Multi-Domain Interventions for Dementia Prevention - A Systematic Review.

OBJECTIVES: There is a growing incidence of cognitive decline and dementia associated with the ageing population. Lifestyle factors such as diet, physical activity, and cognitive activities may individually or collectively be undertaken to increase one's odds of preventing cognitive decline and future dementia. This study will examine whether clinical trials using multidomain lifestyle intervention can significantly decrease the risk of cognitive decline and therefore dementia. DESIGN, SETTING AND PARTICIPANTS: This systematic literature review of multidomain lifestyle interventions for the prevention of cognitive decline and dementia followed the PRISMA guidelines. Clinical trials involving multidomain intervention (i.e., diet and physical activity, or without cognitive training) in older adults (≥ 49 years old) at higher risk of dementia were identified through 5 electronic databases (EMBASE, MEDLINE, CINAHL, Cochrane, and Scopus). A comprehensive search was performed to identify and retrieve publications until 15 November 2022. Trials were published in English. RESULTS: The included studies (n=15) assessed change in cognition in response to a multidomain lifestyle intervention. However, the cognitive outcome measures used in these studies were heterogeneous. Despite this heterogeneity, two thirds of the studies showed improvement in cognition following a multidomain intervention (n=10 with a total of 9,439 participants). However, five studies reported no improvement in cognition following the multidomain intervention. The most common form of dietary intervention included higher amount of fruit and vegetable intake; whole-grain cereal products instead of refined; low fat options in milk and meat products; and limiting sucrose intake to less than 50 g/day. Most clinical trial studies were powered to examining the effects of multidomain interventions in cognition but were not designed to test the contribution of individual domains (i.e., dietary changes, increased physical activity, or increased cognitive stimulation alone). CONCLUSION: This systematic review aimed to determine the effect of multimodal lifestyle interventions on cognitive outcomes in older adults at risk of dementia. We found that participants with conditions that may increase the risk of dementia, (e.g., hypertension, cardiovascular fragility) do benefit from multi-modal lifestyle changes including diet, physical activity, and cognitive training. Two thirds of studies using multidomain lifestyle interventions showed improvements in cognitive function. Trials with a focus on cognitive training, dietary improvement, and physical activity may prevent or delay cognitive decline in older adults including those at risk of developing dementia. Future studies should consider longer follow-up periods and adequate power to be able to examine the effects of each lifestyle component in the context of multimodal interventions.

Observation and understanding of anisotropic strain relaxation in selectively grown SiGe fin structures.

The performance of heterogeneous 3D transistor structures critically depends on the composition and strain state of the buffer, channel and source/drain regions. In this paper we used an in-line high resolution x-ray diffraction (HRXRD) tool to study in detail the composition and strain in selectively grown SiGe/Ge fin structures with widths down to 20 nm. For this purpose we arranged fins of identical dimensions into larger arrays which were then analyzed using an x-ray beam several tens of micrometers in size. Asymmetric reciprocal space maps measured both parallel and perpendicular to the fins allowed us to extract the lattice parameters in all three spatial directions. Our results demonstrate an anisotropic in-plane strain state of the selectively grown SiGe buffer in case of narrower fins with significantly reduced relaxation in the direction along the fin. This observation was verified using nano-beam electron diffraction, and is explained based on the reduced probability for dislocation half-loops to evolve in trenches narrower than a few times the critical radius. Moreover, we introduce and discuss in detail a methodology for the determination of the composition in case of an anisotropic in-plane strain state which differs from the procedure commonly used for blanket layers. Our findings verify the importance of in-line HRXRD measurements for process development and monitoring as well as the fundamental study of relaxation and defect formation in confined volumes.

GeSn/Ge heterostructure short-wave infrared photodetectors on silicon.

A surface-illuminated photoconductive detector based on Ge0.91Sn0.09 quantum wells with Ge barriers grown on a silicon substrate is demonstrated. Photodetection up to 2.2µm is achieved with a responsivity of 0.1 A/W for 5V bias. The spectral absorption characteristics are analyzed as a function of the GeSn/Ge heterostructure parameters. This work demonstrates that GeSn/Ge heterostructures can be used to developed SOI waveguide integrated photodetectors for short-wave infrared applications.

