenal biopsy remains essential for the diagnosis of CD.
The morphological features of established CD have been well described. However, early changes in the duodenum, e.g. an increase in intraepithelial lymphocytes, are not specific for CD. Architectural changes in the duodenal biopsy are more specific for CD, but the pathologist should be aware of other conditions that can cause villous atrophy.
Some patients with CD do not respond to a GFD, and may have refractory CD (RCD), a condition believed to represent a cryptic form of the most common malignancy in CD: enteropathy-associated T-cell lymphoma. Early detection of RCD is essential in guiding more aggressive management.
The aims of this chapter are to describe the histological features of CD and its variations and complications, and to discuss the key differential diagnoses, with particular emphasis on features that help to distinguish CD from other conditions.
Inflammation and metabolic dysregulation are age-related physiological changes and are associated with depressive disorder. We tried to identify subgroups of depressed older patients based on their metabolic-inflammatory profile and examined the course of depression for these subgroups.
This clinical cohort study was conducted in a sample of 364 depressed older (⩾60 years) patients according to DSM-IV criteria. Severity of depressive symptoms was monitored every 6 months and a formal diagnostic interview repeated at 2-year follow-up. Latent class analyses based on baseline metabolic and inflammatory biomarkers were performed. Adjusted for confounders, we compared remission of depression at 2-year follow-up between the metabolic-inflammatory subgroups with logistic regression and the course of depression severity over 2-years by linear mixed models.
We identified a ‘healthy’ subgroup (n = 181, 49.7%) and five subgroups characterized by different profiles of metabolic-inflammatory dysregulation. Compared to the healthy subgroup, patients in the subgroup with mild ‘metabolic and inflammatory dysregulation’ (n = 137, 37.6%) had higher depressive symptom scores, a lower rate of improvement in the first year, and were less likely to be remitted after 2-years [OR 0.49 (95% CI 0.26–0.91)]. The four smaller subgroups characterized by a more specific immune-inflammatory dysregulation profile did not differ from the two main subgroups regarding the course of depression.
Nearly half of the patients with late-life depressions suffer from metabolic-inflammatory dysregulation, which is also associated with more severe depression and a worse prognosis. Future studies should examine whether these depressed older patients benefit from a metabolic-inflammatory targeted treatment.
Less than 40% of depressed older adults treated with an antidepressant achieve remission. Incomplete response to treatment is common. Current augmentation strategies have limited efficacy, and many have side effects that restrict their utilization in older adults. We conducted the first open pilot trial of minocycline augmentation in older adults who had failed to achieve remission after adequate psychopharmacologic treatment. Subjects older than 55 years of age with major depression and failure to achieve substantial improvement of depressive symptoms after at least 6 weeks of antidepressant treatment were given augmentation with minocycline 100 mg twice daily over an 8-week period. At the end of 8 weeks of augmentation with minocycline, 31% (4/13) patients achieved remission. Remitters had higher baseline ratings of hopelessness and apathy. Minocycline was well tolerated with no reported adverse events or discontinuation due to intolerance. Larger placebo-controlled studies are needed to evaluate the effects of minocycline augmentation in older adults who had failed to achieve remission after adequate treatment with antidepressants.
The aims of this study were to evaluate changes in inflammatory and oxidative stress levels following treatment with N-acetylcysteine (NAC) or mitochondrial-enhancing agents (CT), and to assess the how these changes may predict and/or moderate clinical outcomes primarily the Montgomery-Åsberg Depression Rating Scale (MADRS).
This study involved secondary analysis of a placebo-controlled randomised trial (n = 163). Serum samples were collected at baseline and week 16 of the clinical trial to determine changes in Interleukin-6 (IL-6) and total antioxidant capacity (TAC) following adjunctive CT and/or NAC treatment, and to explore the predictability of the outcome or moderator effects of these markers.
