Musical and psychomotor interventions for cognitive, sensorimotor, and cerebral decline in patients with Mild Cognitive Impairment (COPE): a study protocol for a multicentric randomized controlled study.

BACKGROUND: Regular cognitive training can boost or maintain cognitive and brain functions known to decline with age. Most studies administered such cognitive training on a computer and in a lab setting. However, everyday life activities, like musical practice or physical exercise that are complex and variable, might be more successful at inducing transfer effects to different cognitive domains and maintaining motivation. "Body-mind exercises", like Tai Chi or psychomotor exercise, may also positively affect cognitive functioning in the elderly. We will compare the influence of active music practice and psychomotor training over 6 months in Mild Cognitive Impairment patients from university hospital memory clinics on cognitive and sensorimotor performance and brain plasticity. The acronym of the study is COPE (Countervail cOgnitive imPairmEnt), illustrating the aim of the study: learning to better "cope" with cognitive decline. METHODS: We aim to conduct a randomized controlled multicenter intervention study on 32 Mild Cognitive Impairment (MCI) patients (60-80 years), divided over 2 experimental groups: 1) Music practice; 2) Psychomotor treatment. Controls will consist of a passive test-retest group of 16 age, gender and education level matched healthy volunteers. The training regimens take place twice a week for 45 min over 6 months in small groups, provided by professionals, and patients should exercise daily at home. Data collection takes place at baseline (before the interventions), 3, and 6 months after training onset, on cognitive and sensorimotor capacities, subjective well-being, daily living activities, and via functional and structural neuroimaging. Considering the current constraints of the COVID-19 pandemic, recruitment and data collection takes place in 3 waves. DISCUSSION: We will investigate whether musical practice contrasted to psychomotor exercise in small groups can improve cognitive, sensorimotor and brain functioning in MCI patients, and therefore provoke specific benefits for their daily life functioning and well-being. TRIAL REGISTRATION: The full protocol was approved by the Commission cantonale d'éthique de la recherche sur l'être humain de Genève (CCER, no. 2020-00510) on 04.05.2020, and an amendment by the CCER and the Commission cantonale d'éthique de la recherche sur l'être humain de Vaud (CER-VD) on 03.08.2021. The protocol was registered at clinicaltrials.gov (20.09.2020, no. NCT04546451).

Intraoperative ketamine administration to prevent delirium or postoperative cognitive dysfunction: A systematic review and meta-analysis.

BACKGROUND: Postoperative cognitive complications are associated with substantial morbidity and mortality. Ketamine has been suggested to have neuroprotective effects in various settings. This systematic review evaluates the effects of intraoperative ketamine administration on postoperative delirium and postoperative cognitive dysfunction (POCD). METHODS: Medline, Embase and Central were searched to 4 March 2018 without date or language restrictions. We considered randomised controlled trials (RCTs) comparing intraoperative ketamine administration versus no intervention in adults undergoing surgery under general anaesthesia. Primary outcomes were postoperative delirium and POCD. Non-cognitive adverse events, mortality and length of stay were considered as secondary outcomes. Data were independently extracted. The quality of the evidence (GRADE approach) was assessed following recommendations from the Cochrane collaboration. Risk ratios were calculated for binary outcomes, mean differences for continuous outcomes. We planned to explore the effects of age, specific anaesthesia regimen, depth of anaesthesia and intraoperative haemodynamic events through subgroup analyses. RESULTS: Six RCTs were included. The incidence of postoperative delirium did not differ between groups (4 trials, 557 patients, RR 0.83, 95% CI [0.25, 2.80]), but patients receiving ketamine seemed at lower risk of POCD (3 trials, 163 patients, RR 0.34, 95% CI [0.15, 0.73]). However, both analyses presented limitations. Therefore, the quality of the evidence (GRADE) was deemed low (postoperative delirium) and very low (POCD). CONCLUSION: The effect of ketamine on postoperative delirium remains unclear but its administration may offer some protection towards POCD. Large, well-designed randomised trials are urgently needed to further clarify the efficacy of ketamine on neurocognitive outcomes.

Comparison of national and subnational guidelines for hand hygiene.