Single-electron capacitance spectroscopy of individual dopants in silicon.

Motivated by recent transport experiments and proposed atomic-scale semiconductor devices, we present measurements that extend the reach of scanned-probe methods to discern the properties of individual dopants tens of nanometers below the surface of a silicon sample. Using a capacitance-based approach, we have both spatially resolved individual subsurface boron acceptors and detected spectroscopically single holes entering and leaving these minute systems of atoms. A resonance identified as the B+ state is shown to shift in energy from acceptor to acceptor. We examine this behavior with respect to nearest-neighbor distances. By directly measuring the quantum levels and testing the effect of dopant-dopant interactions, this method represents a valuable tool for the development of future atomic-scale semiconductor devices.

The prevalence of obesity among clinical students in a Malaysian medical school.

INTRODUCTION: This study aimed to determine the prevalence of obesity among medical students and its relationship with their dietary intake and physical activities. METHODS: This observational study was carried out on 240 medical students during the clinical phase of their medical course in a private medical school. Their body weight and height were measured, and a standardised questionnaire was used to collect information on their physical activities and dietary intake. RESULTS: The median body weight of the participants was 59.0 kg (interquartile range: 51.3-66.8), the mean body height was 166.1 cm (standard deviation [SD] 8.5 cm), and the mean body mass index (BMI) was 21.8 kg/m2 (SD 3.4 kg/m2). Based on the World Health Organization BMI cut-offs for the Asian population, 30.1 percent (n is equal to 72) of the students were overweight or obese, with a BMI that was equal to or greater than 23.0 kg/m2. Logistic regression analysis showed that, after controlling for various potential confounders, the only significant risk factors associated with overweight/obesity among these students were: male gender (adjusted odds ratio [OR] 2.1; 95 percent confidence intervals [CI] of 1.1 and 4.1; p is equal to 0.03), Malay ethnic group (adjusted OR 2.4; 95 percent CI 1.0 and 5.7; p is equal to 0.04), Indian ethnic group (adjusted OR 3.6; 95 percent CI 1.5 and 8.9; p is equal to 0.005), and the number of soft drinks consumed per week (adjusted OR 1.3; 95 percent CI 1.0 and 1.5; p is equal to 0.02). Skipping breakfast, the frequency of physical exercise per week, the number of hours of sleep per day, and eating noodles or roti canai (a type of Malaysian pancake) for breakfast were not significant risk factors. CONCLUSION: Obesity remains a common problem among medical students in their clinical years.

Human saliva proteome and transcriptome.

This paper tests the hypothesis that salivary proteins and their counterpart mRNAs co-exist in human whole saliva. Global profiling of human saliva proteomes and transcriptomes by mass spectrometry (MS) and expression microarray technologies, respectively, revealed many similarities between saliva proteins and mRNAs. Of the function-known proteins identified in saliva, from 61 to 70% were also found present as mRNA transcripts. For genes not detected at both protein and mRNA levels, we made further efforts to determine if the counterpart is present. Of 19 selected genes detected only at the protein level, the mRNAs of 13 (68%) genes were found in saliva by RT-PCR. In contrast, of many mRNAs detected only by microarrays, their protein products were found in saliva, as reported previously by other investigators. The saliva transcriptome may provide preliminary insights into the boundary of the saliva proteome.

Relationship between aqueous humor protein level and outflow facility in patients with uveitis.

