Associations between saliva and plasma cytokines in cognitively normal, older adults.

BACKGROUND: Inflammatory responses play key roles in the development and progression of many pathological conditions, including neurodegenerative diseases. Accurate quantification of inflammatory factors in saliva would be highly advantageous, given its convenience and non-invasive nature, especially in elderly populations. METHODS: In this study, we measured levels of 10 cytokines, and the pro-inflammatory factor, YKL-40, in plasma and saliva samples from a cohort of nondemented older adults (n = 71; 62% female; 70.3 ± 6.4 years) using sensitive electrochemiluminescence-based immunoassays. RESULTS: We found that the mean levels of all cytokines were higher in saliva compared to plasma and that strong sex differences were observed for both saliva and plasma cytokines in this population. Comparing each cytokine between the two biofluids, we found that levels of interferon-gamma (IFNγ), interleukin (IL)-6 and tumor necrosis factor-alpha (TNFα) in blood were significantly correlated with their respective levels in saliva. We further observed that levels of these cytokines in blood were significantly correlated with additional cytokines in saliva, including IL-1ß, IL-10, IL-8, IL12p70 and IL-13. CONCLUSIONS: These findings show that inflammatory markers in saliva are associated with those found in circulation, suggesting shared inflammatory mechanisms between these two fluids. The higher levels of cytokines measured in saliva suggest that it might represent a better peripheral fluid to gauge inflammatory processes. Finally, our findings of robust sex differences in several salivary cytokines could have important implications for their potential use as disease biomarkers in the elderly and might be related to sex differences in the prevalence of age-related conditions.

Influence of cortisol awakening response on telomere length: Trends for males and females.

Although telomere attrition is associated with the process of normal ageing, shorter telomere length (TL) has been associated with acute and chronic stressors. A neurobiological factor hypothesised to be responsible for this accelerated attrition is the dysregulation of the cortisol stress response, which can induce DNA damage affecting DNA telomeric caps. Marked sex differences are reported in both the cortisol stress response and telomere dynamics, yet no explicit investigation of sex specificity on the relationship between cortisol and TL exists. This study used mathematical equation modelling to describe the relationship between diurnal cortisol levels and telomere length within the context of sex, in a healthy population. Cortisol awakening responses (CAR) were measured via ELISA methodology in fifty-one healthy participants (28 males, 23 females). qPCRs determined TL from genomic DNA extracted from saliva. To assess the effect of free cortisol on relative TL ratio, a semi-log regression plot of the two variables trended for sex were fitted using spline curves. Results demonstrated significant differences between males and females in the relationship defining CAR and TL association (p = 0.03). These results suggest the relationship is not linear and can be represented as a complex arcsin function, and that the patterns are opposite in males and females. Males demonstrate a positive correlation, with higher levels of CAR being associated with longer telomere sequences. Females demonstrated a negative correlation. Future studies must carefully take into consideration moderating factors such as sex, and sex hormones across the lifespan when investigating telomere length.

Child Mouthing of Feces and Fomites and Animal Contact are Associated with Diarrhea and Impaired Growth Among Young Children in the Democratic Republic of the Congo: A Prospective Cohort Study (REDUCE Program).

OBJECTIVE: To identify exposure pathways to fecal pathogens that are significant contributors to diarrheal diseases and impaired growth in young children, and to evaluate scalable interventions to reduce fecal contamination from these pathways. STUDY DESIGN: Reducing Enteropathy, Undernutrition, and Contamination in the Environment (REDUCE) was a prospective cohort study of 370 children <5 years of age was conducted in Walungu Territory, South Kivu, Democratic Republic of the Congo. Child mouthing behaviors were assessed through caregiver reports and 5-hour structured observations. Caregiver reports of child contact with animals and child diarrhea were also obtained. Anthropometric measurements were collected at baseline and at a 6-month follow-up. RESULTS: Children observed putting soil in their mouth during structured observation at baseline had a significantly higher odds of diarrhea at the 6-month follow-up (OR, 1.79; 95% CI, 1.04 to 3.07). Children observed mouthing feces during structured observation had a significant reduction in height-for-age z-score (HAZ) from baseline to the 6-month follow-up (ΔHAZ, -0.69; 95% CI, -1.34 to -0.04). A significant reduction in HAZ was also observed for children with caregiver reports of touching guinea pigs (-0.33; 95% CI, -0.58 to -0.08) and rabbits (-0.34; 95% CI, -0.64 to -0.04) and children with feces in their sleeping space during unannounced spot checks (-0.41; 95% CI, -0.74 to -0.09). CONCLUSIONS: These findings emphasize the urgent need for infant water, sanitation, and hygiene interventions targeting child mouthing behaviors, fecal contamination in child living spaces, and child contact with domestic animals to reduce exposure to fecal pathogens among susceptible populations.

