The LEISURE Study: A Longitudinal Randomized Controlled Trial Protocol for a Multi-Modal Lifestyle Intervention Study to Reduce Dementia Risk in Healthy Older Adults.

Dementia is understood to arise from a mixed etiology, enveloping chronic inflammatory and vascular impacts on the brain, driven by a constellation of modifiable risk factors which are largely mediated by lifestyle-related behaviors. These risk factors manifest over a prolonged preclinical period and account for up to 40% of the population attributable risk for dementia, representing viable targets for early interventions aimed at abating disease onset and progression. Here we outline the protocol for a 12-week randomized control trial (RCT) of a multimodal Lifestyle Intervention Study for Dementia Risk Reduction (LEISURE), with longitudinal follow-up at 6-months and 24-months post-intervention. This trial integrates exercise, diet, sleep, and mindfulness to simultaneously target multiple different etiopathogenetic mechanisms and their interplay in a healthy older adult population (aged 50-85 years), and assesses dementia risk reduction as the primary endpoint. The LEISURE study is located in the Sunshine Coast region of Australia, which has one of the nation's highest proportions of adults aged over 50 years (36.4%), and corresponding dementia prevalence. This trial is novel in its inclusion of mindfulness and sleep as multidomain lifestyle targets, and in its comprehensive suite of secondary outcomes (based on psychological, physical health, sleep activity, and cognitive data) as well as exploratory neuroimaging (magnetic resonance imaging and electroencephalography) and molecular biology measures. These measures will provide greater insights into the brain-behavioral underpinnings of dementia prevention, as well as the predictors and impacts of the proposed lifestyle intervention. The LEISURE study was prospectively registered (ACTRN12620000054910) on 19 January 2020.

Electrophysiological phenotypes of suicidality predict prolonged response to oral ketamine treatment.

Oral ketamine has shown to be a rapid-acting antidepressant and a potential treatment option for suicidality, however, repeated doses are often required. Objective markers of prolonged treatment response are needed to help individuals and clinicians make informed treatment decisions. This secondary analysis sought to identify objective electrophysiological predictors of both prolonged response and dose sensitivity to low-dose oral ketamine in people with chronic suicidality. Individuals with a Beck Scale for Suicide Ideation total score (BSS) ≥ 6 (N = 29) completed a six-week ketamine treatment, pre-treatment electroencephalography and follow-up assessment of suicidality (four weeks from the final ketamine dose). Prolonged response was observed in 52% of participants (follow-up BSS reduced by 50% or ≤6); nearly half were prolonged non-responders. There was decisive evidence for a predictive Bayesian linear regression model with follow-up BSS score as the response variable and pre-treatment auditory evoked power bands as predictors (theta, alpha and beta frequencies, BF10 = 17,948, R2 = 0.70). A Bayesian one-way ANOVA indicated strong evidence for a model of positive association between auditory evoked power and ketamine dose sensitivity (theta-alpha BF+0 = 108, effect size δ = 1.3, 95% CI 0.5-2.1; high-beta BF+0 = 7.4, δ = 0.8, 95% CI 0.1-1.6). Given auditory evoked power may index serotonin neurotransmission, these results suggest that a prolonged response to ketamine may, in part, be mediated by pre-treatment serotonergic functioning. In addition, the observed beta power differences may arise from GABAergic functioning. These suicidality phenotypes, identifiable by pre-treatment electrophysiology, may aid diagnosis, treatment selection and prediction of prolonged treatment outcome.

Why Severe COVID-19 Patients Are at Greater Risk of Developing Depression: A Molecular Perspective.

The prevailing evidence suggests that patients with severe COVID-19 seem to have an overreaction of the immune system demonstrating exacerbated levels of inflammation caused by a "cytokine storm." At this early stage, the mechanisms underpinning COVID-19 are still subject to intense scrutiny and the long-term mental health consequences as a result of the disease are unknown. Here we discuss the hypothesis that patients who survive severe COVID-19 and who experience significant activation of the immune system, are at greater risk of developing depression. We posit that a phenomenon known as cytokine storm dramatically activates the enzyme indoleamine 2,3-dioxygenase (IDO-1), resulting in the increase in kynurenine metabolites. Kynurenine is metabolized by IDO-1 in the brain, producing chemokines, in which a prolonged exposure may result long-term brain impairment. In this article, we also propose the possibility that a SARS-CoV-2 neuroinvasion increases the local levels of angiotensin II by angiotensin-converting enzyme 2 down-regulation. Thereby, angiotensin II could increase kynurenine metabolites producing pro-oxidative and pro-inflammatory effects, resulting in impairment of cognitive function, enhanced oxidative stress and decreased brain-derived neurotrophic factor. It is our premise that patients who experience such a cytokine storm may be at increased risk of long-term mental illness, such as depression.