PURPOSE: To determine whether there is a relationship between the aqueous humor protein level and outflow facility in patients with uveitis. METHODS: Aqueous humor protein levels were determined by laser flare photometry, and outflow facility was determined by Schiotz tonography. RESULTS: Thirty patients with uveitis and 10 control subjects were studied. Outflow facility was lower in patients with uveitis (0.21 +/- 0.12 microl/min x mm Hg) than in control subjects (0.33 +/- 0.05 microl/min x mm Hg, P < 0.001). Patients with uveitis and laser flare photometry results (flare) more than 20 photon units/msec (n = 21) had a lower outflow facility (0.17 +/- 0.07 microl/min x mm Hg) than patients with uveitis and flare less than 20 photon units/msec (n = 9, 0.32 +/- 0.14 microl/min x mm Hg, P = 0.004). Furthermore, no difference was identified between outflow facility in patients with active uveitis (those who had anterior chamber cells) and flare less than 20 photon units/msec and outflow in control subjects. In patients with uveitis, there was a linear correlation between flare and outflow facility (r = -0.50, P = 0.005). There was no relationship between flare measurements and either intraocular pressure or aqueous humor cell levels when scored with a clinical, semiquantitative system. CONCLUSIONS: Outflow facility is significantly reduced in patients with uveitis who have high aqueous humor protein levels. Outflow facility appears to be normal in patients with active uveitis whose flare levels are low, and therefore the association between flare and outflow facility does not appear to be an indirect reflection of elevated anterior chamber cells. It is possible that elevated aqueous humor protein levels contribute to the development of uveitic glaucoma in some individuals by decreasing aqueous humor outflow facility, although a causal relationship cannot be established on the basis of this study.

Virtual 2-D gel electrophoresis: visualization and analysis of the E. coli proteome by mass spectrometry.

Mass spectrometric surface analysis of isoelectric focusing gels provides an ultrasensitive approach to proteome analysis. This "virtual 2-D gel" approach, in which mass spectrometry is substituted for the size-based separation of SDS-PAGE, provides advantages in mass resolution and accuracy over classical 2-D gels and can be readily automated. Protein identities can be postulated from molecular mass (+/-0.1-0.2% for proteins of <50 kDa in size) and pI (+/-0.3 pH unit) and confirmed by MALDI in-source decay of the intact protein (providing sequence spanning up to 43 residues) or by peptide mass mapping following gel-wide chemical cleavage. Additionally, posttranslational modifications such as fatty acid acylation can be detected by the mass-resolved heterogeneity of component hydrocarbon chains. Sensitivity was evaluated by comparing the number of proteins detected by this method to equivalently loaded silver-stained 2-D gels. In the 5.7-6.0 pH range, E. coli is predicted to contain 435 proteins; virtual 2-D gels found 250 proteins ranging from >2 to <120 kDa in size present at levels to tens of femtomoles, as compared to the 100 proteins found by silver-staining 2-D gels. Extrapolating this result to the total theoretical proteome suggests that this technology is capable of detecting over 2500 E. coli proteins.

Macular hole surgery in high myopia.

PURPOSE: To evaluate the anatomic and functional outcomes of macular hole surgery in high myopia and to determine whether surgery is beneficial in myopic eyes with macular holes. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Twenty eyes of 18 highly myopic subjects who underwent pars plana vitrectomy for macular holes. METHODS: We analyzed demographics, preoperative, and postoperative characteristics in 20 eyes with macular holes with a mean of 10.4 months duration and myopia of 6 diopters or greater. MAIN OUTCOME MEASURES: Macular hole closure rate and mean visual acuity preoperatively and postoperatively. RESULTS: Mean subject age was 56.4 years and preoperative visual acuity was 20/100+2. The macular hole was closed with one surgery in 60.0% of eyes and in 85.0% of eyes with one or more surgeries. The mean final acuity in all eyes was 20/63, and 40.0% improved greater than three Snellen lines at the final visit. The use of adjunctive agents seemed to have no effect on macular hole closure or visual acuity. A subgroup of three myopic eyes with retinal detachments surrounding the macular hole had successful closure with visual acuity improvement in two of three eyes. CONCLUSIONS: Macular hole surgery can give substantial visual improvement in myopic eyes with macular holes, but the anatomic closure rates are lower than in eyes with idiopathic macular holes, and thus a higher reoperation rate is required.

