Stability analysis of a steady state of a model describing Alzheimer’s disease and interactions with prion proteins

Journal of Mathematical Biology - Alzheimer’s disease (AD) is a neuro-degenerative disease affecting more than 46 million people worldwide in 2015. AD is in part caused by the accumulation of...     

Variation of a test’s sensitivity and specificity with disease prevalence

Background:

Anecdotal evidence suggests that the sensitivity and specificity of a diagnostic test may vary with disease prevalence. Our objective was to investigate the associations between disease prevalence and test sensitivity and specificity using studies of diagnostic accuracy.

Methods:

We used data from 23 meta-analyses, each of which included 10–39 studies (416 total). The median prevalence per review ranged from 1% to 77%. We evaluated the effects of prevalence on sensitivity and specificity using a bivariate random-effects model for each meta-analysis, with prevalence as a covariate. We estimated the overall effect of prevalence by pooling the effects using the inverse variance method.

Results:

Within a given review, a change in prevalence from the lowest to highest value resulted in a corresponding change in sensitivity or specificity from 0 to 40 percentage points. This effect was statistically significant (p < 0.05) for either sensitivity or specificity in 8 meta-analyses (35%). Overall, specificity tended to be lower with higher disease prevalence; there was no such systematic effect for sensitivity.

Interpretation:

The sensitivity and specificity of a test often vary with disease prevalence; this effect is likely to be the result of mechanisms, such as patient spectrum, that affect prevalence, sensitivity and specificity. Because it may be difficult to identify such mechanisms, clinicians should use prevalence as a guide when selecting studies that most closely match their situation.Diagnostic accuracy plays a central role in the evaluation of medical diagnostic tests. Test accuracy may be expressed as sensitivity and specificity, as positive and negative predictive values or as positive and negative likelihood ratios.¹ Some feel that the positive and negative predictive values of a test are more clinically relevant measures than sensitivity and specificity. However, predictive values directly depend on disease prevalence and can therefore not directly be translated from one situation to another.² In contrast, a test’s sensitivity and specificity are commonly believed not to vary with disease prevalence.^3–5Stability of sensitivity and specificity is an assumption that underlies the use of Bayes theorem in clinical diagnosis. Bayes theorem can be applied in clinical practice by using the likelihood ratio of a test and the probability of the disease before the test was done (pretest probability) to estimate the probability of disease after the test was done.² Because likelihood ratios are a function of sensitivity and specificity, it is assumed that the likelihood ratios also remain the same when prevalence varies.A number of studies have shown that sensitivity and specificity may not be as stable as thought.^6–10 We previously summarized the possible mechanisms through which differences in disease prevalence may lead to changes in a test’s sensitivity and specificity.¹⁰ Prevalence affects diagnostic accuracy because of clinical variability or through artifactual differences, as described in the theoretical framework in 6^,7 Artifactual differences can result from using additional exclusion criteria, verification bias or an imperfect reference standard. For example, using an imperfect reference standard may lead to an underestimate of diagnostic accuracy, but as prevalence increases, the extent to which this happens will vary.^8,9

Table 1:

Theoretical framework of how disease prevalence and test accuracy may be related¹⁰

Variability of Stepping during a Virtual Reality Paradigm in Parkinson’s Disease Patients with and without Freezing of Gait

Background

Freezing of gait is a common and debilitating symptom affecting many patients with advanced Parkinson’s disease. Although the pathophysiology of freezing of gait is not fully understood, a number of observations regarding the pattern of gait in patients with this symptom have been made. Increased ‘Stride Time Variability’ has been one of the most robust of these features. In this study we sought to identify whether patients with freezing of gait demonstrated similar fluctuations in their stepping rhythm whilst performing a seated virtual reality gait task that has recently been used to demonstrate the neural correlate of the freezing phenomenon.

Methods

Seventeen patients with freezing and eleven non-freezers performed the virtual reality task twice, once whilst ‘On’ their regular Parkinsonian medication and once in their practically defined ‘Off’ state.

Results

All patients displayed greater step time variability during their ‘Off’ state assessment compared to when medicated. Additionally, in the ‘Off’ state, patients with freezing of gait had greater step time variability compared to non-freezers. The five steps leading up to a freezing episode in the virtual reality environment showed a significant increase in step time variability although the final three steps preceding the freeze were not characterized by a progressive shortening of latency.

