Studies In Healthy Individuals Research Articles

'Citicoline' and support of the memory function: Evaluation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006.

Following an application from Egde Pharma Sp. z o.o, submitted for authorisation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of Poland, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim related to citicoline and memory. The Panel considers that the food, citicoline (cytidine 5-diphosphocholine, CDP-Choline) inner salt, is sufficiently characterised. Improvement, maintenance or reduced loss of memory is a beneficial physiological effect for middle-aged or elderly adults encountering age-associated subjective memory impairment. The applicant identified three pertinent human intervention studies in healthy individuals that investigated the effect of citicoline on memory. In weighing the evidence, the Panel took into account that only one randomised controlled trial in healthy participants showed a beneficial effect of citicoline on episodic memory when consumed at doses of 500 mg/day for 12 weeks, whereas this effect has not been observed in another study using citicoline at doses of 1 g/day for 3 months or supported by data obtained in patients with dementia using doses of 1 g/day for 12 weeks and 12 months. No convincing evidence of a plausible mechanism by which citicoline or any of its components (in addition to their endogenous synthesis) could exert an effect on memory in humans has been provided. The Panel concludes that a cause-and-effect relationship has not been established between the consumption of citicoline (CDP-Choline) inner salt and improvement, maintenance or reduced loss of memory in middle-aged or elderly adults encountering age-associated subjective memory impairment.

Microdosing psychedelics in the treatment of ADHD and comorbid disorders

AbstractMicrodosing psychedelics has garnered considerable attention within both nonprofessional circles and the scientific community in recent years. This method involves taking small, non-hallucinogenic doses of substances like LSD or psilocybin over weeks or months, purportedly to enhance specific behaviors, emotions, or address psychiatric conditions.Exploring these assertions is crucial given the potential therapeutic value of microdosing, especially in conditions that respond positively to full psychedelic doses, such as depression. The full psychedelic experience might not always be suitable due to various factors like age, capacity to consent or comprehend the experience (e.g., dementia), or individual personality traits that might hinder surrendering to the experience. Microdosing could potentially serve as a maintenance therapy post-full dose administration, aiding specific psychological or biological processes during therapy or therapeutic exercises.Recent studies in healthy individuals highlight that small psychedelic doses have nuanced effects on pain perception, mood, neuroplasticity, sleep duration, brain connectivity, and default mode network synchronicity. However, some parameters show null effects after both single and repeated administration. Our survey research uncovered that individuals with ADHD reported symptom relief through microdosing, deeming it more effective than their conventional treatments. Subsequently, we conducted a naturalistic study following individuals with ADHD across a 4-week microdosing period. Our findings indicated a reduction in symptoms over time, an increase in trait mindfulness, and a decrease in neuroticism compared to baseline. While these results are intriguing, they necessitate validation in a clinical trial. We have recently concluded such a trial and are currently analyzing the data to further explore these effects.Disclosure of InterestK. Kuypers Grant / Research support from: The author is a principal investigator on a research project that is sponsored by Mindmed, a company that is developing psychedelic medicines.

Serum levels of trimethylamine N-oxide and kynurenine novel biomarkers are associated with adult metabolic syndrome and its components: a case-control study from the TEC cohort.

Epidemiologic research suggests that gut microbiota alteration (dysbiosis) may play a role in the pathogenesis of metabolic syndrome (MetS). Dysbiosis can influence Trimethylamine N-oxide (TMAO) a gut microbiota-derived metabolite, as well as kynurenine pathways (KP), which are known as a new marker for an early predictor of chronic diseases. Hence, the current study aimed to investigate the association between KYN and TMAO with MetS and its components. This case-control study was conducted on 250 adults aged 18 years or over of Tehran University of Medical Sciences (TUMS) Employee's Cohort study (TEC) in the baseline phase. Data on the dietary intakes were collected using a validated dish-based food frequency questionnaire (FFQ) and dietary intakes of nitrite and nitrate were estimated using FFQ with 144 items. MetS was defined according to the NCEP ATP criteria. Serum profiles TMAO and KYN were measured by standard protocol. The mean level of TMAO and KYN in subjects with MetS was 51.49 pg/mL and 417.56 nmol/l. High levels of TMAO (≥30.39 pg/mL) with MetS were directly correlated, after adjusting for confounding factors, the odds of MetS in individuals 2.37 times increased (OR: 2.37, 95% CI: 1.31-4.28, P-value = 0.004), also, high levels of KYN (≥297.18 nmol/L) increased odds of Mets+ 1.48 times, which is statistically significant (OR: 1.48, 95% CI: 0.83-2.63, P-value = 0.04). High levels of TMAO compared with the reference group increased the odds of hypertriglyceridemia and low HDL in crude and adjusted models (P < 0.05). Additionally, there was a statistically significant high level of KYN increased odds of abdominal obesity (P < 0.05). Our study revealed a positive association between serum TMAO and KYN levels and MetS and some of its components. For underlying mechanisms and possible clinical implications of the differences. Prospective studies in healthy individuals are necessary.

