Exploring the relationship of sleep, cognition, and cortisol in sickle cell disease

Background: Neurocognitive impairment is common in people with Sickle Cell Disease (SCD) and evidence is accumulating that sleep disturbances play a role. The interaction between cortisol and sleep in the general population is associated with cognition as well as general wellbeing but there are few data in SCD. We aimed to understand the relationship between cortisol and sleep in individuals with SCD and explored associations with cognition. Methods: Forty-five participants of black heritage (SCD: N = 27, 9–29 years, 16 females; Controls: N = 18, 11–25 years, 13 females) were recruited from the community between 2018 - 2020. Participants completed standardized questionnaires about their sleep behaviour and wore actigraphy MotionWatch8 for 7 nights to assess nocturnal sleep patterns. Salivary cortisol samples were taken on wakening and 3 times after 14:00. Cognition was assessed using the Wechsler Intelligence Scales for children and adults. Results: People with SCD took longer to fall asleep and experienced greater wake bouts, mobile minutes and fragmented sleep compared to controls. Although non-significant, people with SCD experienced lower morning cortisol, with a flattened diurnal cortisol ratio compared to controls. Interestingly, SCD participants, but not controls, with low diurnal variation scored lowest on processing speed (PSI) and perceptual reasoning index (PRI). A moderator analysis revealed that the effect of morning cortisol and diurnal cortisol ratio on PRI by group health (i.e., SCD and healthy controls) depended on sleep quality. Discussion: Sleep and cortisol may play a crucial role in the expression of cognitive difficulties seen in SCD. This should be considered for the development of interventions to optimise cognitive functioning and sleep. This, in turn, could positively impact on secretion of cortisol and general health in SCD

Anti-Heparanase Aptamers as Potential Diagnostic and Therapeutic Agents for Oral Cancer

Peer reviewe

Exploring the relationship of sleep, cognition, and cortisol in sickle cell disease.

BACKGROUND: Neurocognitive impairment is common in people with Sickle Cell Disease (SCD) and evidence is accumulating that sleep disturbances play a role. The interaction between cortisol and sleep in the general population is associated with cognition as well as general wellbeing but there are few data in SCD. We aimed to understand the relationship between cortisol and sleep in individuals with SCD and explored associations with cognition. METHODS: Forty-five participants of black heritage (SCD: N = 27, 9-29 years, 16 females; Controls: N = 18, 11-25 years, 13 females) were recruited from the community between 2018 - 2020. Participants completed standardized questionnaires about their sleep behaviour and wore actigraphy MotionWatch8 for 7 nights to assess nocturnal sleep patterns. Salivary cortisol samples were taken on wakening and 3 times after 14:00. Cognition was assessed using the Wechsler Intelligence Scales for children and adults. RESULTS: People with SCD took longer to fall asleep and experienced greater wake bouts, mobile minutes and fragmented sleep compared to controls. Although non-significant, people with SCD experienced lower morning cortisol, with a flattened diurnal cortisol ratio compared to controls. Interestingly, SCD participants, but not controls, with low diurnal variation scored lowest on processing speed (PSI) and perceptual reasoning index (PRI). A moderator analysis revealed that the effect of morning cortisol and diurnal cortisol ratio on PRI by group health (i.e., SCD and healthy controls) depended on sleep quality. DISCUSSION: Sleep and cortisol may play a crucial role in the expression of cognitive difficulties seen in SCD. This should be considered for the development of interventions to optimise cognitive functioning and sleep. This, in turn, could positively impact on secretion of cortisol and general health in SCD

Elevated brain serotonin turnover in patients with depression : effect of genotype and therapy