Conclusions

The results of this study suggest that characteristic features of gait disturbance observed in patients with freezing of gait can also be demonstrated with a virtual reality paradigm. These findings suggest that virtual reality may offer the potential to further explore the freezing phenomenon in Parkinson’s disease.     

Electrooptical properties of the microbial suspensions during a cell’s interaction with the antibodies of a different specificity

The electrooptical abilities of the microbial suspensions during a cells interaction with antibodies (ABs) of a different specificity have been studied on the example of the Azospirillum brasilense Sp245 cells and their interaction with the polyclonal monospecific and polyspecific antibodies. Measuring of the orientational spectra of the cells has been performed using the ELUS electrooptical analyzer. A discrete frequency set of an orienting electric field (740, 1000, 1450, 2000, and 2800 kHz) was used. It has been shown that an interaction of the polyspecific AB with the investigated cells redoubles the value of an electrooptical signal of the cells’ suspension as compared with the monospecific antibodies. These findings can be used for a development a new method of microorganism detection.     

Antioxidative system’s responses in the leaves of six Caragana species during drought stress and recovery

For investigating the protective roles of antioxidative system in desiccation tolerance of Caragana species as they adapt to arid environments, we monitored a variety of ecophysiological parameters in the leaves of Caragana arborescens (mesophyte), C. microphylla (semiarid species), C. roborovskyi, C. stenophylla, C. acanthophylla, and C. tragacanthoides (xerophyte) grown under a drying-rehydration cycle. Relative leaf water content and chlorophyll content were decreased by 17.4?C39.2?%, and by 14?C40?%, respectively, after exposure to 48?days of drought stress. Malondialdehyde did not increase in xeric Caragana species. Hydrogen peroxide concentrations increased by 13.1?C43.9?% except in C. acanthophylla. The activities of superoxide dismutase (SOD), guaiacol peroxidase (POD), ascorbate peroxidase (APX), glutathione reductase (GR) and reduced glutathione (GSH) in xeric Caragana species were significantly elevated with progressing drought stress. However, catalase in all species decreased markedly before drought stress treatment reached 40?days. The xeric Caragana species showed higher SOD, POD, APX, and GR activities, as well as ascorbate content, and more manganese SOD isoenzymes. C. arborescens and C. microphylla accumulated more free proline. Our data indicate that SOD and POD with the ascorbate?Cglutathione cycle have important protective effects in xeric Caragana species under drought stress. Free proline may be crucial in the resistance of C. arborescens and C. microphylla to drought stress.     

Genome-wide pathway analysis of a genome-wide association study on psoriasis and Behcet’s disease

The aim of this study was to identify candidate causal single nucleotide polymorphisms (SNPs) and candidate causal mechanisms of psoriasis and Behcets’s disease (BD) and to generate an SNP → gene → pathway hypothesis. A psoriasis genome-wide association study (GWAS) dataset that included 436,192 SNPs in 1,409 psoriasis cases and 1,436 controls of European descent and a BD GWAS dataset that contained 310,324 SNPs in 1,215 BD cases and 1,278 controls were used in this study. Identify candidate causal SNPs and pathways (ICSNPathway) analysis was applied to the GWAS datasets. ICSNPathway analysis identified 15 candidate causal SNPs and 28 candidate causal pathways. The top five candidate causal SNPs were rs1063478 (P = 1.45E−10), rs8084 (P = 2.20E−08), rs7192 (P = 5.18E−08), rs20541 (P = 5.30E−06), and rs1130838 (P = 5.65E−06), which with the exception of rs20541 [interleukin (IL)-13] are at human leukocyte antigen (HLA) loci. These candidate causal SNPs and pathways provided ten hypothetical biological mechanisms. The most strongly associated pathway concerned HLA. When HLA loci were excluded, ICSNPathway analysis provided one hypothetical biological mechanism. rs20541 (non_synonymous_coding) → IL-13 → dendritic cell involvement in the regulation of Th1 and Th2 development, and the GATA3 pathway. ICSNPathway analysis identified four candidate causal SNPs, eleven candidate causal pathways, and three hypothetical biological mechanisms. One of them was as follows: rs2072895 (non_synonymous_coding & splice-site) and rs2735059 (non_synonymous_coding) → HLA-F → type I diabetes mellitus, antigen processing and presentation, and autoimmune thyroid disease. The application of ICSNPathway analysis to GWAS dataset of psoriasis and BD resulted in the identification of candidate causal SNPs and candidate pathways that might contribute to psoriasis susceptibility.     