Static autoregulation in humans.

The process by which cerebral blood flow (CBF) remains approximately constant in response to short-term variations in arterial blood pressure (ABP) is known as cerebral autoregulation. This classic view, that it remains constant over a wide range of ABP, has however been challenged by a growing number of studies. To provide an updated understanding of the static cerebral pressure-flow relationship and to characterise the autoregulation curve more rigorously, we conducted a comprehensive literature research. Results were based on 143 studies in healthy individuals aged 18 to 65 years. The mean sensitivities of CBF to changes in ABP were found to be 1.47 ± 0.71%/% for decreased ABP and 0.37 ± 0.38%/% for increased ABP. The significant difference in CBF directional sensitivity suggests that cerebral autoregulation appears to be more effective in buffering increases in ABP than decreases in ABP. Regression analysis of absolute CBF and ABP identified an autoregulatory plateau of approximately 20 mmHg (ABP between 80 and 100 mmHg), which is much smaller than the widely accepted classical view. Age and sex were found to have no effect on autoregulation strength. This data-driven approach provides a quantitative method of analysing static autoregulation that can be easily updated as more experimental data become available.

Real world evidence of improved attention and cognition during physical therapy paired with neuromodulation: a brain vital signs study.

Non-invasive neuromodulation using translingual neurostimulation (TLNS) has been shown to advance rehabilitation outcomes, particularly when paired with physical therapy (PT). Together with motor gains, patient-reported observations of incidental improvements in cognitive function have been noted. Both studies in healthy individuals and case reports in clinical populations have linked TLNS to improvements in attention-related cognitive processes. We investigated if the use of combined TLNS/PT would translate to changes in objective neurophysiological cognitive measures in a real-world clinical sample of patients from two separate rehabilitation clinics. Brain vital signs were derived from event-related potentials (ERPs), specifically auditory sensation (N100), basic attention (P300), and cognitive processing (N400). Additional analyses explored the attention-related N200 response given prior evidence of attention effects from TLNS/PT. The real-world patient sample included a diverse clinical group spanning from mild-to-moderate traumatic brain injury (TBI), stroke, Multiple Sclerosis (MS), Parkinson's Disease (PD), and other neurological conditions. Patient data were also acquired from a standard clinical measure of cognition for comparison. Results showed significant N100 variation between baseline and endpoint following TLNS/PT treatment, with further examination showing condition-specific significant improvements in attention processing (i.e., N100 and N200). Additionally, CogBAT composite scores increased significantly from baseline to endpoint. The current study highlighted real-world neuromodulation improvements in neurophysiological correlates of attention. Overall, the real-world findings support the concept of neuromodulation-related improvements extending beyond physical therapy to include potential attention benefits for cognitive rehabilitation.