Hand hygiene promotion is considered as the cornerstone for healthcare-associated infection prevention. Over the past years, hand hygiene guidelines have been developed by different agencies at international, national and subnational levels. A comparison of these documents could help in understanding recommendations in different parts of the world and the methods used for their development. Guidelines were identified through search engines, electronic libraries, and personal contacts, and their content was analysed using an adapted version of a tool from the European DG XII-funded HARMONY project. Twenty-two guidelines were retrieved and 21 were evaluated. Documents varied in scope, approach, content and terminology. Some were primarily advisory directives, whereas others focused on the technical issues of why, when, and how to perform hand hygiene. The extent to which evidence was collected and assessed varied considerably and details were provided only in very few. Grading systems and definitions to indicate the strength of evidence and recommendations also differed. The intended outcome was to improve hand hygiene practices in healthcare, thus leading to a reduction of healthcare-associated infections and/or antimicrobial resistance. Although overall agreement on indications and procedures was noted, the range and depth of recommendations on best practices and implementation varied. Essential aspects such as compliance measurement and audits to assess guideline effectiveness were neglected in most documents. In conclusion, there is a need for a more consistent approach leading to recommendations based on a thorough evaluation of evidence and applicable worldwide. Aspects related to implementation and impact monitoring deserve greater attention.

Flowcytometric analysis of basophil counts in human blood and inaccuracy of hematology analyzers.

BACKGROUND: Differential leukocyte counts are of proven clinical value, but information about basophil counts in normal and disease conditions is scarce although basophils are regarded as key effector cells in allergy. AIMS: To establish and validate flowcytometric methods for counting basophils in peripheral human blood, to determine reference values, and to examine the accuracy of two widely used hematology analyzers. METHODS: Basophils were measured in whole blood by flowcytometry after staining with antibodies against the IL-3-receptor (CD123) or the eotaxin-receptor (CCR3) combined with other markers used for gating or validation purposes. RESULTS: The basophil percentages in 95 healthy adults showed an excellent correlation between the two independent flowcytometric methods, demonstrating that both are accurate and precise. The most robust maker is CCR3, which seems to be sufficient to specifically identify basophils. Normal values of relative and absolute blood basophils counts were 0.22-1.28% and 0.014-0.087 G/L (95% reference intervals), respectively. Basophil counts measured with two hematology analyzers Coulter GEN-S and ADVIA-120 showed no correlation between these instruments. Comparing the data obtained by flowcytometry and the analyzers demonstrate that basophil counts of the GEN-S are erratic, while the ADVIA-120 gives at least an estimation of true basophil numbers. CONCLUSIONS: We provide a solid description and validation of a novel and rapid method for the flowcytometric enumeration of basophil in whole blood. The fact that the most heavily used Hematology autoanalyzer gives completely erroneous results could explain why basophils counts have not yet received recognition as a clinically useful diagnostic marker.

Negative regulation of protein translation by mitogen-activated protein kinase-interacting kinases 1 and 2.

Eukaryotic initiation factor 4E (eIF4E) is a key component of the translational machinery and an important modulator of cell growth and proliferation. The activity of eIF4E is thought to be regulated by interaction with inhibitory binding proteins (4E-BPs) and phosphorylation by mitogen-activated protein (MAP) kinase-interacting kinase (MNK) on Ser209 in response to mitogens and cellular stress. Here we demonstrate that phosphorylation of eIF4E via MNK1 is mediated via the activation of either the Erk or p38 pathway. We further show that expression of active mutants of MNK1 and MNK2 in 293 cells diminishes cap-dependent translation relative to cap-independent translation in a transient reporter assay. The same effect on cap-dependent translation was observed when MNK1 was activated by the Erk or p38 pathway. In line with these findings, addition of recombinant active MNK1 to rabbit reticulocyte lysate resulted in a reduced protein synthesis in vitro, and overexpression of MNK2 caused a decreased rate of protein synthesis in 293 cells. By using CGP 57380, a novel low-molecular-weight kinase inhibitor of MNK1, we demonstrate that eIF4E phosphorylation is not crucial to the formation of the initiation complex, mitogen-stimulated increase in cap-dependent translation, and cell proliferation. Our results imply that activation of MNK by MAP kinase pathways does not constitute a positive regulatory mechanism to cap-dependent translation. Instead, we propose that the kinase activity of MNKs, eventually through phosphorylation of eIF4E, may serve to limit cap-dependent translation under physiological conditions.

Serum amyloid A (apoSAA) expression is up-regulated in rheumatoid arthritis and induces transcription of matrix metalloproteinases.

The acute-phase reactant rabbit serum amyloid A 3 (SAA3) was identified as the major difference product in Ag-induced arthritis in the rabbit, a model resembling in many aspects the clinical characteristics of rheumatoid arthritis (RA) in humans. In Ag-induced arthritis, up-regulated SAA3 transcription in vivo was detected in cells infiltrating into the inflamed joint, in the area where pannus formation starts and, most notably, also in chondrocytes. The proinflammatory cytokine IL-1beta induced SAA3 transcription in primary rabbit chondrocytes in vitro. Furthermore, rSAA3 protein induced transcription of matrix metalloproteinases in rabbit chondrocytes in vitro. In the human experimental system, IL-1beta induced transcription of acute-phase SAA (A-SSA; encoded by SAA1/SAA2) in primary chondrocytes. Similar to the rabbit system, recombinant human A-SAA protein was able to induce matrix metalloproteinases' transcription in chondrocytes. Further, immunohistochemistry demonstrated that A-SAA was highly expressed in human RA synovium. A new finding of our study is that A-SSA expression was also detected in cartilage in osteoarthritis. Our data, together with previous findings of SAA expression in RA synovium, suggest that A-SAA may play a role in cartilage destruction in arthritis.