Saliva testing as a means to monitor therapeutic lithium levels in patients with psychiatric disorders: Identification of clinical and environmental covariates, and their incorporation into a prediction model.

OBJECTIVE: The narrow therapeutic window of lithium medications necessitates frequent serum monitoring, which can be expensive and inconvenient for the patient. Compared to blood, saliva collection is easier, non-invasive, requires less processing, and can be done without the need for trained personnel. This study investigated the utility of longitudinal salivary lithium level monitoring. METHODS: We measured salivary lithium levels using ICP-OES in n = 169 passive drool samples, collected both as single observations and longitudinally for up to 18 months, from a multi-center cohort of n = 75 patients with bipolar disorder or other psychiatric conditions. RESULTS: Saliva and serum lithium levels were highly correlated. Adjustment for daily lithium dose, diabetes, and smoking improved this relationship (r = 0.77). Using the adjusted intersubject equation and a patient's salivary lithium value, we observed a strong correlation between the predicted vs. observed serum lithium levels (r = 0.70). Most patients had highly stable saliva/serum ratios across multiple visits, with longitudinal variability significantly greater with age. Use of the intrasubject saliva/serum ratio from a single prior observation had similar predictive power to the use of the adjusted intersubject equation. However, the use of the mean intrasubject ratio from three prior observations could robustly predict serum lithium levels (predicted vs. observed r = 0.90). CONCLUSIONS: These findings strongly suggest that saliva could be used for lithium monitoring, and open the door for the development and implementation of a point-of-care salivary lithium device for use at home or the clinic. We propose that the use of saliva will dramatically improve treatment opportunities for patients with mood disorders.

Levels of Interleukin-6 in Saliva, but Not Plasma, Correlate with Clinical Metrics in Huntington's Disease Patients and Healthy Control Subjects.

Growing evidence suggests that inflammatory responses, in both the brain and peripheral tissues, contribute to disease pathology in Huntington's disease (HD), an inherited, progressive neurodegenerative disorder typically affecting adults in their 30-40 s. Hence, studies of inflammation-related markers in peripheral fluids might be useful to better characterize disease features. In this study, we measured levels of C-reactive protein (CRP), Interleukin-6 (IL-6), interleukin 1 beta (IL-1B), and alpha-amylase (AA) in saliva and plasma from n = 125 subjects, including n = 37 manifest HD patients, n = 36 premanifest patients, and n = 52 healthy controls, using immunoassays. We found increases in salivary levels of IL-6, IL-1B and CRP across different disease groups and increased levels of IL-6 in the plasma of HD patients as compared to premanifest patients and controls. The levels of salivary IL-6 were significantly correlated with each of the other salivary markers, as well as with IL-6 levels measured in plasma. Further, salivary IL-6 and IL-1B levels were significantly positively correlated with Total Motor Score (TMS) and chorea scores and negatively correlated with Total Functional Capacity (TFC) in HD patients, whereby in healthy control subjects, IL-6 was significantly negatively correlated with Montreal Cognitive Assessment (MoCA) and the Symbol Digit Modalities test (SDM). Interestingly, the plasma levels of IL-6 did not show similar correlations to any clinical measures in either HD or control subjects. These findings suggest that salivary IL-6 is particularly relevant as a potential non-invasive biomarker for HD symptoms. The advent of an effective, dependable salivary biomarker would meet the urgent need for a less invasive means of identifying and monitoring HD disease progression.

Environmental tobacco smoke exposure is associated with increased levels of metals in children's saliva.