In the NAC-treated group, no difference was observed in serum IL-6 and TAC levels after 16 weeks of treatment with NAC or CT. However, results from a moderator analysis showed that in the CT group, lower IL-6 levels at baseline was a significant moderator of MADRS χ2 (df) = 4.90, p = 0.027) and Clinical Global Impression-Improvement (CGI-I, χ2 (df) = 6.28 p = 0.012). In addition, IL-6 was a non-specific but significant predictor of functioning (based on the Social and Occupational Functioning Assessment Scale (SOFAS)), indicating that individuals with higher IL-6 levels at baseline had a greater improvement on SOFAS regardless of their treatment (p = 0.023).
Participants with lower IL-6 levels at baseline had a better response to the adjunctive treatment with the mitochondrial-enhancing agents in terms of improvements in MADRS and CGI-I outcomes.
Whole-grain wheat, in particular coloured varieties, may have health benefits in adults with chronic metabolic disease risk factors. Twenty-nine overweight and obese adults with chronic inflammation (high-sensitivity C-reactive protein) > 1·0 mg/l) replaced four daily servings of refined grain food products with bran-enriched purple or regular whole-wheat convenience bars (approximately 41–45 g fibre, daily) for 8 weeks in a randomised, single-blind parallel-arm study where body weight was maintained. Anthropometrics, blood markers of inflammation, oxidative stress, and lipaemia and metabolites of anthocyanins and phenolic acids were compared at days 1, 29 and 57 using repeated-measures ANOVA within groups and ANCOVA between groups at day 57, with day 1 as a covariate. A significant reduction in IL-6 and increase in adiponectin were observed within the purple wheat (PW) group. TNF-α was lowered in both groups and ferulic acid concentration increased in the regular wheat (RW) group. Comparing between wheats, only plasma TNF-α and glucose differed significantly (P < 0·05), that is, TNF-α and glucose decreased with RW and PW, respectively. Consumption of PW or RW products showed potential to improve plasma markers of inflammation and oxidative stress in participants with evidence of chronic inflammation, with modest differences observed based on type of wheat.
We examined whether breakfast frequency was associated with chronic inflammatory, as assessed by high-sensitivity C-reactive protein (CRP) concentration.
Kailuan community, China.
Included were 70 092 Chinese adults without CVD and cancer in 2014 with CRP concentrations <10 mg/l, when breakfast frequency was assessed via a questionnaire, and plasma CRP concentration was measured.
Breakfast frequency was associated with CRP concentration (P-trend < 0·001). The adjusted mean CRP was 1·33 mg/l (95 % CI 1·23, 1·44) for the ‘no breakfast’ group and 1·07 mg/l (95 % CI 1·0, 1·14) for the ‘breakfast everyday’ group (P-difference < 0·001), adjusting for age, sex, diet quality, total energy, obesity, education, occupation, marital status, smoking, alcohol consumption, blood pressure, sleep parameters, fasting blood glucose and lipid profiles. Consistently, the adjusted OR for CRP ≥ 1·0 mg/l and CRP ≥ 3·0 mg/l were 1·86 (95 % CI 1·73, 2·00) and 1·27 (95 % CI 1·15, 1·40), respectively, when comparing these two breakfast consumption groups (P-trend < 0·001 for both). The associations were more pronounced among older adults, relative to those who were younger (P-interaction < 0·001). Significant association between breakfast skipping and elevated CRP concentration was observed in those with poor diet quality, but not those with good diet quality.
Habitually skipping breakfast was associated with elevated concentrations of CRP. Future prospective studies including repeated assessment of inflammatory biomarkers and a collection of detailed information on type and amount of breakfast foods are warranted.
A hyperinflammatory response to COVID-19 is being described in children. While this presents, and responds to management, similar to that of Kawasaki Disease it is being coined a new entity. But is it really? We explore how this phenomenon may be Kawasaki Disease with a new trigger.
Primary deficit schizophrenia (DS) is characterized by enduring negative symptoms and represents a qualitatively different disease entity with respect to non-deficit schizophrenia (NDS). No studies investigated the association between the enzyme paraoxonase 1 (PON1) and DS and its phenomenology.