Phosphorylation of eIF-4E on Ser 209 in response to mitogenic and inflammatory stimuli is faithfully detected by specific antibodies.

Phosphorylation of Ser 209 is thought to modulate the activity of the cap-binding factor eIF-4E which is a crucial component in the initiation complex for cap-dependent translation of mRNA. We report here the full reconstitution of the p38 Map kinase cascade leading to phosphorylation of eIF-4E in vitro and the generation of antibodies specific for phospho-serine 209 in eIF-4E. These antibodies were used to probe the phosphorylation of eIF-4E in mammalian cells stimulated with mitogens and pro-inflammatory cytokines. Treatment of human dermal fibroblasts with FCS led to a transient hyperphosphorylation, followed by hypophosphorylation and return to normal state phosphorylation at 16 h after the initial stimulation. By using a potent small molecular weight inhibitor of Mnk1, the upstream kinase for eIF-4E, we observed a rapid dephosphorylation of eIF-4E within 45 min after addition of the inhibitor, suggesting a high turnover of phosphate on eIF-4E mediated by Mnk1 and a yet unidentified phosphatase.

Does visual sensitivity improve between 5 and 8 years? A study of automated visual field examination.

In 74 normal subjects (62 children aged 5-8 years and 12 adults), we tested the widely-held belief that visual sensitivity improves substantially during childhood. Maturation of the retino-striate pathways is generally invoked to account for age-related changes in visual sensitivity. We evaluated the extent to which attentional factors unduly emphasized the effect of age on the purely physiological mechanisms. After a specially-designed familiarization procedure, sensitivity was fully evaluated at two locations in the superior temporal field using a bracketing technique (Octopus 2000R). False-positive (FP) and false-negative (FN) catch-trials were interspersed with the sequence of stimuli. Analyses demonstrated that: (1) age affected sensitivity; and (2) the general level of attentiveness varied not only with age, but also among subjects in the same age group. We then estimated the extent to which improved visual sensitivity may reflect a concomitant evolution of vigilance. Firstly, controlled variance analyses indicated that factors for evaluating attentiveness (rate of FN responses, slope of the psychometric function at the median, and goodness of fit) were indeed much better predictors than age of the sensitivity measured. Secondly and more significantly, the grouping of subjects into homogeneous subgroups, on the basis of their attentional performance, showed that children as young as 5 years may have a visual sensitivity that is only marginally lower than that of adults.

Overexpression of a C-terminal fragment of presenilin 1 delays anti-Fas induced apoptosis in Jurkat cells.

Most cases of early onset familial Alzheimer's disease (FAD) involve mutations in presenilins (PS1 and PS2) genes. The C-terminal portion of PS2 is a homologue with an apoptosis-linked gene (ALG-3). To characterise the role of PS1 in apoptosis, we overexpressed the corresponding C-terminal fragment of PS1 (PS1-f) under the control of the tetracycline-responsive transactivator in Jurkat cells. The tight regulation of the expression of the 11 kDa PS1-f peptide was verified. A 50% inhibition of anti-Fas induced apoptosis was observed upon PS1-f transient overexpression compared to the repressed state. Stable transfectants selectively overexpressing PS1-f revealed a transient protective effect of 30% after apoptosis induction.

Automated visual field examination in children aged 5-8 years. Part I: Experimental validation of a testing procedure.

In 106 children aged 5-8 years, we determined how much training was needed to stabilize the response strategy prior to actual visual field assessment and we evaluated the reliability and acceptable duration of automated static perimetry (Octopus 2000R). A specially designed familiarization procedure was used to train the children to: (1) gaze at the center of the visual field while paying attention to light stimuli projected onto the periphery and (2) press the buzzer only when light stimuli were perceived. The subsequent examination phase consisted of 15 successive identical blocks of 27 trials (12 stimulus trials, 12 false-positive catch-trials, and three false-negative catch-trials), and was stopped before the end if signs of fatigue appeared. Age had a marked influence both on endurance (the number of blocks performed increased significantly) and on response reliability (false-positive responses decreased between 5- and 6-year-olds). The increase in false-negative responses toward the end indicates that examination is no longer reliable, and should be stopped. We concluded that most children as young as five can undergo examination by automated static perimetry. Changes regarding learning, stimulus intensity and testing procedure are suggested in order to adapt the examination to age, level of vigilance and health condition of the children.