Anorexia nervosa, zinc deficiency and the glutamate system: The ketamine option.

Anorexia nervosa (AN) is a severe, biological brain disorder with significant medical risks and a tenacious development over time. Unfortunately, few treatments show efficacy in people with AN although numerous therapies including pharmacological have been explored. Zinc deficiency has been implicated in AN and zinc is important in a large range of processes in the brain. In particular, it is an allosteric modulator of NMDA receptors - the maintenance of zinc levels within a normal, narrow range is essential for glutamatergic functioning. Chronic zinc deficiency increases neuronal stores of calcium and reduces direct modulation of NMDA receptors which collectively lead to overactivation and upregulation of NMDA receptors. This may facilitate pathologically high levels of glutamate, calcium influx and subsequent excitotoxicity, which can disrupt synaptogenesis and synaptic plasticity. While studies of zinc supplementation in AN have shown some promise, the efficacy of this treatment is limited. This may be due to AN illness chronicity and the significant changes already made, as well as a reduced potency of zinc to inhibit NMDA receptors in a pathological state. Thus, we propose that the safe (at low doses) yet more potent NMDA receptor antagonist, ketamine, may act to normalise a perturbed glutamatergic system and increase synaptogenesis in the short term. This 'kickstart' via ketamine could then allow zinc supplementation and other forms of treatment to enhance recovery in AN.

Improvement of human pancreatic islet quality after co-culture with human adipose-derived stem cells.

The aim of this study was to investigate whether co-culture of human islets with adipose-derived stem cells (ASCs) can improve islet quality and to evaluate which factors play a role in the protective effect of ASCs against islet dysfunction. Islets and ASCs were cultured in three experimental groups for 24 h, 48 h, and 72 h: 1) indirect co-culture of islets with ASC monolayer (Islets/ASCs); 2) islets alone; and 3) ASCs alone. Co-culture with ASCs improved islet viability and function in all culture time-points analyzed. VEGFA, HGF, IL6, IL8, IL10, CCL2, IL1B, and TNF protein levels were increased in supernatants of islet/ASC group compared to islets alone, mainly after 24 h. Moreover, VEGFA, IL6, CCL2, HIF1A, XIAP, CHOP, and NFKBIA genes were differentially expressed in islets from the co-culture condition compared to islets alone. In conclusion, co-culture of islets with ASCs promotes improvements in islet quality.

Role of Innate Immunity in Preeclampsia: A Systematic Review.

Innate immune system dysfunction has been known to be a key player in preeclampsia (PE). Activation of the maternal innate immunity may be triggered by invading microorganisms or endogenous ligands, which are detected by different pattern recognition receptors (PRRs). Although some studies have linked PRR activation to PE, it is still unclear if dysregulated PRR expression is associated with the development of this complication. Therefore, we conducted a systematic review of the literature, searching articles that evaluated associations of PRRs with PE. Twenty-six studies met the inclusion criteria: 20 of them analyzed PRR expressions and 6 studies investigated the association between PRR polymorphisms and PE. Among the PRRs, only few studies analyzed retinoic acid-inducible gene I-like helicase (RLH) and/or toll-like receptor (TLR)-1, 5, 6, 7, 8, and 9 expressions in immune cells or placentas from women with PE and controls; thus, it is inconclusive if these PRRs are involved in PE. Results from the 10 studies that analyzed TLR-2 expressions in women with PE and controls are also contradictory. The majority of the studies that investigated TLR-3 and -4 expressions indicate that these PRRs are increased in placenta or immune cells from women with PE compared to pregnant control woman. To date, polymorphisms in TLR-2, - 3, and - 4 and nucleotide-binding oligomerization domain-like receptor 2 genes do not seem to be associated with PE development. No study has evaluated the association between polymorphisms in genes codifying other TLRs or RLHs genes. In conclusion, available data in literature support a role for TLR-3 and TLR-4 in the pathogenesis of PE.