In this case-control study, Thai women and men, aged 18 to 65 years, were divided in DS (n = 40) and NDS (n = 40) and were compared to controls (n = 40). PON1 activities against 4-(chloromethyl)phenyl acetate (CMPA) and phenylacetate were determined. Moreover, subjects were genotyped for their PON1 Q192R polymorphism and immunoglobulin A (IgA) levels responses directed to Gram-negative bacteria were measured.
DS is significantly associated with the QQ genotype and the Q allele as compared with NDS and controls. PON1 activities are significantly and inversely associated with negative symptoms, formal thought disorders, psychomotor retardation, excitation and DS. The presence of the Q allele is associated with increased IgA responses to Pseudomonas aeruginosa, Morganella morganii, and Pseudomonas putida as compared with RR carriers.
The PON1 Q allele and lower PON1 activities especially against CMPA are associated with DS, indicating lowered quorum quenching abilities as well as lowered defenses against lipoperoxidation and immune activation. It is suggested that lowered PON1 activity in DS constitutes an impairment in the innate immune system which together with lowered natural IgM may cause lower immune regulation thereby predisposing toward greater neurotoxic effects of immune-inflammatory, oxidative and nitrosative pathways and Gram-negative microbiota.
Inflammation is a normal part of the immune response and should be self-limiting. Excessive or unresolved inflammation is linked to tissue damage, pathology and ill health. Prostaglandins and leukotrienes produced from the n-6 fatty acid arachidonic acid are involved in inflammation. Fatty acids may also influence inflammatory processes through mechanisms not necessarily involving lipid mediators. The n-3 fatty acids EPA and DHA possess a range of anti-inflammatory actions. Increased content of EPA and DHA in the membranes of cells involved in inflammation has effects on the physical nature of the membranes and on the formation of signalling platforms called lipid rafts. EPA and DHA interfere with arachidonic acid metabolism which yields prostaglandins and leukotrienes involved in inflammation. EPA gives rise to weak (e.g. less inflammatory) analogues and both EPA and DHA are substrates for the synthesis of specialised pro-resolving mediators. Through their effects on early signalling events in membranes and on the profile of lipid mediators produced, EPA and DHA alter both intracellular and intercellular signals. Within cells, this leads to altered patterns of gene expression and of protein production. The net result is decreased production of inflammatory cytokines, chemokines, adhesion molecules, proteases and enzymes. The anti-inflammatory and inflammation-resolving effects of EPA and DHA are relevant to both prevention and treatment of human diseases that have an inflammatory component. This has been widely studied in rheumatoid arthritis where there is good evidence that high doses of EPA + DHA reduce pain and other symptoms.
The present study aimed to investigate the effect of acute changes in serum C-reactive protein (CRP) on appetite and food intake among older hospitalised patients. A total of 200 patients (age range 65–94 years, 62·5 % women) participated in this prospective longitudinal observational study. Risk of malnutrition was measured according to the Mini Nutritional Assessment Short Form. The Simplified Nutritional Appetite Questionnaire (SNAQ) and Edmonton Symptom Assessment System (ESAS) were used to evaluate patients’ appetite at the time of hospital admission (baseline) and after 7 d (follow-up). Food intake was measured according to the plate diagram and serum CRP was analysed at baseline and follow-up. At baseline, 30·5 % of the patients had moderate to severe inflammation, 31·0 % were malnourished and 48·0 % had food intake <75 % of the meals offered. Also, 32·5 and 23·5 % reported poor and very poor appetite or severe loss of appetite according to the SNAQ and ESAS, respectively. Of the patients, 40 % displayed a pronounced reduction in median CRP levels by −1·2 mg/dl and 19 % demonstrated an increase in median CRP levels by +1·2 mg/dl. Appetite significantly improved (P = 0·006) in patients with a decrease in CRP level and deteriorated in those with an increase in CRP level (P = 0·032). Changes in CRP levels did not show any significant impact on food intake. In a regression analysis, changes of inflammation were the major independent predictor for changes of patients’ appetite. We conclude that inflammation has a significant impact on appetite and should therefore be considered in the diagnosis and treatment of malnutrition.