Moisture status during a strong El Niño explains a tropical montane cloud forest’s upper limit

Growing evidence suggests short-duration climate events may drive community structure and composition more directly than long-term climate means, particularly at ecotones where taxa are close to their physiological limits. Here we use an empirical habitat model to evaluate the role of microclimate during a strong El Niño in structuring a tropical montane cloud forest’s upper limit and composition in Hawai‘i. We interpolate climate surfaces, derived from a high-density network of climate stations, to permanent vegetation plots. Climatic predictor variables include (1) total rainfall, (2) mean relative humidity, and (3) mean temperature representing non-El Niño periods and a strong El Niño drought. Habitat models explained species composition within the cloud forest with non-El Niño rainfall; however, the ecotone at the cloud forest’s upper limit was modeled with relative humidity during a strong El Niño drought and secondarily with non-El Niño rainfall. This forest ecotone may be particularly responsive to strong, short-duration climate variability because taxa here, particularly the isohydric dominant Metrosideros polymorpha, are near their physiological limits. Overall, this study demonstrates moisture’s overarching influence on a tropical montane ecosystem, and suggests that short-term climate events affecting moisture status are particularly relevant at tropical ecotones. This study further suggests that predicting the consequences of climate change here, and perhaps in other tropical montane settings, will rely on the skill and certainty around future climate models of regional rainfall, relative humidity, and El Niño.     

Delay-induced oscillations in Wilson and Cowan’s model: an analysis of the subthalamo-pallidal feedback loop in healthy and parkinsonian subjects

The model proposed by Wilson and Cowan (1972) describes the dynamics of two interacting subpopulations of excitatory and inhibitory neurons. It has been used to model neural structures like the olfactory bulb, whisker barrels, and the subthalamo-pallidal system. It is well-known that this system can exhibit an oscillatory behavior that is amplified by the presence of delays. In the absence of delays, the conditions for stability are well-known. The aim of our paper is to clarify these conditions when delays are included in the model. The first ingredient of our methods is a new necessary and sufficient condition for the existence of multiple equilibria. This condition is related to those for local asymptotic stability. In addition, a sufficient condition for global stability is also proposed. The second and main ingredient is a stability analysis of the system in the frequency-domain, based on the Nyquist criterion, that takes the four independent delays into account. The methods proposed in this paper can be applied to analyse the stability of the subthalamo-pallidal feedback loop, a deep brain structure involved in Parkinson’s disease. Our stability conditions are easy to compute and characterize sharply the system’s parameters for which spontaneous oscillations appear.     

Power spectral density and coherence analysis of Alzheimer’s EEG

In this paper, we investigate the abnormalities of electroencephalograph (EEG) signals in the Alzheimer’s disease (AD) by analyzing 16-scalp electrodes EEG signals and make a comparison with the normal controls. The power spectral density (PSD) which represents the power distribution of EEG series in the frequency domain is used to evaluate the abnormalities of AD brain. Spectrum analysis based on autoregressive Burg method shows that the relative PSD of AD group is increased in the theta frequency band while significantly reduced in the alpha2 frequency bands, particularly in parietal, temporal, and occipital areas. Furthermore, the coherence of two EEG series among different electrodes is analyzed in the alpha2 frequency band. It is demonstrated that the pair-wise coherence between different brain areas in AD group are remarkably decreased. Interestingly, this decrease of pair-wise electrodes is much more significant in inter-hemispheric areas than that in intra-hemispheric areas. Moreover, the linear cortico-cortical functional connectivity can be extracted based on coherence matrix, from which it is shown that the functional connections are obviously decreased, the same variation trend as relative PSD. In addition, we combine both features of the relative PSD and the normalized degree of functional network to discriminate AD patients from the normal controls by applying a support vector machine model in the alpha2 frequency band. It is indicated that the two groups can be clearly classified by the combined feature. Importantly, the accuracy of the classification is higher than that of any one feature. The obtained results show that analysis of PSD and coherence-based functional network can be taken as a potential comprehensive measure to distinguish AD patients from the normal, which may benefit our understanding of the disease.     