Confirmatory factor analyses of the full and short versions of the Marlowe-Crowne Social Desirability Scale.

Over the years, researchers have developed various short versions of the Marlowe-Crowne Social Desirability Scale (D. P. Crowne & D. Marlowe, 1960). The authors used confirmatory factor analyses (J. L. Arbuckle, 1997) as well as item and scale analyses to evaluate the adequacy of the full version and various short versions. Overall, the results from 232 Canadian undergraduates showed (a) that all the short versions in the present study are a significant improvement in fit over the 33-item full scale and (b) that W. M. Reynolds's (1982) Forms A and B are the best fitting short versions. No gender differences were found for the full scale or any of the short versions. The results show that the full scale could be improved psychometrically and that the psychometrically sound short versions should be available because they require less administration time than the full scale.

Interaction of flavodoxin with cobalamin-dependent methionine synthase.

Cobalamin-dependent methionine synthase catalyzes the transfer of a methyl group from methyltetrahydrofolate to homocysteine, forming tetrahydrofolate and methionine. The Escherichia coli enzyme, like its mammalian homologue, is occasionally inactivated by oxidation of the cofactor to cob(II)alamin. To return to the catalytic cycle, the cob(II)alamin forms of both the bacterial and mammalian enzymes must be reductively remethylated. Reduced flavodoxin donates an electron for this reaction in E. coli, and S-adenosylmethionine serves as the methyl donor. In humans, the electron is thought to be provided by methionine synthase reductase, a protein containing a domain with a significant degree of homology to flavodoxin. Because of this homology, studies of the interactions between E. coli flavodoxin and methionine synthase provide a model for the mammalian system. To characterize the binding interface between E. coli flavodoxin and methionine synthase, we have employed site-directed mutagenesis and chemical cross-linking using carbodiimide and N-hydroxysuccinimide. Glutamate 61 of flavodoxin is identified as a cross-linked residue, and lysine 959 of the C-terminal activation domain of methionine synthase is assigned as its partner. The mutation of lysine 959 to threonine results in a diminished level of cross-linking, but has only a small effect on the affinity of methionine synthase for flavodoxin. Identification of these cross-linked residues provides evidence in support of a docking model that will be useful in predicting the effects of mutations observed in mammalian homologues of E. coli flavodoxin and methionine synthase.

Trifluoromethyl ketones and methyl fluorophosphonates as inhibitors of group IV and VI phospholipases A(2): structure-function studies with vesicle, micelle, and membrane assays.

A series of fatty alkyl trifluoromethyl ketones and methyl fluorophosphonates have been prepared and tested as inhibitors and inactivators of human groups IV and VI phospholipases A(2) (cPLA(2) and iPLA(2)). Compounds were analyzed with phospholipid vesicle-, detergent-phospholipid mixed-micelle-, and natural membrane-based assays, and, with few exceptions, the relative inhibitor potencies measured with the three assays were similar. Ph(CH(2))(4)COCF(3) and Ph(CH(2))(4)PO(OMe)F emerged as a potent inhibitor and inactivator, respectively, of iPLA(2), and both are poorly effective against cPLA(2). Of all 13 fatty alkyl trifluoromethyl ketones tested, the trifluoromethyl ketone analog of arachidonic acid is the most potent cPLA(2) inhibitor, and structurally similar compounds including the trifluoromethyl ketone analog of docosahexenoic acid are much poorer cPLA(2) inhibitors. Inactivation of cPLA(2) by fatty alkyl fluoromethylphosphonates is greatly promoted by binding of enzyme to the interface. The use of both vesicles and mixed micelles to assay phospholipase A(2) inhibitors and inactivators present at low mol fraction in the interface provides reliable rank order potencies of a series of compounds that correlate with their behavior in a natural membrane assay.

Application of mass spectrometry for target identification and characterization.