Diet has direct and indirect effects on health through inflammation and the gut microbiome. We investigated total dietary inflammatory potential via the literature-derived index (Dietary Inflammatory Index (DII®)) with gut microbiota diversity, composition and function. In cancer-free patient volunteers initially approached at colonoscopy and healthy volunteers recruited from the medical centre community, we assessed 16S ribosomal DNA in all subjects who provided dietary assessments and stool samples (n 101) and the gut metagenome in a subset of patients with residual fasting blood samples (n 34). Associations of energy-adjusted DII scores with microbial diversity and composition were examined using linear regression, permutational multivariate ANOVA and linear discriminant analysis. Spearman correlation was used to evaluate associations of species and pathways with DII and circulating inflammatory markers. Across DII levels, α- and β-diversity did not significantly differ; however, Ruminococcus torques, Eubacterium nodatum, Acidaminococcus intestini and Clostridium leptum were more abundant in the most pro-inflammatory diet group, while Akkermansia muciniphila was enriched in the most anti-inflammatory diet group. With adjustment for age and BMI, R. torques, E. nodatum and A. intestini remained significantly associated with a more pro-inflammatory diet. In the metagenomic and fasting blood subset, A. intestini was correlated with circulating plasminogen activator inhibitor-1, a pro-inflammatory marker (rho = 0·40), but no associations remained significant upon correction for multiple testing. An index reflecting overall inflammatory potential of the diet was associated with specific microbes, but not overall diversity of the gut microbiome in our study. Findings from this preliminary study warrant further research in larger samples and prospective cohorts.
Emerging research suggests that maternal immune activation (MIA) may be associated with an increased risk of adverse neurodevelopmental and mental health outcomes in offspring. Using data from the Raine Study, we investigated whether MIA during pregnancy was associated with increased behavioral and emotional problems in offspring longitudinally across development.
Mothers (Generation 1; N = 1905) were classified into the following categories: AAAE (Asthma/Allergy/Atopy/Eczema; N = 1267); infection (during pregnancy; N = 1082); no AAAE or infection (N = 301). The Child Behavior Checklist (CBCL) was administered for offspring at ages 5, 8, 10, 14, and 17. Generalized estimating equations were used to investigate the effect of maternal immune status on CBCL scores.
AAAE conditions were associated with significant increases in CBCL Total (β 2.49; CI 1.98–3.00), Externalizing (β 1.54; CI 1.05–2.03), and Internalizing (β 2.28; CI 1.80–2.76) scores. Infection conditions were also associated with increased Total (β 1.27; CI 0.77–1.78), Externalizing (β 1.18; CI 0.70–1.66), and Internalizing (β 0.76; CI 0.28–1.24) scores. Exposure to more than one AAAE and/or infection condition was associated with a greater elevation in CBCL scores than single exposures in males and females. Females showed greater increases on the Internalizing scale from MIA, while males showed similar increases on both Internalizing and Externalizing scales.
MIA was associated with increased behavioral and emotional problems in offspring throughout childhood and adolescence. This highlights the need to understand the relationship between MIA, fetal development, and long-term outcomes, with the potential to advance early identification and intervention strategies.
The aging of any biological system results in quantifiable change which may affect the output of the system in subtle or substantial ways. Human cognitive aging is no exception and the manner in which the system, in this case the brain, is able to withstand and/or adapt to the effects of age-related physiological change will determine the individual cognitive trajectory. In this chapter, we review the emerging field of blood biomarkers of cognitive aging with a focus on specific metabolic pathways implicated in cognitive health including cellular energetics, lipid metabolism, the maintenance of redox state, and inflammation. Challenges to blood biomarker development, including methodological and inferential limitations, are also reviewed. Ultimately, blood biomarkers of age-related neurodegenerative disease and cognitive success will provide clues for how we might all age successfully, reducing health care burden on societies and improving quality of life for individuals.