SNP analysis of genes related to cholesterol metabolism and associated with late-onset Alzheimer’s disease

Late onset Alzheimer’s disease (LOAD) is the most common type of dementia and is characterized by impaired cholesterol homeostasis. Genome-wide association studies (GWAS) have shown that APOE, TOMM40, CLU, SORL1, PICALM, and BIN1 are related to cholesterol metabolism. To characterize the association between single-nucleotide polymorphisms (SNPs) and LOAD, we sequenced the SNP regions of the identified genes in a total of 11 LOAD cases and 12 healthy case controls in the Korean population. The SNP data showed a relatively high frequency in LOAD samples compared to the control samples. LOAD samples showed an average of 2.9 SNPs, whereas normal controls showed an average of 1.5 SNPs in the genes. Taken together, six genes associated with cholesterol metabolism using SNP analysis have shown frequent genetic variations in LOAD.     

Chemical, microbiological and plant analysis of soil fertilized with alkaline hydrolysate of sheep’s wool waste

Summary The effect of adding alkaline hydrolysate of sheep’s wool waste on the chemical and microbiological properties of a park soil (Sofia, Bulgaria) has been assessed in a 9 month laboratory experiment. The waste product contained 75–80% water-soluble materials: peptides, amino acids, salts, dyes, lipids, some carbohydrates, potassium ions, and it seemed likely that the hydrolysate obtained could be used as a harmless and valuable fertilizer in agriculture. It was demonstrated that the organic material positively influenced microbial soil populations and ryegrass growth. As the remaining partially degraded keratin is highly dispersed it should act as a slow release fertilizer thus feeding plants additionally. The results suggest that the wool hydrolysate is beneficial for improving soil characteristics and could successfully be used as alternative biofertilizer. The authors hope that by utilization of the keratin wastes, the environment around leather and fur plants could be influenced positively and that the expense of removing the wastes to controlled landfill sites and part of the expenses for sustaining the latter will be saved.     

Comparing auditory,visual and vibrotactile cues in individuals with Parkinson’s disease for reducing risk of falling over different types of soil

Introduction: Several researchers have demonstrated the positive benefits of auditory and visual cueing in the gait improvements among individuals with Parkinson’s disease (PD). However, few studies have evaluated the role of vibrotactile cueing when compared to auditory and visual cueing. This paper compares how these stimuli affect the risk of falling while walking on six types of soil (concrete, sand, parquet, broken stone, two types of carpet).

Methods: An instrumented Timed Up and Go (iTUG) test served to evaluate how audio, visual and vibrotactile cueing can affect the risk of falling of elderly. This pilot study proposes 12 participants with PD (67.7?±?10.07?years) and nine age-matched controls (66.8?±?8.0?years). Both groups performed the iTUG test with and without cueing. The cueing frequency was set at 10% above the cadence computed at the lower risk level of falling (walking over the concrete). A computed risk of falling (ROFA) index has been compared to the TUG time (total TUG duration).

Results: The index for evaluating the risk of falling appears to have a good reliability (ICC >?0.88) in this pilot study. In addition, the minimal detectable change (MDC) suggests that the proposed index could be more sensitive to the risk of falling variation compared to the TUG time. Moreover, while using the cueing, observed results suggest a significant decrease in the computed risk of falling compared to ‘without cueing’ for most of types of soil, especially for deformable soils, which can lead to falls.

Conclusion: When compared to other cueing, it seems that audio could be a better neurofeedback for reducing the risk of falling over different walking surfaces, which represent important risk factors for persons with gait disorder or lost functional autonomy.     

