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.

Automated visual field examination in children aged 5-8 years. Part II: Normative values.

We determined normative values for the visual sensitivity threshold in 118 children aged 5-8 years, using automated static perimetry (Octopus 2000R, program 32). In addition, 17 normal adults were tested. The children first underwent a familiarization procedure. One week later, quantitative examination was performed according to a specially designed schedule divided into three phases. For each of the 76 points tested, mean thresholds and standard deviations were calculated as a function of age. In contrast to previous studies, sensitivity difference between adults and children over the central 30 degrees of the visual field emerged only for the youngest age groups (5- and 6-year olds). Both the response rate in false-negative trials, and values of a within-subject threshold variability index, suggested that 5- and 6-year-olds' higher thresholds were inflated by non physiological factors, such as vigilance and cognitive processes. For these ages, the data reported here should therefore be considered as an approximation of the upper level of the thresholds. In contrast, our results for 7- and 8 year-old children provided reliable normative values for light sensitivity across the visual field.

Rapid identification of phosphopeptide ligands for SH2 domains. Screening of peptide libraries by fluorescence-activated bead sorting.

A method for the identification of high-affinity ligands to SH2 domains by fluorescence-activated bead sorting (FABS) was established. Recombinant SH2 domains, expressed as glutathione S-transferase (GST) fusion proteins, were incubated with a phosphotyrosine (Y*)-containing peptide library. 6.4 x 10(5) individual peptides of nine amino acids in length (EPX6Y*X19X7X19X7X6) were each displayed on beads. Phosphopeptide interaction of a given SH2 domain was monitored by binding of fluorescein isothiocyanate-labeled antibodies directed against GST. High-fluorescence beads were isolated by flow cytometric sorting. Subsequent pool sequencing of the selected beads revealed a distinct pattern of phosphotyrosine-containing motifs for each individual SH2 domain: the SH2 domain of the adapter protein Grb2 predominantly selected beads with the sequence Y*ENDP, whereas the C-terminal SH2 domain of the tyrosine kinase Syk selected Y*EELD, each motif representing the most frequently found residues C-terminal to the phosphotyrosine. For deconvolution studies, soluble phosphopeptides comprising variations of the Grb2 motifs were resynthesized and analyzed by surface plasmon resonance.

Feasibility of automated visual field examination in children between 5 and 8 years of age.

AIMS: To investigate how young children develop the ability to undergo a visual field evaluation using regular automated perimetry. METHODS: The study included 42 normal girls aged 5, 6, 7, and 8 years. Twelve locations in the 15 degrees eccentricity were tested in one eye, using an Octopus 2000R perimeter with a two level strategy. False positive and false negative catch trials were presented. The examination was performed three times in succession. Before the examination procedure, a specially designed programme was conducted for progressive familiarisation. RESULTS: During the familiarisation procedure, it was found that all of the 5-year-old children, seven of the 6-year-old children, and three of the 7-year-old children were unable to perform immediately, and correctly, the instructions given during the familiarisation phase; these children took from 30 seconds to 3 minutes to comply with the examiner's requests. With the exception of one 5-year-old child, all tested subjects completed the planned procedure. The mean proportion of false negative answers in catch trials was 1.6%. The mean proportion of false positive answers was 12.2%. The quadratic dependency on age suggested by the averages was not significant (F(3,116) = 0.88; p = 0.45). Detection stimulus improved with age, as shown by the fact that probability of perceiving dim stimulus increases significantly (F(3,116) = 12.68; p < 0.0001). CONCLUSION: Children did remarkably well regarding both the duration of the examination and the reliability of the answers. A preliminary familiarisation phase with a specially designed adaptation programme was found to be mandatory with children aged 7 or under. To our knowledge, this is the first time that such an investigation has been performed.

[Automated static perimetry in the child: methodologic and practical problems]. / Périmétrie statique automatisée chez l'enfant: problèmes méthodologiques et pratiques.

PURPOSE: In a pediatric population, the use of computerized static perimetry is known as particularly difficult. The specific difficulties which may occur when testing young subjects are stability of fixation, ability to maintain concentration, resistance throughout the procedure, and reliability of the answers. It seems important to investigate and to develop appropriate strategies for the examination of children aged 8 years and younger according to their ability to undergo visual field evaluation using automated static perimetry. PATIENTS AND METHODS: Eighty normal children aged 5 to 8 years old were evaluated using an Octopus 2000R perimeter, with a one-level strategy. Adaptation of the procedure were included. RESULTS: The analysis of answers and false-positive catch-trials showed that children as young as five years old did remarkably well regarding both the duration of the examination and the reliability of answers. CONCLUSIONS: Automated static perimetry examination can provide reliable results in children as young as five years old once a familiarization procedure has been conducted and if the duration of examination does not exceed the child's capacity to remain task focused.

In vitro characterization of major ligands for Src homology 2 domains derived from protein tyrosine kinases, from the adaptor protein SHC and from GTPase-activating protein in Ramos B cells.