Nitric oxide levels in patients with diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Altered serum nitric oxide (NO) levels in patients with diabetes mellitus (DM) have been reported by different studies; however, results are still controversial. Until this date, no meta-analysis evaluated the association of NO levels with DM. Thus, this paper describes a meta-analysis conducted to evaluate if there is a relationship between NO levels and type 1 DM (T1DM) or type 2 DM (T2DM). METHODS: A literature search was done to identify all studies that investigated NO levels between T1DM or T2DM patients (cases) and non-diabetic subjects (controls). Measurement of nitrate and nitrite (NOx - the stable NO products) were used to estimate NO concentrations because they closely reflect NO bioavailability. Weighted mean differences (WMD) of NOx levels between case and control samples were calculated for T1DM and T2DM groups. RESULTS: Thirty studies were eligible for inclusion in the meta-analysis (8 in T1DM samples and 22 in T2DM samples). NOx levels were increased in European T1DM patients compared with controls [random effect model (REM) WMD = 8.55, 95% CI 2.88 - 14.21]. No other ethnicity was evaluated in T1DM studies. NOx levels were also increased in both European (REM WMD = 18.76, 95% CI 1.67 - 35.85) and Asian (REM WMD = 18.41, 95% CI 8.01 - 28.81) T2DM patients, but not in Latin American patients compared with controls. CONCLUSIONS: This meta-analysis detected a significant increase in NOx levels in European T1DM patients as well as European and Asian T2DM patients. Further studies in other ethnicities are necessary to confirm these data.

Human pancreatic islet transplantation: an update and description of the establishment of a pancreatic islet isolation laboratory.

Type 1 diabetes mellitus (T1DM) is associated with chronic complications that lead to high morbidity and mortality rates in young adults of productive age. Intensive insulin therapy has been able to reduce the likelihood of the development of chronic diabetes complications. However, this treatment is still associated with an increased incidence of hypoglycemia. In patients with "brittle T1DM", who have severe hypoglycemia without adrenergic symptoms (hypoglycemia unawareness), islet transplantation may be a therapeutic option to restore both insulin secretion and hypoglycemic perception. The Edmonton group demonstrated that most patients who received islet infusions from more than one donor and were treated with steroid-free immunosuppressive drugs displayed a considerable decline in the initial insulin independence rates at eight years following the transplantation, but showed permanent C-peptide secretion, which facilitated glycemic control and protected patients against hypoglycemic episodes. Recently, data published by the Collaborative Islet Transplant Registry (CITR) has revealed that approximately 50% of the patients who undergo islet transplantation are insulin independent after a 3-year follow-up. Therefore, islet transplantation is able to successfully decrease plasma glucose and HbA1c levels, the occurrence of severe hypoglycemia, and improve patient quality of life. The goal of this paper was to review the human islet isolation and transplantation processes, and to describe the establishment of a human islet isolation laboratory at the Endocrine Division of the Hospital de Clínicas de Porto Alegre - Rio Grande do Sul, Brazil.

Human pancreatic islet transplantation: an update and description of the establishment of a pancreatic islet isolation laboratory

Type 1 diabetes mellitus (T1DM) is associated with chronic complications that lead to high morbidity and mortality rates in young adults of productive age. Intensive insulin therapy has been able to reduce the likelihood of the development of chronic diabetes complications. However, this treatment is still associated with an increased incidence of hypoglycemia. In patients with “brittle T1DM”, who have severe hypoglycemia without adrenergic symptoms (hypoglycemia unawareness), islet transplantation may be a therapeutic option to restore both insulin secretion and hypoglycemic perception. The Edmonton group demonstrated that most patients who received islet infusions from more than one donor and were treated with steroid-free immunosuppressive drugs displayed a considerable decline in the initial insulin independence rates at eight years following the transplantation, but showed permanent C-peptide secretion, which facilitated glycemic control and protected patients against hypoglycemic episodes. Recently, data published by the Collaborative Islet Transplant Registry (CITR) has revealed that approximately 50% of the patients who undergo islet transplantation are insulin independent after a 3-year follow-up. Therefore, islet transplantation is able to successfully decrease plasma glucose and HbA1c levels, the occurrence of severe hypoglycemia, and improve patient quality of life. The goal of this paper was to review the human islet isolation and transplantation processes, and to describe the establishment of a human islet isolation laboratory at the Endocrine Division of the Hospital de Clínicas de Porto Alegre – Rio Grande do Sul, Brazil.

Meta-analysis reveals the association of common variants in the uncoupling protein (UCP) 1-3 genes with body mass index variability.