0631 Overnight Emotional Memory in Insomnia versus Good Sleepers

Abstract Introduction “Sleep to forget and sleep to remember” model postulates that the content of emotional memory is strengthened during sleep while the arousal component is attenuated. Experimental sleep deprivation studies in healthy individuals have supported the model, but it is not known if sleep in individuals with insomnia, a condition of chronic poor sleep, provides the same effect on emotional memory. Methods Individuals reporting insomnia and good sleepers (n = 76 and n = 83 respectively; 83% female, mean age of 43.2 years) completed a picture-rating task to assess a) emotional valence ratings pre and post sleep and b) recognition accuracy post-sleep. In addition, an autobiographical memory task was completed during the day to assess a) the number of recalled memories in a 2-minute period for good and bad past events respectively, and b) emotional intensity ratings of the retrieved memories at the time the event occurred and how they feel now. Results Wilcoxon rank-sum test was used to assess group differences. Sleep diary variables on the experimental night showed that individuals with insomnia experienced a significantly more disrupted sleep than good sleepers (SOL: r = 0.537; WASO: r = 0.620; TST: r = 0.669). In the picture-rating task, there was no significant group difference for recognition accuracy (neutral stimuli: r = 0.016; negative stimuli: r = 0.018) or change in emotional valence pre-to-post sleep (neutral stimuli: r = 0.003; negative stimuli: r = 0.008). In the autobiographical memory task, individuals with insomnia remembered significantly fewer good days (r = 0.245) and rated their bad days at the time of its occurrence as significantly worse than good sleepers (r = 0.235). There was no significant group difference in the extent to which emotional intensity faded more for bad days than good days (r = 0.113). Conclusion We have shown that autobiographical memory is altered in insomnia which may have important influence on mental health. Our findings also suggest that overnight memory consolidation for negative stimuli is not affected in insomnia versus good sleepers. This may be a reflection of our one-night protocol; future work is needed across consecutive days. Support (if any) Dr-Mortimer-&amp;-Theresa-Sackler-Foundation

Evaluation of the hypocoagulatory role of the lungs using thromboelastography in postpartum women with multiple organ failure

Aim. To evaluate the hypocoagulatory role of the lungs in postpartum women with multiple organ failure using thromboelastography.Materials and methods. Sixty-six postpartum women aged 19 to 45 with multiple organ failure were examined. Postpartum women were divided into three groups depending on the nonrespiratory lung function impairment stage.The first group included 23 (34.8%) postpartum women with compensated nonrespiratory pulmonary function; the second group included 24 (36.4%) postpartum women with subcompensated stage of nonrespiratory pulmonary function disorder; the third group included 19 (28.8%) postpartum women with a decompensated form of nonrespiratory pulmonary function disorder.Results and discussion. When analyzing the results of studies in healthy individuals noted TEG constant R reflecting the rate of thromboplastin formation. Thrombin constant K, nonspecific coagulation constant R+K, prothrombin use constant R/K, T - total clotting, syneresis (compaction) C are prolonged in the arterial blood flowing from the lungs compared to the mixed venous blood.Conclusions. In healthy humans, the lungs act as a coagulation filter, reducing the hemostatic potential of the blood. The hypocoagulatory function of the lungs in postpartum women with multiple organ failure is impaired in stages. The thromboelastographic hemostasis study allows rapid and complete assessment of the hypocoagulatory role of the lungs in parturient women with multiple organ failure.

The effect of high-dose vitamin D supplementation on hepcidin-25 and erythropoiesis in patients with chronic kidney disease