Mass spectrometry-based methodologies span the vast expanse of drug discovery. Both electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI) support proteomics-based research projects by identifying proteins separated and isolated by polyacrylamide gel electrophoresis. MALDI-MS-based surface scanning of one-dimensional isoelectric focusing gels, "virtual 2-D gel electrophoresis," represents a potentially high throughput means to map proteins and to determine protein profiles. Mass spectrometry can also be used to directly study the covalent and noncovalent interactions of drug molecules and biomolecule targets. Drug binding examples discussed include the binding of covalent and noncovalent inhibitors to src SH2 domain protein, and the interaction of aminoglycoside antibiotic neomycin and HIV Tat peptide-TAR RNA.

High sensitivity mass spectrometric methods for obtaining intact molecular weights from gel-separated proteins.

The molecular weight measurement of intact Escherichia coli proteins separated by isoelectric focusing-immobilized pH gradient (IEF-IPG) gels and analyzed by mass spectrometry is presented. Two methods are discussed: (i) electrospray ionization (ESI) mass spectrometry (MS) of extracted proteins, and (ii) matrix-assisted laser desorption/ionization (MALDI)-MS analysis directly from IEF-IPG gels. Both ESI and MALDI methods yield sub-picomole sensitivity and good mass measurement accuracy. The use of an array detector for ESI-MS was essential to discriminate against contaminating background ions and to selectively detect high mass protein ions. MALDI-MS offers high-throughput analysis of one- and potentially two-dimensional (2-D) gels. The "virtual 2-D" gel method with first-dimensional IEF separation and the second dimension as molecular mass determination by MS, is a particularly promising method for protein analysis due to its ultra high sensitivity and correspondence to classical 2-D gels. Further sensitivity enhancements for the MALDI-MS method are provided by post acceleration detection optimized for high mass time-of-flight analysis.

User needs and demands of a computer-based patient record.

Prior to the implementation of a computer-based patient record, it is necessary to outline the requirements of the medical personnel. The paper is an account of a survey on information needs and demands on computer-based patient records. The study was conducted among physicians, nursing staff and therapists in two Dutch hospitals. In order to conduct the study, a measuring-instrument in form of a questionnaire was developed. Based on the results, it may be concluded, that health service staff does not only require improved input- and consultation uses with regard to the hard copy, but is also in need of additional functions. The developed measuring instrument appeared to be a proficient aid in outlining the information needs and demands of the health service staff. Through the developed questionnaire, the staff was able to obtain an idea of the possibilities of the computer-based patient record and state their own interest in same.

Activation, inhibition, and regiospecificity of the lysophospholipase activity of the 85-kDa group IV cytosolic phospholipase A2.

The 85-kDa Group IV calcium-dependent cytosolic phospholipase A2 (cPLA2) catalyzes the hydrolysis of palmitoylglycero-3-phosphocholine to palmitic acid and glycero-3-phosphocholine. Palmitoylglycero-3-phosphocholine exists as a 9:1 equilibrium mixture of the sn-1 and sn-2 isomers, with the fatty acid predominately at the sn-1 position. We have monitored this reaction by 31P NMR to determine which palmitoylglycero-3-phosphocholine isomer is processed by cPLA2. When both lysophospholipid isomers are present in a 1:1 mixture under conditions in which acyl migration is minimized, cPLA2 rapidly consumes both isomers. However, 1-palmitoylglycero-3-phosphocholine is consumed seven times faster than the 2-palmitoylglycero-3-phosphocholine isomer. We have previously reported that this lysophospholipase reaction is accelerated in the presence of glycerol. We now find that this apparent increase in activity is accounted for, in part, by glycerol acting as an alternative acceptor for the cleaved fatty acid, as is the case for this enzyme's phospholipase A2 (PLA2) activity. In contrast, dioleoylglycerol, which accelerates the PLA2 activity, does not act as an acceptor in either the lysophospholipase or the PLA2 reaction, but can affect enzyme activities by altering substrate presentation. We also show that a known inhibitor of the PLA2 activity of cPLA2 is able to inhibit its lysophospholipase activity with a similar IC50 to its PLA2 activity. However, the effect of inhibitors is dependent on the manner in which they are presented to the enzyme.