BACKGROUND: The relationship between uncoupling protein (UCP) 1-3 polymorphisms and susceptibility to obesity has been investigated in several genetic studies. However, the impact of these polymorphisms on obesity is still under debate, with contradictory results being reported. Until this date, no meta-analysis evaluated the association of UCP polymorphisms with body mass index (BMI) variability. Thus, this paper describe a meta-analysis conducted to evaluate if the -3826A/G (UCP1); -866G/A, Ala55Val and Ins/Del (UCP2) and -55C/T (UCP3) polymorphisms are associated with BMI changes. METHODS: A literature search was run to identify all studies that investigated associations between UCP1-3 polymorphisms and BMI. Weighted mean differences (WMD) were calculated for different inheritance models. RESULTS: Fifty-six studies were eligible for inclusion in the meta-analysis. Meta-analysis results showed that UCP2 55Val/Val genotype was associated with increased BMI in Europeans [Random Effect Model (REM) WMD 0.81, 95% CI 0.20, 1.41]. Moreover, the UCP2 Ins allele and UCP3-55T/T genotype were associated with increased BMI in Asians [REM WMD 0.46, 95% CI 0.09, 0.83 and Fixed Effect Model (FEM) WMD 1.63, 95% CI 0.25, 3.01]. However, a decreased BMI mean was observed for the UCP2-866 A allele in Europeans under a dominant model of inheritance (REM WMD -0.18, 95% CI -0.35, -0.01). There was no significant association of the UCP1-3826A/G polymorphism with BMI mean differences. CONCLUSIONS: The meta-analysis detected a significant association between the UCP2-866G/A, Ins/Del, Ala55Val and UCP3-55C/T polymorphisms and BMI mean differences.

Associations between UCP1 -3826A/G, UCP2 -866G/A, Ala55Val and Ins/Del, and UCP3 -55C/T polymorphisms and susceptibility to type 2 diabetes mellitus: case-control study and meta-analysis.

BACKGROUND: Some studies have reported associations between five uncoupling protein (UCP) 1-3 polymorphisms and type 2 diabetes mellitus (T2DM). However, other studies have failed to confirm the associations. This paper describes a case-control study and a meta-analysis conducted to attempt to determine whether the following polymorphisms are associated with T2DM: -3826A/G (UCP1); -866G/A, Ala55Val and Ins/Del (UCP2) and -55C/T (UCP3). METHODS: The case-control study enrolled 981 T2DM patients and 534 nondiabetic subjects, all of European ancestry. A literature search was run to identify all studies that investigated associations between UCP1-3 polymorphisms and T2DM. Pooled odds ratios (OR) were calculated for allele contrast, additive, recessive, dominant and co-dominant inheritance models. Sensitivity analyses were performed after stratification by ethnicity. RESULTS: In the case-control study the frequencies of the UCP polymorphisms did not differ significantly between T2DM and nondiabetic groups (P>0.05). Twenty-three studies were eligible for the meta-analysis. Meta-analysis results showed that the Ala55Val polymorphism was associated with T2DM under a dominant model (OR = 1.27, 95% CI 1.03-1.57); while the -55C/T polymorphism was associated with this disease in almost all genetic models: allele contrast (OR = 1.17, 95% CI 1.02-1.34), additive (OR = 1.32, 95% CI 1.01-1.72) and dominant (OR = 1.18, 95% CI 1.02-1.37). However, after stratification by ethnicity, the UCP2 55Val and UCP3 -55C/T alleles remained associated with T2DM only in Asians (OR = 1.25, 95% CI 1.02-1.51 and OR = 1.22, 95% CI 1.04-1.44, respectively; allele contrast model). No significant association of the -3826A/G, -866G/A and Ins/Del polymorphisms with T2DM was observed. CONCLUSIONS: In our case-control study of people with European ancestry we were not able to demonstrate any association between the UCP polymorphisms and T2DM; however, our meta-analysis detected a significant association between the UCP2 Ala55Val and UCP3 -55C/T polymorphisms and increased susceptibility for T2DM in Asians.

The A allele of the rs1990760 polymorphism in the IFIH1 gene is associated with protection for arterial hypertension in type 1 diabetic patients and with expression of this gene in human mononuclear cells.