BackgroundHepcidin is considered to play a central role in the pathophysiology of renal anemia. Recent studies in healthy individuals have demonstrated a suppressive effect of vitamin D (VD) on the expression of hepcidin. In this post-hoc analysis based on a randomized controlled study, we evaluated the effect of supplementing chronic kidney disease (CKD) patients (stage G3-G4) with a high daily dose of native VD on serum levels of hepcidin-25, the hepcidin/ferritin ratio, as well as on markers of erythropoiesis.MethodsPatients with CKD stage G3-G4 included in a double blind, randomized, placebo (PBO) controlled study with available hepcidin measurements were analyzed. Study subjects received either 8000 international units (IU) of cholecalciferol daily or PBO for 12 weeks. We evaluated the change in markers of hepcidin expression, erythropoiesis, and iron status from baseline to week 12 and compared the change between the groups.ResultsEighty five patients completed the study. Calcitriol, but not 25-hydroxyvitamin D (25(OH) D), was inversely correlated with serum levels of hepcidin-25 (rho = -0,38; p = < 0, 01 and rho = -0,02; p = 0, 89, respectively) at baseline. Supplementation with VD significantly raised the serum concentration of serum 25(OH)D in the treatment group (from 54 (39–71) to 156 (120–190) nmol/L; p = < 0, 01)) but had no effect on any of the markers of hepcidin, erythropoiesis, or iron status in the entire cohort. However, we did observe an increase in hemoglobin (HB) levels and transferrin saturation (TSAT) as compared to the PBO group in a subgroup of patients with low baseline 25(OH)D levels (< 56 nmol/L). In contrast, in patients with high baseline 25(OH)D values (≥ 56 nmol/L), VD supplementation associated with a decrease in HB levels and TSAT (p = 0,056) within the VD group in addition to a decrease in hepcidin levels as compared to the PBO group.ConclusionHigh-dose VD supplementation had no discernible effect on markers of hepcidin or erythropoiesis in the entire study cohort. However, in patients with low baseline 25(OH)D levels, high-dose VD supplementation associated with beneficial effects on erythropoiesis and iron availability. In contrast, in patients with elevated baseline 25(OH)D levels, high-dose VD supplementation resulted in a decrease in hepcidin levels, most likely due to a deterioration in iron status.

Acute Effects of Insulin Infusion on Kidney Hemodynamic Function in People With Type 2 Diabetes and Normal Kidney Function

Acute Effects of Insulin Infusion on Kidney Hemodynamic Function in People With Type 2 Diabetes and Normal Kidney Function

Auricular transcutaneous vagus nerve stimulation for alcohol use disorder: A chance to improve treatment?

Alcohol use disorder (AUD) is a relapsing-remitting condition characterized by excessive and/or continued alcohol consumption despite harmful consequences. New adjuvant tools, such as noninvasive brain stimulation techniques, might be helpful additions to conventional treatment approaches or even provide an alternative option for patients who fail to respond adequately to other treatment options. Here, we discuss the potential use of auricular transcutaneous vagus nerve stimulation (atVNS) as an ADD-ON intervention in AUD. Compared with other techniques, atVNS has the advantage of directly stimulating nuclei that synthesize GABA and catecholamines, both of which are functionally altered by alcohol intake in AUD patients. Pharmacological options targeting those neurotransmitters are widely available, but have relatively limited beneficial effects on cognition, even though restoring normal cognitive functioning, especially cognitive control, is key to maintaining abstinence. Against this background, atVNS could be a particularly useful add-on because there is substantial meta-analytic evidence based on studies in healthy individuals that atVNS can enhance cognitive control processes that are crucial to regaining control over drug intake. We discuss essential future research on using atVNS as an ADD-ON intervention in AUD to enhance clinical and cognitive outcomes by providing a translational application. Given that this novel technique can be worn like an earpiece and can be employed without medical supervision/outside the clinical settings, atVNS could be well integratable into the daily life of the patients, where the task of regaining control over drug intake is most challenging.

Diet, Fecal Microbiome, and Trimethylamine N-Oxide in a Cohort of Metabolically Healthy United States Adults.

TMAO is elevated in individuals with cardiometabolic diseases, but it is unknown whether the metabolite is a biomarker of concern in healthy individuals. We conducted a cross-sectional study in metabolically healthy adults aged 18–66 years with BMI 18–44 kg/m2 and assessed the relationship between TMAO and diet, the fecal microbiome, and cardiometabolic risk factors. TMAO was measured in fasted plasma samples by liquid chromatography mass spectrometry. The fecal microbiome was assessed by 16S ribosomal RNA sequencing and recent food intake was captured by multiple ASA24 dietary recalls. Endothelial function was assessed via EndoPAT. Descriptive statistics were computed by fasting plasma TMAO tertiles and evaluated by ANOVA and Tukey’s post-hoc test. Multiple linear regression was used to assess the relationship between plasma TMAO and dietary food intake and metabolic health parameters. TMAO concentrations were not associated with average intake of animal protein foods, fruits, vegetables, dairy, or grains. TMAO was related to the fecal microbiome and the genera Butyribrio, Roseburia, Coprobaciullus, and Catenibacterium were enriched in individuals in the lowest versus the highest TMAO tertile. TMAO was positively associated with α-diversity and compositional differences were identified between groups. TMAO was not associated with classic cardiovascular risk factors in the healthy cohort. Similarly, endothelial function was not related to fasting TMAO, whereas the inflammatory marker TNF-α was significantly associated. Fasting plasma TMAO may not be a metabolite of concern in generally healthy adults unmedicated for chronic disease. Prospective studies in healthy individuals are necessary.