Identification and characterization of functional cation coordination sites in platelet endothelial cell adhesion molecule-1.

We have employed 45CaCl2 binding studies, terbium (Tb3+) luminescence spectroscopy, and electrospray mass spectroscopy (ESI-MS) to identify divalent metal binding properties of soluble recombinant human PECAM-1 (srPECAM-1), and to define unique cation binding domains using short, linear peptide sequences from the protein. PECAM-1 was found to directly interact with 45CaCl2, binding 2.3 nmol of Ca2+/nmol of srPECAM-1 with a Kd of 1.17 nM. PECAM-1 was found to contain high-affinity cation binding sites involving amino acids Asp443, Asp444, and Glu446 of Ig-domain 5 and residues Glu487, Glu490, Asp491, Glu538, Glu540, and Glu542 of Ig-domain 6. The PECAM cation binding sites demonstrated broad specificity for all divalent cations, with Mn2+ having a higher affinity than Ca2+ or Mg2+. Direct binding of Tb3+ to these PECAM peptides was confirmed by ESI-MS. Modeling studies predict that the six cation binding residues within Ig-domain 6 are proximal to each other in three-dimensional space, and may form a single cation coordination site. The identification of cation binding sites in PECAM-1 will direct further work in examining its cation-dependent roles in cellular signaling.

Regiospecificity and catalytic triad of lysophospholipase I.

A 25-kDa murine lysophospholipase (LysoPLA I) has been cloned and expressed, and Ser-119 has been shown to be essential for the enzyme activity (Wang, A., Deems, R. A., and Dennis, E. A. (1997) J. Biol. Chem. 272, 12723-12729). In the present study, we show that LysoPLA I represents a new member of the serine hydrolase family with Ser-119, Asp-174, and His-208 composing the catalytic triad. The Asp-174 and His-208 are conserved among several esterases and are demonstrated herein to be essential for LysoPLA I activity as the mutation of either residue to Ala abolished LysoPLA I activity, whereas the global conformation of the mutants remained unchanged. Furthermore, the predicted secondary structure of LysoPLA I resembles that of the alpha/beta-hydrolase fold, with Ser-119, Asp-174, and His-208 occupying the conserved topological location of the catalytic triad in the alpha/beta-hydrolases. Structural modeling of LysoPLA I also indicates that the above three residues orient in such a manner that they would comprise a charge-relay network necessary for catalysis. In addition, the regiospecificity of LysoPLA I was studied using 31P NMR, and the result shows that LysoPLA I has similar LysoPLA1 and LysoPLA2 activity. This finding suggests that LysoPLA I may play an important role in removing lysophospholipids produced by both phospholipase A1 and A2 in vivo.

Sensitivity and mass accuracy for proteins analyzed directly from polyacrylamide gels: implications for proteome mapping.

Matrix-assisted laser desorption ionization (MALDI) mass spectra have been obtained directly from thin-layer isoelectric focusing (IEF) gels with as little as 700 femtomoles of alpha- and beta-chain bovine hemoglobin and bovine carbonic anhydrase, and 2 picomoles of bovine trypsinogen, soybean trypsin inhibitor, and bovine serum albumin all loaded onto a single lane. By soaking the gel in a matrix solution, matrix was deposited over the entire gel surface, allowing MALDI scanning down complete lanes of the one-dimensional gel. As long as matrix crystals were deposited finely on the surface of the gel, time-lag focusing techniques were capable of ameliorating some of the mass accuracy limitations inherent in desorbing from uneven insulator surfaces with external calibration. Eleven measurements on the 5 kDa alpha-subunit proteins of lentil lectin measured over the course of 1 h and referenced to a single calibration yielded a standard deviation of 0.025%. Colloidal gold staining was found to be compatible with desorption directly from IEF and sodium dodecyl sulfate (SDS)-polyacrylamide gels. This direct approach simplifies the interface between gel electrophoresis and mass spectrometry dramatically, making the process more amenable to automation.