BACKGROUND: Exposure to environmental tobacco smoke (ETS) has been associated with detectable levels of cotinine (a nicotine metabolite) in children's saliva. However, tobacco smoke also contains toxic and essential trace metals, including chromium (Cr), copper (Cu), lead (Pb), manganese (Mn), nickel (Ni) and zinc (Zn). OBJECTIVE: The current study examines whether there is a relationship between ETS exposure, as gauged by salivary cotinine, and salivary levels of these metals in a subset (n = 238) of children from the Family Life Project. METHODS: Using inductively-coupled-plasma optical emission spectrophotometry, we measured levels of metals in saliva from children at ~90 months of age. Salivary cotinine was measured using a commercial immunoassay. RESULTS: We found that Cr, Cu, Mn, and Zn were detected in most samples (85-99%) with lower levels of detection for Pb and Ni (9.3% and 13.9% respectively). There were no significant differences in any of the metal concentrations between males and females, nor were levels associated with body mass index, although significant differences in salivary Cr and Mn by race, state and income-to-needs ratio were observed. Children with cotinine levels >1 ng/ml had higher levels of Zn (b = 0.401, 95% CI: 0.183 to 0.619; p = 0.0003) and Cu (b = 0.655, 95% CI: 0.206 to 1.104; p = 0.004) compared to children with levels <1 ng/ml, after controlling for multiple confounders, including sex, race, BMI and income-to-needs ratio. Further, we show that children whose cotinine levels were >1 µg/L were more likely to have detectable levels of Pb in their saliva (b = 1.40, 95% CI: 0.424 to 2.459; p = 0.006) compared to children with cotinine levels <1 ng/ml, also considering confounders. IMPACT STATEMENT: This is the first study to demonstrate significant associations between salivary cotinine and salivary levels of Cu, Zn and Pb, suggesting that environmental tobacco smoke exposure my be one source of increased children's exposure to heavy metals. This study also demonstrates that saliva samples can be used to measure heavy metal exposure, and thus serve as a non-invasive tool for assessing a broader range of risk indicators.

Amitriptyline's anticholinergic adverse drug reactions-A systematic multiple-indication review and meta-analysis.

BACKGROUND: Half the US population uses drugs with anticholinergic properties. Their potential harms may outweigh their benefits. Amitriptyline is among the most frequently prescribed anticholinergic medicinal products, is used for multiple indications, and rated as strongly anticholinergic. Our objective was to explore and quantify (anticholinergic) adverse drug reactions (ADRs) in patients taking amitriptyline vs. placebo in randomized controlled trials (RCTs) involving adults and healthy individuals. METHODS: We searched electronic databases from their inception until 09/2022, and clinical trial registries from their inception until 09/2022. We also performed manual reference searches. Two independent reviewers selected RCTs with ≥100 participants of ≥18 years, that compared amitriptyline (taken orally) versus placebo for all indications. No language restrictions were applied. One reviewer extracted study data, ADRs, and assessed study quality, which two others verified. The primary outcome was frequency of anticholinergic ADRs as a binary outcome (absolute number of patients with/without anticholinergic ADRs) in amitriptyline vs. placebo groups. RESULTS: Twenty-three RCTs (mean dosage 5mg to 300mg amitriptyline/day) and 4217 patients (mean age 40.3 years) were included. The most frequently reported anticholinergic ADRs were dry mouth, drowsiness, somnolence, sedation, fatigue, constitutional, and unspecific anticholinergic ADRs. Random-effects meta-analyses showed anticholinergic ADRs had a higher odd's ratio for amitriptyline versus placebo (OR = 7.41; [95% CI, 4.54 to 12.12]). Non-anticholinergic ADRs were as frequent for amitriptyline as placebo. Meta-regression analysis showed anticholinergic ADRs were not dose-dependent. DISCUSSION: The large OR in our analysis shows that ADRs indicative of anticholinergic activities can be attributed to amitriptyline. The low average age of participants in our study may limit the generalizability of the frequency of anticholinergic ADRs in older patients. A lack of dose-dependency may reflect limited reporting of the daily dosage when the ADRs occurred. The exclusion of small studies (<100 participants) decreased heterogeneity between studies, but may also have reduced our ability to detect rare events. Future studies should focus on older people, as they are more susceptible to anticholinergic ADRs. REGISTRATION: PROSPERO: CRD42020111970.

Long-term efficacy and safety of vibegron versus mirabegron and anticholinergics for overactive bladder: a systematic review and network meta-analysis.