The Contribution of Liver Sinusoidal Endothelial Cells to Clearance of Therapeutic Antibody.

Many chronic inflammatory diseases are treated by administration of “biological” therapies in terms of fully human and humanized monoclonal antibodies or Fc fusion proteins. These tools have widespread efficacy and are favored because they generally exhibit high specificity for target with a low toxicity. However, the design of clinically applicable humanized antibodies is complicated by the need to circumvent normal antibody clearance mechanisms to maintain therapeutic dosing, whilst avoiding development of off target antibody dependent cellular toxicity. Classically, professional phagocytic immune cells are responsible for scavenging and clearance of antibody via interactions with the Fc portion. Immune cells such as macrophages, monocytes, and neutrophils express Fc receptor subsets, such as the FcγR that can then clear immune complexes. Another, the neonatal Fc receptor (FcRn) is key to clearance of IgG in vivo and serum half-life of antibody is explicitly linked to function of this receptor. The liver is a site of significant expression of FcRn and indeed several hepatic cell populations including Kupffer cells and liver sinusoidal endothelial cells (LSEC), play key roles in antibody clearance. This combined with the fact that the liver is a highly perfused organ with a relatively permissive microcirculation means that hepatic binding of antibody has a significant effect on pharmacokinetics of clearance. Liver disease can alter systemic distribution or pharmacokinetics of antibody-based therapies and impact on clinical effectiveness, however, few studies document the changes in key membrane receptors involved in antibody clearance across the spectrum of liver disease. Similarly, the individual contribution of LSEC scavenger receptors to antibody clearance in a healthy or chronically diseased organ is not well characterized. This is an important omission since pharmacokinetic studies of antibody distribution are often based on studies in healthy individuals and thus may not reflect the picture in an aging or chronically diseased population. Therefore, in this review we consider the expression and function of key antibody-binding receptors on LSEC, and the features of therapeutic antibodies which may accentuate clearance by the liver. We then discuss the implications of this for the design and utility of monoclonal antibody-based therapies.

Nailfold Capillaroscopy of Healthy Individuals - An Observational Study.

Background:Nailfold capillaroscopy (NFC) is a noninvasive quick method to visualize capillaries in the nailfold. There is paucity of these studies in healthy individuals in skin of color.Aim:To evaluate the morphological characteristics and density of nailfold capillaries in healthy individuals.Settings and Design:This observational cross-sectional study was conducted in the Department of Dermatology at a tertiary care hospital. About 150 healthy individuals by consecutive sampling were included in the study.Materials and Methods:A total of 150 healthy individuals aged between 20 and 60 years were enrolled from January 2021 to September 2021 after consenting to the study protocol and qualifying the inclusion and exclusion criteria. NFC was performed for various morphological parameters and mean capillary density was also calculated. Comparison was done in male vs female, age group 20–40 vs 41–60, and body mass index (BMI) <24.9 vs >25.Statistical Analysis:Different morphological parameters and capillary density were recorded and analyzed. The Mann–Whitney and Pearson’s chi square was used according to type of data.Results:The study observed tortuous capillaries (45.33%), meandering capillaries (44.66%), neoangiogenesis (38.66%), plexus visibility (36.66%), dilated capillaries (33.33%), receding capillaries (31.33%), angulated capillaries (14.66%), and ramified capillaries (6.6%). The study found significantly decreased plexus visibility in those with BMI > 25.Tortuous and receding capillaries were significantly increased in age group >40 years.Conclusion:Various capillary morphological findings can be present in normal individuals but their presence in more number of fingers should be considered to be pathological. This data on normal morphology and capillary density add to the physiological NFC findings and thus aid in identifying the abnormalities.