BACKGROUND: The rs1990760 polymorphism of interferon induced with helicase C domain 1 (IFIH1) has been associated with type 1 diabetes mellitus (T1DM). Here, we investigated whether this polymorphism is associated with T1DM or its clinical characteristics in a Brazilian population, and if IFIH1 gene expression in mononuclear cells from T1DM patients differs according to the genotypes of this polymorphism. A meta-analysis was also conducted to evaluate if the rs1990760 polymorphism is associated with T1DM. METHODS: Frequencies of the rs1990760 polymorphism were analyzed in 527 T1DM patients and in 517 healthy subjects. IFIH1 gene expressions according to genotypes were measured in a sub-sample of 26 T1DM patients by quantitative real-time PCR. RESULTS: Our data show the association of the A allele with risk to T1DM under a dominant model of inheritance [odds ratio (OR) = 1.421, P = 0.037], adjusting for ethnicity. The meta-analysis revealed significant association between the rs199760A allele and risk for T1DM for all analyzed inheritance models. Surprisingly, T1DM patients carrying the A allele showed lower levels of systolic (P = 0.001) and diastolic (P = 1 × 10(-10)) blood pressures as compared to G/G carriers. Furthermore, the A/A genotype seems to be associated with protection to arterial hypertension (AH) after adjustment for covariates (OR = 0.339, P = 0.019). IFIH1 gene expression in mononuclear cells from 26 T1DM patients did not differ among genotypes (P = 0.274). Nevertheless, IFIH1 gene expression was increased in mononuclear cells from T1DM patients with AH as compared with T1DM patients without AH [6.7 (1.7-2.0) vs. 1.8 (1.3-7.1) arbitrary units; P = 0.036]. The association with blood pressures and AH was not observed in patients with type 2 diabetes mellitus. CONCLUSIONS: Our results indicate that the rs1990760 polymorphism is associated with T1DM. Interestingly, the rs1990760 A allele seems to be associated with protection for AH in T1DM patients. Further studies are needed to confirm the association with AH.

D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms interact in the modulation of insulin resistance in type 2 diabetic patients.

Type 2 deiodinase (D2) converts T4 into its active metabolite T3, an essential step in thyroid metabolism. A Thr92Ala polymorphism in the gene encoding D2 has been inconsistently associated with insulin resistance (IR). Recently, it was reported that the D2 Thr92Ala (rs225014) and the peroxisome proliferator-activated receptor (PPAR) γ2 Pro12Ala (rs1801282) polymorphisms interact in the modulation of metabolic syndrome in nondiabetic subjects. Here, we investigated the effect of both polymorphisms, isolated or in combination, on IR in patients with type 2 diabetes mellitus (DM2). The D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms were genotyped in 721 DM2 patients. IR was evaluated using the homeostasis model assessment-IR (HOMA(IR)) index in a subgroup of 246 DM2 subjects. The frequencies of D2 Ala92 and PPARγ2 Ala12 variants were 0.390 and 0.074, respectively. Patients carrying D2 Ala/Ala genotype had a higher fasting plasma insulin and HOMA(IR) index as compared to patients carrying Thr/Ala or Thr/Thr genotypes (P = 0.022 and P = 0.001, respectively). A significant synergistic effect was observed between D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms on HOMA(IR) index, with carriers of both D2 Ala/Ala genotype and PPARγ2 Ala12 allele showing the highest HOMA(IR) values, after adjusting for age, gender, BMI, and use of medication for DM2 (P = 0.010). In conclusion, DM2 patients harboring both D2 Ala/Ala genotype and PPARγ2 Ala12 allele seem to present more severe IR than those with other D2/PPARγ2 genotype combinations. These findings suggest that these polymorphisms interact in the IR modulation, which may constitute a potential therapeutic target.

Polymorphisms of the UCP2 gene are associated with proliferative diabetic retinopathy in patients with diabetes mellitus.

BACKGROUND AND OBJECTIVE: Uncoupling protein 2 (UCP2) plays a role in controlling reactive oxygen species (ROS) production by mitochondria. As ROS overproduction is related to diabetic retinopathy (DR), UCP2 gene polymorphisms might be involved in the development of this complication. We investigated whether the -866G/A (rs659366), Ala55Val (rs660339) and 45 bp insertion/deletion (Ins/Del) polymorphisms in the UCP2 gene might be associated with proliferative DR (PDR). DESIGN AND METHODS: In this case-control study, we analysed 501 type 2 diabetic patients (242 patients with PDR and 259 subjects without any degree of DR) and 196 type 1 diabetic patients (85 cases with PDR and 111 without DR). Haplotypes constructed from the combination of the three UCP2 polymorphisms were inferred using a Bayesian statistical method. RESULTS: In the type 2 diabetic group, multivariate analyses confirmed that the haplotype [A Val Ins] was an independent risk factor for PDR when present in one [adjusted odds ratio (aOR) = 2.12; P = 0.006], at least one (aOR = 2.75; P = 0.00001), or two copies (aOR = 5.30; P = 0.00001), suggesting an additive model of inheritance. Nevertheless, in type 1 diabetic patients, the association of this haplotype with PDR was confirmed only when it was present in at least one (aOR = 2.68; P = 0.014) or two copies (aOR = 6.02; P = 0.005). CONCLUSIONS: The haplotype [A Val Ins] seems to be an important risk factor associated with PDR in both type 2 and 1 diabetic groups.