An ecological network analysis of the structure,development and sustainability of China’s natural gas supply system security

Mitigating the impacts of climate change and ensuring energy supply security has compelled China’s policy makers to maximise the use of alternative and low carbon fuels. Use and production of natural gas (an energy source with low carbon emissions) has experienced remarkable growth in China during the last decade, making China the third largest consumer and importer in the world. This study applied a powerful system-oriented ecological network analysis (ENA) technique to study China’s natural gas policies as they pertain to guarantee supply security. Several indicators based on the ENA were measured to analyse the degree of connectivity, the contributions of different compartments, resource utilisation (aggradation), development (ascendancy) and sustainability of China’s natural gas supply system. It was found that China’s source and route diversification policy have caused the natural gas supply system to exhibit considerable network complexity, demonstrating the high level of development, flexibility and diversity of China’s natural gas supply system. However, the policy also has caused a decrease in the aggradation and sustainability from the perspective of an ecological system network. The most important compartments in terms of their contribution to China’s natural gas supply system were found to be domestic natural gas production and transit compartments.     

Lipid analysis of the plasma membrane and mitochondria of brewer’s yeast

The plasma membrane and mitochondria of bottom fermenting brewer's yeast obtained as a by-product of industrial beer production were isolated and the lipid fraction was analyzed. The phospholipid content accounted for 78 mg/g protein in the plasma membrane and 59 mg/g protein in the mitochondria. Major phospholipids in both preparations were phosphatidylinositol, phosphatidylcholine and phosphatidylethanolamine but their proportions differed significantly. In the plasma membrane phosphatidylinositol, and in the mitochondria phosphatidylcholine were present in the highest concentration (37 and 30%, respectively). The main classes of neutral lipids (triacylglycerols, ergosterol, squalene and steryl esters) were twice more abundant in the plasma membrane than in the mitochondria (61 and 33 mg/g protein, respectively). A characteristic of the neutral lipid composition of both organelles was the low content of ergosterol (12 and 7 mg/g protein, respectively) and a high content of squalene (25 and 22 mg/g protein). The main feature of the fatty acid composition of both organelles was the preponderance of saturated fatty acids (78 and 79%, respectively), among which palmitic acid was the principal one. The most expressed characteristics of lipid fractions of the analyzed plasma membranes and mitochondria, high concentration of squalene and preponderance of saturated fatty acids are the consequences of anaerobic growth conditions. The lack of oxygen had possibly the strongest effect on the lipid composition of the plasma membranes and mitochondria of bottom fermenting brewer's yeast.     

Predictive association of copper metabolism proteins with Alzheimer’s disease and Parkinson’s disease: a preliminary perspective

Neurodegenerative diseases, Alzheimer’s disease (AD) and Parkinson’s disease (PD), constitute a major worldwide health problem. Several hypothesis have been put forth to elucidate the basis of onset and pathogenesis of AD and PD; however, till date, none of these seems to clearly elucidate the complex pathoetiology of these disorders. Notably, copper dyshomeostasis has been shown to underlie the pathophysiology of several neurodegenerative diseases including AD and PD. Numerous studies have concluded beyond doubt that imbalance in copper homeostatic mechanisms in conjunction with aging causes an acceleration in the copper toxicity elicited oxidative stress, which is detrimental to the central nervous system. Amyloid precursor protein and α-synuclein protein involved in AD and PD are copper binding proteins, respectively. In this review, we have discussed the possible association of copper metabolism proteins with AD and PD along with briefly outlining the expanding proportion of “copper interactome” in human biology. Using network biology, we found that copper metabolism proteins, superoxide dismutase 1 and ceruloplasmin may represent direct and indirect link with AD and PD, respectively.     

Isolation and identification of a staphylococal strain with an anti-mycobacterial activity and study of it’s mode of action

The resistance of mycobacteria to the clinical applied antibiotics poses a serious problem to deal with the infections they cause. So, the search for new antibiotics active against these bacteria becomes urgent. We report here the isolation from a Moroccan biotope of a bacterial strain secreting an active substance of protein nature that inhibits the growth of several mycobacterial species (Mycobacterium smegmatis; M. aurum A+;M. vaccae; M. bovis BCG andM. kansasii). PCR amplification and DNA sequecing of the 16S ribosomal RNA gene allowed the identification of this strain asStaphylococcus haemolyticus. Moreover, the substance produced by this strain was able to lyse the wall ofM. smegmatis and to extract its genomic DNA indicating that it acts probably, like others anti-mycobacterial antibiotics, on this envelope. The identification and characterisation of the active substance would open the way for further technological and therapeutic investigations.     