Abstract P161: Impaired serological response to SARS-CoV-2 mRNA vaccination in patients with hematologic malignancies

Abstract Although SARS-CoV-2 vaccines induce a robust immune response in healthy individuals, limited reports indicate that some immunocompromised patients may not produce anti-spike antibodies after vaccination. In this report, we assessed anti-spike antibody levels among 2200 patients with hematologic malignancies after SARS-CoV-2 mRNA vaccination (NCT04794387). Diagnoses and treatments were self-reported using a national online registry. The side-effects profile of the vaccines was not different compared to previous studies in healthy individuals. The serological response &amp;gt;14 days after full vaccination was evaluated using the Roche Elecsys total immunoglobulin anti-spike assay (range: 0-250 U/ml; positive cutoff of &amp;gt; 0.8 U/mL). Approximately 40% and 60% were male and females, respectively, 96% were white or Caucasian, and the median age was 67 (range, 21 to 92 years). Patients received the BNT162b (Pfizer/BioNtech: 55%) or mRNA1246 (Moderna: 45%) vaccines. The largest patient populations had chronic lymphocytic leukemia (CLL: N = 978, 44%), multiple myeloma (MM: 253, 11.4%), follicular lymphoma (FL: 147, 6.6%), Waldenstrom’s macroglobulinemia (WM: 115, 5.9%), Hodgkin lymphoma (HL: 79, 3.5%), diffuse large B-cell lymphoma (DLBCL: 83, 3.7%), mantle cell lymphoma (MCL: 58, 2.6%), or marginal zone lymphomas (MZL: 52, 2.3%). Ninety-one patients (3.8%) were positive for the nucleocapsid antibodies and deleted from the initial analysis. Overall, 564 patients (25%) were seronegative after full vaccination. The largest percentages of seronegative patients had B-cell derived hematologic malignancies: MCL (50%), MZL (37%), DLBCL (34%), CLL (32%), FL (28%), and WM (25%). Seronegative rates of 5.9% and 14% were found in patients with multiple myeloma and acute lymphoblastic leukemia, respectively. All but one HL patient and no patients with smoldering multiple myeloma, myeloproliferative neoplasms, myelodysplastic syndrome were seronegative. Anti-spike antibody levels did not markedly change within 35 individual patients &amp;gt;45 days after the initial vaccine assessment except for one patient who seroconverted after a third vaccine dose. High seronegative rates correlated with treatment regimens that contained anti-CD20 mAbs, any Bruton tyrosine kinase inhibitor, and CD19-directed CAR T-therapy. Seronegative rates were higher with the BioNTech/Pfizer vs. Moderna vaccines in an unadjusted analysis (odds ratio, 1.5; 95% confidence interval, 1.05-1.55; p= 0.015). The overall seronegative rate was ~1% among nucleocapsid-positive patients. Among CLL patients, the seronegative rate was lower among nucleocapsid-positive patients compared to nucleocapsid-negative patients (0% vs. 32%, p&amp;lt;0.001). Providers should be aware that a substantial subset of vaccinated blood cancer patients may be at high risk of breakthrough COVID-19 infections. Alternate therapies with monoclonal antibodies or booster vaccination including those that would allow exposure to more than the spike protein, may offer additional protection for this vulnerable population. Citation Format: Lee M. Greenberger, Larry A. Saltzman, Jonathon W. Senefeld, Patrick W. Johnson, Louis J. DeGennaro, Gwen L. Nichols. Impaired serological response to SARS-CoV-2 mRNA vaccination in patients with hematologic malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P161.

Plasma microRNA Interindividual Variability in Healthy Individuals, Pregnant Women, and an Individual with a Stably Altered Neuroendocrine Phenotype.