Context: The biological basis for the development of major depressive disorder (MDD) remains incompletely understood. Objective: To quantify brain serotonin (5-hydroxytryptamine [5-HT]) turnover in patients with MDD. Design: Patients with depression were studied both untreated and during administration of a selective serotonin reuptake inhibitor (SSRI) in an unblinded study of sequential design. Healthy volunteers were examined on only 1 occasion. Direct internal jugular venous blood sampling was used to directly quantify brain serotonin turnover. The effect of serotonin transporter (5-HTT) genotype on brain serotonin turnover was evaluated and the influence of SSRI therapy on serotonin turnover was investigated. Setting: Participants were recruited from the general community following media advertisement. Experimental procedures were performed in the research catheterization laboratory of a major training hospital and medical research institute. Participants: Studies were performed in 21 patients fulfilling the DSM-IV and International Statistical Classification of Diseases, 10th Revision diagnostic criteria forMDD and in 40 healthy volunteers. Interventions: Treatment for patients consisted of SSRI administration for approximately 12 weeks. Main Outcome Measures: Brain serotonin turnover before and after SSRI therapy. Results: Brain serotonin turnover was significantly elevated in unmedicated patients withMDDcompared with healthy subjects (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 4.4 [4.3] vs 1.6 [2.4] nmol/L, respectively; P=.003). Analysis of the influence of the 5-HTT genotype in MDD indicated that carriage of the s allele compared with the l allele was associated with greater than a 2-fold increase in brain serotonin turnover (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.5 [4.7] vs 2.7 [2.9] nmol/L, respectively; P=.04). Following SSRI therapy, brain serotonin turnover was substantially reduced (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.0 [4.0] nmol/L prior to treatment vs 2.0 [3.3] nmol/L following therapy; P=.008). Conclusions: Brain serotonin turnover is elevated in unmedicated patients with MDD and is influenced by the 5-HTT genotype. The marked reduction in serotonin turnover following SSRI treatment and the accompanying improvement in symptoms suggest that high brain serotonin turnover may be a biological substrate of MDD

Stern-Volmer plots for HSA titrated by short and long apatmers 37°C.

<p>Excitation wavelength 290 nm, [HSA]  =  6 µM. Excitation wavelength at 290 mM in a solution of sodium phosphate. Data is the mean of six values showing no greater standard deviation than 11%. The quenching effect is more considerable for long than short aptamer.</p

EIA and RIA assays.

<p>A: EIA (IIINTP indirect enzyme immunoassays) detecting N-terminal telopeptide from collagen type III degradation products at day 10 media change. Increasing absorbance means less collagen degradation product present. Hpa Ab (p = 0.03), 1.5 M Short (p = 0.007) and 1.5 M Long (p = 0.03) showed significant increase in absorbance compared to no inhibitor, suggesting they have inhibited the invasion of HSC-3 cells. B: The graph shows previous EIA values adjusted for negative control at day 10 media change. C: RIA (radioimmunoassay for type III collagen) detecting C-terminal telopeptide at day 10 media change. Increasing levels mean less collagen degradation product. Hpa Ab (p = 0.07), 1.5 M Short (p = 0.004) and 1.5 M Long (p = 0.02). D: RIA has confirmed the EIA assays showing significantly lower collagen degradation products than that for tissues without inhibitor added, indicating that they were successful inhibitors of invasion.</p

UV wavelength scan of HSA (left) and plot of PBS (right) titrated with 1.5 M short aptamer (A) and UV wavelength scan of HSA (left) and plot of PBS (right) titrated with 1.5 M long aptamer (B).

<p>UV wavelength scan of HSA (left) and plot of PBS (right) titrated with 1.5 M short aptamer (A) and UV wavelength scan of HSA (left) and plot of PBS (right) titrated with 1.5 M long aptamer (B).</p

The aptamer sequences used in this study.

<p>In bold the sequence of the short aptamer, which is the part of the long aptamer that is structured.</p><p>The aptamer sequences used in this study.</p

HSC-3 invasion in myoma discs.

<p><b>A:</b> Paraffin-embedded 14-day myoma organotypic sections were stained for pancytokeratin marker AE1/AE3 to analyze HSC-3 invasion after various treatments: no inhibitor, Hpa Ab, (the polyclonal heparanase antibody as a positive control), unrelated aptamer, (selected against a target involved in Alzheimer's disease), anti-heparanase aptamers 1.5 M Short, 1.5 M long and 3 M; linker peptide aptamers Pink and Yellow. Scale bar is 100 µm. The differences in invasion area (B) and invasion depth (C) after various treatments (n = 27/treatment). The statistics were done as two-sample <i>t</i>-test and Mann-Whitney test.</p

The MTS absorbance at 490 nm is shown over 24, 48 and 72 h in the presence and absence of the 1.5 M short aptamer.

<p>The presence of the aptamer at 1 mM concentration was found to have no effect on the cell growth in comparison with the control.</p