This chapter reviews both seminal and recent work on late-life depression (LLD), with an emphasis on the vascular depression subtype of LLD. We first describe the clinical features and symptom presentation of LLD, highlighting executive functioning deficits that are a core feature of the “depression with executive dysfunction” syndrome. We discuss both vascular and nonvascular etiological pathways to depression with executive dysfunction in older adults. We highlight recent findings on the association between vascular disease, altered structural and functional brain network connectivity, and clinical symptoms in LLD. Vascular depression is associated with nonresponse to standard pharmacologic treatment. As such, behavioral interventions offer promising avenues for treatment. Novel behavioral approaches encompass psychotherapy, noninvasive brain stimulation, and cognitive remediation that are targeted toward the specific neural circuitry dysfunctions that underlie both affective and cognitive symptoms in older adults. We review these approaches, as well as psychosocial, exercise, and lifestyle interventions.
To examine whether negative symptoms, psychosis, hostility, excitation, and mannerism (PHEM symptoms), formal thought disorders (FTD) and psychomotor retardation (PMR) are interrelated phenomena in major neurocognitive psychosis (MNP) or deficit schizophrenia and whether those domains belong to an underlying latent vector reflecting general psychopathology.
In this study, we recruited 120 patients with MNP or deficit schizophrenia and 54 healthy subjects and measured the above-mentioned symptom domains.
In MNP, there were significant associations between negative and PHEM symptoms, FTD and PMR. A single latent trait, which is essentially unidimensional, underlies these key domains of schizophrenia and MNP and additionally shows excellent internal consistency reliability, convergent validity, and predictive relevance. Confirmatory Tedrad Analysis indicates that this latent vector fits a reflective model. The lack of discriminant validity shows that positive (and PHEM or psychotic) and negative symptoms greatly overlap and probably measure the same latent construct. Soft independent modeling of class analogy (SIMCA) shows that MNP (diagnosis based on negative symptoms) is better modeled using PHEM symptoms, FTD, and PMR than negative symptoms.
In stable phase MNP, which is a restricted sample of the schizophrenia population, negative and PHEM symptoms, FTD and PMR belong to one underlying latent vector reflecting overall severity of schizophrenia (OSOS). The bi-dimensional concept of “positive” and “negative” symptoms cannot be validated and, therefore, future research in stable phase schizophrenia should consider that the latent phenomenon OSOS as well as its reflective manifestations are the key factors of schizophrenia phenomenology.
A high dietary fibre intake has been associated with improvements in inflammatory conditions in adults. However, little is known on whether associations between dietary fibre and inflammation are evident during adolescence. We examined the relationship between dietary fibre intake measured by food frequency questionnaire and the inflammatory marker high-sensitivity C-reactive protein (hs-CRP) and the adipokines leptin and adiponectin cross-sectionally in 17-year-olds participating in the Raine Study (n=621). In weighted analysis using tobit and linear regression, and after excluding participants with hs-CRP>10mg/L, higher total dietary fibre intake (per 5g/day) was significantly associated with lower leptin (β=-0.13, 95% CI -0.17, -0.09) and adiponectin (β=-0.28, 95% CI -0.49, -0.07), but not hs-CRP, in unadjusted analyses. These associations were no longer significant after adjustment for gender, anthropometry and a number of lifestyle factors. However, higher cereal and grain fibre intake was significantly associated with lower leptin (β=-0.06, 95% CI -0.10, -0.01) in fully adjusted analysis. Our findings suggest that a higher intake of cereal and grain fibre may contribute to lower leptin in adolescents. This may contribute to reductions in low-grade chronic inflammation and improved health outcomes.
Sleep disturbance has been consistently identified as an independent contributor to suicide risk. Inflammation has emerged as a potential mechanism linked to both sleep disturbance and suicide risk. This study tested associations between sleep duration, insomnia, and inflammation on suicidal ideation (SI) and history of a suicide attempt (SA).