Extracellular RNAs (exRNAs) in biofluids are amenable to quantitative analysis and proposed as noninvasive biomarkers for monitoring organ function. Cell-lineage-specific microRNAs (miRNAs) are present in plasma as soluble ribonucleoproteins or enclosed in exRNA carriers and transported through the vasculature. However, more extensive studies of healthy individuals are needed to gain insights into the variability of plasma miRNA abundance and composition. The exRNA composition of platelet-depleted plasma collected twice from 236 healthy individuals was characterized by small RNA sequencing. Plasma of pregnant women featuring dramatically increased placental miRNAs and samples from subject P12 with noticeably increased epithelial- and neuroendocrine-origin miRNAs were included for comparison. The miRNA content of 10 000g and 100 000g pellet fractions of plasma generated by ultracentrifugation was also determined. Data analysis methods included Pearson correlation, differential gene expression, and unsupervised clustering. The abundance changes for more variable miRNAs in plasma of normal individuals correlated between coexpressed cell-lineage-specific miRNAs of the liver, neuroendocrine organs, epithelial cells, and muscle. ExRNA of pellet fractions contained <2% of total plasma miRNA with modest enrichment of lineage-specific and variable miRNAs compared to supernatant. The abundance fold changes of miRNAs observed in pregnancy and P12 compared to normal exceeded interquartile variability of healthy individuals. The neuroendocrine miRNA signature of P12 persisted for more than 4 years and was absent in other individuals. This study defines the framework and effect size for screening of extensive plasma collections for miRNA phenotypes and biomarker discovery.

An acute dose-ranging evaluation of the antidepressant properties of Sceletium tortuosum (Zembrin®) versus escitalopram in the Flinders Sensitive Line rat.

Ethnopharmacological relevanceSceletium tortuosum (L.) N.E.Br. (ST) has been used by the Khoisan people of South Africa as a mood elevator. Its various pharmacological mechanisms of action suggest distinct potential as an antidepressant. Clinical studies in healthy individuals suggest beneficial effects on mood, cognition, and anxiety. Aim of the studyTo obtain a chromatographic fingerprint of a standardized extract of S. tortuosum (Zembrin®), and to evaluate the acute antidepressant-like properties of Zembrin® versus the reference antidepressant, escitalopram, in the Flinders Sensitive Line (FSL) rat, a genetic rodent model of depression. Materials and methodsThe chemical profile of Zembrin® was determined by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) chromatogram method using alkaloid standards. Twelve saline treated FSL and six Flinders Resistant Line (FRL) control rats were used to confirm face validity of the FSL model using the forced swim test (FST). Thereafter, FSL rats (n = 10) received either 5, 10, 25, 50 or 100 mg/kg of Zembrin®, or 5, 10 or 20 mg/kg escitalopram oxalate (ESC), both via oral gavage, and subjected to the open field test (OFT) and FST. ResultsFour main ST alkaloids were identified and quantified in Zembrin® viz. mesembrenone, mesembrenol, mesembrine, and mesembranol (47.9%, 32%, 13.2%, and 6.8% of the total alkaloids, respectively). FSL rats showed significantly decreased swimming and climbing (coping) behaviours, and significantly increased immobility (despair), versus FRL controls. ESC 5 mg/kg and Zembrin® 25 mg/kg and 50 mg/kg showed significant dose-dependent reversal of immobility in FSL rats and variable effects on coping behaviours. Zembrin® 50 mg/kg was the most effective antidepressant dose, showing equivalence to ESC 5. ConclusionsZembrin® (25 and 50 mg/kg) and ESC (5 mg/kg) are effective antidepressants after acute treatment in the FST, as assessed in FSL rats. Moreover, Zembrin® 50 mg/kg proved equivalent to ESC 5. Further long-term bio-behavioural studies on the antidepressant properties of Zembrin® are warranted.

Individual-level interventions to reduce personal exposure to outdoor air pollution and their effects on people with long-term respiratory conditions.

Individual-level interventions to reduce personal exposure to outdoor air pollution and their effects on people with long-term respiratory conditions.

Contributions of HFE polymorphisms to brain and blood iron load, and their links to cognitive and motor function in healthy adults.