Background: Few randomized controlled trials evaluate the long-term efficacy and safety of pharmacotherapy for overactive bladder (OAB). This network meta- analysis compares the long-term (52-week) efficacy and safety of vibegron, mirabegron and anticholinergics for the treatment of OAB. Methods: A systematic literature review and network meta-analysis were conducted following PRISMA guidelines using MEDLINE, Embase and Cochrane Central Register of Controlled Trials and terms related to OAB. Efficacy outcomes included change from baseline to week 48-52 in mean daily total urinary incontinence (UI) episodes, mean daily number of micturitions and volume voided/micturition. Efficacy outcomes were analysed using Bayesian models. Commonly reported adverse events (AEs) are described. Results: Of 2098 hits retrieved, 5 publications and 1 study report describing 5 unique randomized controlled trials were included in the analyses. Mean (95% credible interval) change from baseline in total UI episodes for vibegron 75 mg (-2.2; -2.9 to -1.5) showed a significantly greater reduction than mirabegron 50 mg (-1.3; -1.9 to -0.8) and tolterodine 4 mg extended release (-1.6; -2.1 to -1.1). No significant differences were observed between vibegron and comparators for daily micturitions or volume voided/micturition. Within the manuscripts, the 4 most common AEs (range) for anticholinergics included dry mouth (5.2-90.0%), constipation (7.7-65.0%), blurred vision (3.8-35.0%) and hypertension (8.6-9.6%); the 4 most commonly reported AEs for ß3-adrenergic agonists included hypertension (8.8-9.2%), urinary tract infection (5.9-6.6%), headache (5.5%) and nasopharyngitis (4.8-5.2%). Conclusion: Vibegron was associated with significantly greater improvement in daily total UI episodes at 52 weeks than mirabegron and tolterodine. When reported, the most common AE for anticholinergics was dry mouth and for ß3-adrenergic agonists was hypertension. Hypertension incidence was similar between drug classes.

Efficacy of Vibegron and Mirabegron for Overactive Bladder: A Systematic Literature Review and Indirect Treatment Comparison.

BACKGROUND: In the absence of head-to-head trials, we performed an indirect treatment comparison of the ß3-adrenergic agonists vibegron and mirabegron in the treatment of overactive bladder (OAB). METHODS: PubMed, Embase, and Cochrane Library were searched for articles related to phase 3, double-blind, controlled trials of vibegron 75 mg and mirabegron 25/50 mg in patients with OAB. Efficacy outcomes included change from baseline at weeks 4, 12, and 52 in mean daily number of total urinary incontinence episodes and micturitions and mean volume voided/micturition. Effect size was computed as placebo-subtracted change from baseline (weeks 4, 12) or active control (tolterodine)-subtracted change from baseline (week 52) for each treatment group. Adverse events (AEs) are presented descriptively. RESULTS: After removal of duplicates, 49 records were identified, and after screening 9 met inclusion criteria for analysis. Vibegron showed significantly greater reduction in mean daily number of total incontinence episodes than mirabegron 25 mg at week 4, mirabegron 50 mg (weeks 4, 52), and tolterodine (weeks 4, 12) (P < 0.05, each) and significantly greater improvement in volume voided versus mirabegron 25 mg (week 12), mirabegron 50 mg (weeks 12, 52), and tolterodine (week 4) (P < 0.05, each). Confidence intervals of point estimates overlapped zero for all other comparisons of vibegron and mirabegron (25 or 50 mg) or tolterodine, indicating no significant differences between treatments for these time/endpoints. Urinary tract infection, hypertension, and dry mouth were the most commonly occurring AEs for vibegron, mirabegron, and tolterodine, respectively, in the short-term trials; hypertension was the most commonly occurring AE with all three treatments in the long-term trials. CONCLUSIONS: Vibegron was associated with significant improvement in total incontinence episodes versus mirabegron at 4 and 52 weeks and volume voided at 12 and 52 weeks. Improvement in micturitions was similar between vibegron and mirabegron or tolterodine. Incidence of AEs was generally comparable between vibegron and mirabegron.

Identifying psychosocial determinants of water, sanitation, and hygiene (WASH) behaviors for the development of evidence-based Baby WASH interventions (REDUCE program).