Participants included 2329 adults with current or remitted depression and/or anxiety enrolled in the Netherlands Study of Depression and Anxiety. Sleep duration, insomnia, past week SI, and SA were assessed with self-report measures. Plasma levels of C-reactive protein, interleukin-6, and tumor necrosis factor-α were obtained.
Short sleep duration (⩽6 h) compared to normal sleep duration (7–9 h) was associated with reporting a prior SA, adjusting for covariates [adjusted odds ratio (AOR) 1.68, 95% CI 1.13–2.51]. A higher likelihood of SI during the past week was observed for participants with long sleep duration (⩾10 h) compared to normal sleep duration (AOR 2.22, 95% CI 1.02–4.82), more insomnia symptoms (AOR 1.44, 95% CI 1.14–1.83), and higher IL-6 (AOR 1.31, 95% CI 1.02–1.68). Mediation analyses indicated that the association between long sleep duration and SI was partially explained by IL-6 (AOR 1.02, 95% CI 1.00–1.05).
These findings from a large sample of adults with depression and/or anxiety provide evidence that both short and long sleep duration, insomnia symptoms, and IL-6 are associated with the indicators of suicide risk. Furthermore, the association between long sleep duration and SI may operate through IL-6.
Clinical and experimental studies show an association between maternal periodontitis and adverse outcomes during gestation. On the other hand, there were no studies evaluating the impact of maternal periodontitis on the offspring. Thus, our objective was to investigate the repercussion of maternal periodontitis on the development of asthma in the offspring. Pregnant rats were submitted or not to periodontitis by ligature technique. Thirty days after birth, the puppies were sensitized and challenged with ovalbumin (OVA) in order to induce asthmatic response. Our results showed that maternal periodontitis reduced cellular infiltrate in the parenchyma of offspring, tracheal responsiveness, lung edema, and anti-OVA antibodies, without alter mucus as well as cytokines production. We concluded that periodontitis has relevant impact on the offspring’s immune system, blunting the response to allergic and inflammatory stimulus. This study shows the important role of oral health during pregnancy and opens possibilities for future studies in order to explain the effects of periodontitis during pregnancy in the offspring.
The experiment reported in this research paper aimed to determine whether clinical and subclinical effects on cattle were similar if provided with isoenergetic and isonitrogenous challenge diets in which carbohydrate sources were predominantly starch or sugar. The study was a 3 × 3 Latin square using six adult Jersey cows with rumen cannulae, over 9 weeks. In the first 2 weeks of each 3 week experimental period cows were fed with a maintenance diet and, in the last week, each animal was assigned to one of three diets: a control diet (CON), being a continuation of the maintenance diet; a high starch (HSt) or a high sugar (HSu) diet. Reticuloruminal pH and motility were recorded throughout the study period. Blood and ruminal samples were taken on day-1 (TP-1), day-2 (TP-2) and day-7 (TP-7) of each challenge week. Four clinical variables were recorded daily: diarrhoea, inappetence, depression and ruminal tympany. The effects of treatment, hour of day and day after treatment on clinical parameters were analysed using linear mixed effects (LME) models. Although both challenge diets resulted in a decline in pH, an increase in the absolute pH residuals and an increase in the number of minutes per day under pH 5.8, systemic inflammation was only detected with the HSt diet. The challenge diets differentially modified amplitude and period of reticuloruminal contractions compared with CON diet and both were associated with an increased probability of diarrhoea. The HSu diet reduced the probability of an animal consuming its complete allocation. Because the challenge diets were derived from complex natural materials (barley and molasses respectively), it is not possible to assign all the differential effects to the difference in starch and sugar concentration: non-starch components of barley or non-sugar components of molasses might have contributed to some of the observations. In conclusion, substituting much of the starch with sugar caused no substantial reduction in the acidosis load, but inflammatory response was reduced while feed rejection was increased.