Children’s and Adults’ On-Line Processing of Syntactically Ambiguous Sentences during Reading

While there has been a fair amount of research investigating children’s syntactic processing during spoken language comprehension, and a wealth of research examining adults’ syntactic processing during reading, as yet very little research has focused on syntactic processing during text reading in children. In two experiments, children and adults read sentences containing a temporary syntactic ambiguity while their eye movements were monitored. In Experiment 1, participants read sentences such as, ‘The boy poked the elephant with the long stick/trunk from outside the cage’ in which the attachment of a prepositional phrase was manipulated. In Experiment 2, participants read sentences such as, ‘I think I’ll wear the new skirt I bought tomorrow/yesterday. It’s really nice’ in which the attachment of an adverbial phrase was manipulated. Results showed that adults and children exhibited similar processing preferences, but that children were delayed relative to adults in their detection of initial syntactic misanalysis. It is concluded that children and adults have the same sentence-parsing mechanism in place, but that it operates with a slightly different time course. In addition, the data support the hypothesis that the visual processing system develops at a different rate than the linguistic processing system in children.     

Interregional bio-physical connections—A ‘footprint family’ analysis of Israel’s beef supply system

The need to advance bio-physical accounting as a base for sustainability assessment has been acknowledged and advanced in recent years. One approach highly relevant to the 21st century global reality is the ‘Footprint’—Ecological, Land, Water and Carbon. While each has merits and limitations, the potential to bring all together under the title of the ‘Footprint Family’ is emerging. This paper embraces a footprint family approach to analyze beef consumption in the state of Israel over a decade (1999–2010) and explore some tradeoffs between different biophysical components. The research results reveal that on average a tonne of beef consumed in Israel, reflecting a mixture of sources of supply from all over the world requires 9.5 ha of land and 10,000 m³ of water, mostly for grazing in Latin America (in Brazil and Argentina) but also for growing feed in the U.S and the E.U. Enteric fermentation, manure management, farm operations, shipping and slaughtering generate approximately 19.7 t of CO₂e and the above can be integrated into an ecological footprint figure of approximately 6 global hectares. The paper also demonstrates the utility of inter-regional biophysical accounting at the detailed commodity level. Inter-regional accounting identifies the geographic locations that contribute resources to, and are affected by, the production of specific consumption products. Comprehensive interregional biophysical accounting can be used to generate a better understanding of the complex ecological impacts associated with most consumption products, and the implications of the relationship between these impacts for sustainability.     

Electromyographic activity of the rectus abdominis during a traditional crunch and the basic jackknife exercise with the Ab Lounge™

The use of nontraditional exercise devices such as the Ab Lounge? has been promoted as being as effective as the traditional abdominal crunch in strengthening the abdominal musculature. Evidence for this is lacking, however. The purpose of this study was to compare the degree of activation of the upper and lower rectus abdominis using electromyography (EMG) during a traditional crunch with the basic jackknife using the Ab Lounge?. Twenty-two subjects (6 men and 16 women) were randomly selected from the student population at the University of the West Indies (Mona Campus). The mean age of the participants was 20.5 ± 1.5 years, height 166.4 ± 6.2 cm, weight 64 ± 10.3 kg, and waist-hip ratio 0.7 ± 0.1. Surface EMG was used to assess the muscle activity from the upper and lower rectus abdominis while each exercise was performed. The EMG data were full-wave rectified and normalized using a mathematical model that was set up in Microsoft Excel for Windows XP. Statistical analysis was performed on the data using a univariate analysis of variance with gender as a covariate. Significance was determined by p < 0.05. The mean EMG data recorded for the upper rectus abdominis was significantly higher with the traditional crunch when compared with the basic jackknife performed on the Ab Lounge? (F = 4.39, p = 0.04). The traditional crunch produced a higher level of activity in the lower rectus abdominis when compared with the basic jackknife, but this was not statistically significant (F = 0.249, p = 0.62). There was no significant interaction between gender and the effect of the type of exercise on upper and lower rectus abdominis activation. These results suggest that the traditional abdominal crunch is more effective than the basic jackknife is in activating the rectus abdominis musculature.