Antigen receptors of B lymphocytes transmit their activation signal to the cell interior by associating with and activation of specific non-receptor tyrosine kinases. Most of these kinases as well as other cytoplasmic effectors contain at least one Src homology 2 (SH2) domain, known to bind tyrosine-phosphorylated proteins. We examined the binding specificity of SH2 domains from different signaling molecules in B cells and found that each of the SH2 domains tested bound distinct subsets of stimulation-dependent phosphoproteins in vitro. SH2 domains from Src-like tyrosine kinases bound predominantly to the HS1 phosphoprotein. The tandem SH2 domains of the ZAP-70 tyrosine kinase bound to phosphorylated Ig-beta but only weakly to Ig-alpha. Also the SHC-derived SH2 domain formed complexes with the tyrosine-phosphorylated Ig-alpha/beta heterodimer, while the C- and N-terminal SH2 domains of GTPase-activating protein displayed completely different binding preferences. These results suggest that cytoplasmic effector molecules can be recruited to the activated B cell receptor in an SH2-phosphotyrosine-mediated manner. The data also provide a possible explanation for the notion that Ig-alpha and Ig-beta might couple to different biochemical pathways.

IL-2 promoter-driven lacZ expression as a monitoring tool for IL-2 expression in primary T cells of transgenic mice.

A transgenic mouse system has been established to follow the pattern of IL-2 expression at the level of single T cells. This was achieved by introducing a human IL-2 promoter-driven reporter gene (Escherichia coli lacZ) into the germline of mice and monitoring its product, beta-galactosidase (beta-gal), by FACS analysis. Ex vivo experiments confirmed that the regulated expression of the transgene is comparable with that of the endogenous IL-2 gene. Transgene expression is inducible by mitogens, restricted to T cells, and diminished by immunosuppressive agents, such as cyclosporin A, at concentrations known to suppress IL-2 transcription. Depending on the mitogens used, 30-50% of peripheral T cells produced IL-2 with an asynchronous induction pattern, as measured by transgenic beta-gal activity. Both helper (CD4+CD8-) and cytotoxic T cells (CD4-CD8+) respond with comparable heterogenous expression levels but they show different frequencies of beta-gal production. Transgenic beta-gal-producing T cells were detectable as early as 2 h after mitogen stimulation. These cells represent a transitional IL-2 secreting, IL-2 receptor alpha-chain negative T cell population, which occurs in the autocrine process of T cell activation. Administration of staphylococcal enterotoxin A (SEA), a bacterial superantigen, resulted in a T cell specific (Thy-1.2) increase (2.5-fold) of reporter gene expression in vivo. In summary, we could demonstrate that IL-2 promoter-driven reporter gene expression in transgenic mice is a sensitive tool to characterize IL-2 expressing cells phenotypically.(ABSTRACT TRUNCATED AT 250 WORDS)

[Mood and body image of women after surgery for breast cancer]. / Stimmung und Körperbefinden von Frauen nach der Mammakarzinomoperation.

The purpose of the following study is an intensive, longitudinal assessment of psychophysical well-being, stress and stress development after breast cancer diagnosis and surgery. 15 patients were investigated by means of a semistructured diary guiding to systematic daily self-observation during the first ninety days after primary treatment. Although the general trend over time is positive, the results show a considerable variability in the development of mood and body states which cannot exhaustively be explained by medical parameters. The experience of stress is often related to somatic disorders and adjuvant treatment. The results afford an insight in the psychological characteristics of this difficult period and may help to support the patient's rehabilitation more efficiently.

Nasopharyngeal carcinoma in Alaskan Eskimos Indians, and Aleuts: a review of cases and study of Epstein-Barr virus, HLA, and environmental risk factors.

The records of thirty-one patients with nasopharyngeal carcinoma (NPC) diagnosed from 1966 through 1976 among the Alaskan native population (Eskimo, Aleut, Indian) were reviewed. There were 25 males and six females, which results in relatively high incidence rates per 100,000 of 13.5 for males and 3.7 for females. Clinical and pathologic features were similar to those found among southern Chinese NPC patients. Five-year survival rate was 48%. Antibodies to Epstein-Barr virus were higher in NPC patients than in patients with other tumors or matched controls. On histocompatibility testing Sin-2 was not detected, nor was there significantly increased frequency of A2. Instead, BW40 and a second locus blank occurred more often among NPC patients than among other groups. In response to a questionnaire, NPC patients more often reported use of salt fish in the childhood diet, smoking of cigarettes, and exposure to noxious inhalants than did controls, but the differences were not statistically significant.

Nasopharyngeal carcinoma in an Alaskan Eskimo family: report of three cases.

Nasopharyngeal carcinoma (NPC) has been reported to occur in Alsaka Natives (Eskimos, Indians, and Aleuts) at a rate greater than 15 times the rate for U.S. whites. At least 3 cases of NPC have occurred in close relatives of a Northern Alaskan Eskimo family. All 3 patients had poorly differentiated tumors and have died. Blood groups, HLA antigens, and antibodies to Epstein-Barr virus (EBV) were studied in the family members. EBV titers were elevated in the 1 NPC patient tested and in 1 of 15 other family members tested. All family members studied except 1 were of blood group A, Rh-positive, and HLA types AW24, CW3, CW40/A2, CW2 and B27. This was the first report of more than 2 cases of NPC in a single family in the United States.