BackgroundBrain iron overload is linked to brain deterioration, and cognitive and motor impairment in neurodegenerative disorders and normal aging. Mutations in the HFE gene are associated with iron dyshomeostasis and are risk factors for peripheral iron overload. However, links to brain iron load and cognition are less consistent and data are scarce.Aims and methodsUsing quantitative susceptibility mapping with magnetic resonance imaging, we investigated whether C282Y and H63D contributed to aging‐related increases in brain iron load and lower cognitive and motor performance in 208 healthy individuals aged 20‐79 years. We also assessed the modulatory effects of HFE mutations on associations between performance and brain iron load, as well as peripheral iron metabolism.ResultsIndependent of age, carriers of either C282Y and/or H63D (HFE‐pos group, n = 66) showed a higher load of iron in putamen than non‐carriers (HFE‐neg group, n = 142), as well as higher transferrin saturation and lower transferrin and transferrin receptors in blood. In the HFE‐neg group, higher putaminal iron was associated with lower working memory. In the HFE‐pos group, higher putaminal iron was instead linked to higher executive function, and lower plasma transferrin was related to higher episodic memory. Iron‐performance associations were modest albeit reliable.ConclusionOur findings suggest that HFE status is characterized by higher regional brain iron load across adulthood, and support the presence of a modulatory effect of HFE status on the relationships between iron load and cognition. Future studies in healthy individuals are needed to confirm the reported patterns.

Effects of Face Masks on Oxygen Saturation and Functional Measures in Patients with Connective Tissue Disorder Associated Interstitial Lung Disease

Face masks are a first line defense against the COVID-19 pandemic. Many patients with lung disease complain of worsening dyspnoea on wearing face masks. Concerns about face masks reducing oxygen saturation have been negated by controlled studies in healthy individuals. In this study we have attempted to estimate the effects of face masks in patients with connective tissue disease (CTD) associated ILD (CTD-ILD). Patients with an established CTD, having HRCT (High Resolution Computed Tomography) findings of ILD and FVC(Forced Vital Capacity) of less than 70% on PFT with MRC grades 1 to 3 dyspnoea, and not requiring oxygen to maintain saturation, were included in this cross over trial. Initial oxygen saturation (SpO2) was recorded and a standard 6-minutes walk test (6MWT) was carried out with and without a standard 3-layer surgical face mask. All 36 patients completed 6 minutes of walking both with and without masks. When patients were in masks, they covered lesser distance and developed drop in saturation significantly more than while not wearing them. Without masks, 14 persons had a decline in SpO2 of 3% or more while, with masks, 19 persons had the same [p=0.3; Fisher exact test]. Thus, the use of face masks reduced the functional capacity and oxygen saturation during mild activity in patients with CTD-ILD. Through this study, it should be brought to the attention of ILD patients, their care-givers that the functional capacity is reduced with masks. The patients should limit physical exertion while wearing masks.

Pharmacological Neuroenhancement: Current Aspects of Categorization, Epidemiology, Pharmacology, Drug Development, Ethics, and Future Perspectives.

Recent pharmacoepidemiologic studies suggest that pharmacological neuroenhancement (pNE) and mood enhancement are globally expanding phenomena with distinctly different regional characteristics. Sociocultural and regulatory aspects, as well as health policies, play a central role in addition to medical care and prescription practices. The users mainly display self-involved motivations related to cognitive enhancement, emotional stability, and adaptivity. Natural stimulants, as well as drugs, represent substance abuse groups. The latter comprise purines, methylxanthines, phenylethylamines, modafinil, nootropics, antidepressants but also benzodiazepines, β-adrenoceptor antagonists, and cannabis. Predominant pharmacodynamic target structures of these substances are the noradrenergic/dopaminergic and cholinergic receptor/transporter systems. Further targets comprise adenosine, serotonin, and glutamate receptors. Meta-analyses of randomized-controlled studies in healthy individuals show no or very limited verifiability of positive effects of pNE on attention, vigilance, learning, and memory. Only some members of the substance abuse groups, i.e., phenylethylamines and modafinil, display positive effects on attention and vigilance that are comparable to caffeinated drinks. However, the development of new antidementia drugs will increase the availability and the potential abuse of pNE. Social education, restrictive regulatory measures, and consistent medical prescription practices are essential to restrict the phenomenon of neuroenhancement with its social, medical, and ethical implications. This review provides a comprehensive overview of the highly dynamic field of pharmacological neuroenhancement and elaborates the dramatic challenges for the medical, sociocultural, and ethical fundaments of society.