Diarrheal disease remains a leading cause of child mortality, globally. In the Democratic Republic of the Congo (DRC), each year there are an estimated 45 million episodes of diarrhea in children under five years of age. The Reducing Enteropathy, Diarrhea, Undernutrition, and Contamination in the Environment (REDUCE) program seeks to develop theory-driven, evidence-based approaches to reduce diarrheal diseases among young children. The REDUCE prospective cohort study in Walungu Territory in Eastern DRC took guidance from the risks, attitudes, norms, abilities, and self-regulation model, the integrated behavioral model for water, sanitation, and hygiene (WASH), and other behavior change theories to identify psychosocial factors associated with WASH behaviors. Psychosocial factors were measured among 417 caregivers at baseline and caregiver responses to child mouthing of dirty fomites and handwashing with soap was assessed by 5-hour structured observation at the 6-month follow-up. Caregivers who agreed that their child could become sick if they put dirt in their mouth (perceived susceptibility) and caregivers that agreed they could prevent their child from playing with dirty things outside (self-efficacy) were significantly more likely to stop their child from mouthing a dirty fomite. Higher perceived susceptibility, self-efficacy, and disgust, and lower dirty reactivity, were associated with higher handwashing with soap behaviors. This study took a theory-driven and evidence-based approach to identify psychosocial factors to target for intervention development. The findings from this study informed the development of the REDUCE Baby WASH Modules that have been delivered to over 1 million people in eastern DRC.

Salivary levels of total huntingtin are elevated in Huntington's disease patients.

Patients with Huntington's disease (HD), an autosomal-dominant neurodegenerative disease, show substantial variability in age-of-onset, symptom severity and course of illness, warranting the need for biomarkers to anticipate and monitor these features. The HD gene encodes the disease protein huntingtin (Htt), a potentially useful biomarker for this disease. In the current study, we determined whether total Htt protein (normal plus mutant; "tHtt") could be reliably measured in human saliva, a body fluid that is much more accessible compared to cerebral spinal fluid or even blood, and whether salivary levels of tHtt were clinically meaningful. We collected 146 saliva samples from manifest HD patients, early-premanifest individuals, late-premanifest patients, gene-negative family members and normal controls. We found that tHtt protein could be reliably and stably detected in human saliva and that tHtt levels were significantly increased in saliva from HD individuals compared to normal controls. Salivary tHtt showed no gender effects, nor were levels correlated with total protein levels in saliva. Salivary tHtt was significantly positively correlated with age, but not age-of-onset or CAG-repeat length. Importantly, salivary tHtt was significantly correlated with several clinical measures, indicating relevance to disease symptom onset and/or severity. Measurements of salivary tHtt offer significant promise as a relevant, non-invasive disease biomarker for HD, and its use could be implemented into clinical applications.

Structure activity relationship studies of carboxamido-biaryl ethers as opioid receptor antagonists (OpRAs). Part 2.

A series of 6-bicycloaryloxynicotinamides were identified as opioid receptor antagonists at mu, kappa, and delta receptors. Compounds in the 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide scaffold exhibited potent in vitro functional antagonism at all three receptors.

The impact of oligofructose on stimulation of gut hormones, appetite regulation and adiposity.

OBJECTIVE: To investigate the effect of nutrient stimulation of gut hormones by oligofructose supplementation on appetite, energy intake (EI), body weight (BW) and adiposity in overweight and obese volunteers. METHODS: In a parallel, single-blind and placebo-controlled study, 22 healthy overweight and obese volunteers were randomly allocated to receive 30 g day(-1) oligofructose or cellulose for 6 weeks following a 2-week run-in. Subjective appetite and side effect scores, breath hydrogen, serum short chain fatty acids (SCFAs), plasma gut hormones, glucose and insulin concentrations, EI, BW and adiposity were quantified at baseline and post-supplementation. RESULTS: Oligofructose increased breath hydrogen (P < 0.0001), late acetate concentrations (P = 0.024), tended to increase total area under the curve (tAUC)420 mins peptide YY (PYY) (P = 0.056) and reduced tAUC450 mins hunger (P = 0.034) and motivation to eat (P = 0.013) when compared with cellulose. However, there was no significant difference between the groups in other parameters although within group analyses showed an increase in glucagon-like peptide 1 (GLP-1) (P = 0.006) in the cellulose group and a decrease in EI during ad libitum meal in both groups. CONCLUSIONS: Oligofructose increased plasma PYY concentrations and suppressed appetite, while cellulose increased GLP-1 concentrations. EI decreased in both groups. However, these positive effects did not translate into changes in BW or adiposity.