Plasma isoprostanoids assessment as Alzheimer's disease progression biomarkers.

Alzheimer's Disease (AD) is the most common neurodegenerative disease worldwide. So, there is a need to identify AD early diagnosis and monitoring biomarkers in blood samples. The aim of this study was to analyse the utility of lipid peroxidation biomarkers in AD progression evaluation. Participants (n = 19) were diagnosed with AD at early stages (Time 0, T0), and they were re-evaluated 2 years later (Time 1, T1). Plasma biomarkers from AD patients were determined at both times. Some analytes, such as dihomo-isoprostanes (17-epi-17-F2t-dihomo-IsoP, 17-F2t-dihomo-IsoP, Ent-7(RS)-7-F2t-dihomo-IsoP), and neuroprostanes (10-epi-10-F4t-NeuroP) showed very high probability of showing an increasing trend over time. Baseline values allowed to develop an affordable preliminary regression model to predict long-term cognitive status. So, some lipid peroxidation biomarkers would deserve consideration as useful progression AD biomarkers. The developed prediction model would constitute an important minimally invasive approach in AD personalized prognosis and perhaps could have some interest also in experimental treatments evaluation.

Breast Cancer Stem Cell Culture and Enrichment Using Poly(ε-Caprolactone) Scaffolds.

The cancer stem cell (CSC) population displays self-renewal capabilities, resistance to conventional therapies, and a tendency to post-treatment recurrence. Increasing knowledge about CSCs' phenotype and functions is needed to investigate new therapeutic strategies against the CSC population. Here, poly(ε-caprolactone) (PCL), a biocompatible polymer free of toxic dye, has been used to fabricate scaffolds, solid structures suitable for 3D cancer cell culture. It has been reported that scaffold cell culture enhances the CSCs population. A RepRap BCN3D+ printer and 3 mm PCL wire were used to fabricate circular scaffolds. PCL design and fabrication parameters were first determined and then optimized considering several measurable variables of the resulting scaffolds. MCF7 breast carcinoma cell line was used to assess scaffolds adequacy for 3D cell culture. To evaluate CSC enrichment, the Mammosphere Forming Index (MFI) was performed in 2D and 3D MCF7 cultures. Results showed that the 60° scaffolds were more suitable for 3D culture than the 45° and 90° ones. Moreover, 3D culture experiments, in adherent and non-adherent conditions, showed a significant increase in MFI compared to 2D cultures (control). Thus, 3D cell culture with PCL scaffolds could be useful to improve cancer cell culture and enrich the CSCs population.

Manufacturing PLA/PCL Blends by Ultrasonic Molding Technology.

Ultrasonic molding (USM) is a good candidate for studying the plasticization of polymer mixtures or other composite materials due to either the little amount of material needed for processing, low waste or the needed low pressure and residence time of the mold. Thus, the novelty of this research is the capability of USM technology to process PLA/PCL blends and their corresponding neat materials, encompassing all the production stages, from raw material to the final specimen. The major findings of the work revealed that the thermal properties of the blends were not affected by the USM process, although the crystallinity degree experienced variations, decreasing for PLA and increasing for PCL, which was attributed to the crystallization rate of each polymer, the high process speed, the short cooling time and the small particle size. The employed ultrasonic energy increased the molecular weight with low variations through the specimen. However, the degradation results aligned with the expected trend of these material blends. Moreover, this study also showed the effect pellet shape and dimensions have over the process parameters, as well as the effect of the blend composition. It can be concluded that USM is a technology suitable to successfully process PLA/PCL blends with the correct determination of process parameter windows.

Obstructive sleep apnea and Alzheimer's disease-related cerebrospinal fluid biomarkers in mild cognitive impairment.

Previous studies have demonstrated that sleep-breathing disorders, and especially obstructive sleep apnea (OSA), can be observed in patients with a higher risk of progression to Alzheimer's disease (AD). Recent evidence indicates that cerebrospinal fluid (CSF) AD-biomarkers are associated with OSA. In this study, we investigated these associations in a sample of patients with mild cognitive impairment (MCI), a condition that is considered the first clinical phase of AD, when patients showed biomarkers consistent with AD pathology. A total of 57 patients (mean age = 66.19; SD = 7.13) with MCI were included in the study. An overnight polysomnography recording was used to assess objective sleep parameters (i.e. apnea/hypopnea index [AHI], total sleep time, sleep efficiency, sleep latency, arousal index, awakening, stage 1, 2, and slow-wave sleep and rapid eye movement sleep, periodic limb movement index, O2 saturation during sleep, and percentage of time O2 saturation <90%). Phosphorylated-tau (P-tau), total-tau (T-tau), and amyloid-beta 42 (Aß42) were measured in CSF. Unadjusted correlation analyses showed that a higher AHI (reflecting higher OSA severity) was related to higher P-tau and T-tau (both results remained significant after Bonferroni correction, p = 0.001). Importantly, these associations were observed even after adjusting for potential confounders (i.e. age, sex, body mass index, sleep medication, smoking, hypertension, and heart disease). Although more research is needed to establish a causal link, our findings provide evidence that OSA could be related to the pathophysiological mechanisms involved in neurodegeneration in MCI patients.

Lipid Peroxidation Assessment in Preclinical Alzheimer Disease Diagnosis.

BACKGROUND: Alzheimer disease (AD) is an increasingly common neurodegenerative disease, especially in countries with aging populations. Its diagnosis is complex and is usually carried out in advanced stages of the disease. In addition, lipids and oxidative stress have been related to AD since the earliest stages. A diagnosis in the initial or preclinical stages of the disease could help in a more effective action of the treatments. METHODS: Isoprostanoid biomarkers were determined in plasma samples from preclinical AD participants (n = 12) and healthy controls (n = 31) by chromatography and mass spectrometry (UPLC-MS/MS). Participants were accurately classified according to cerebrospinal fluid (CSF) biomarkers and neuropsychological examination. RESULTS: Isoprostanoid levels did not show differences between groups. However, some of them correlated with CSF biomarkers (t-tau, p-tau) and with cognitive decline. In addition, a panel including 10 biomarkers showed an area under curve (AUC) of 0.96 (0.903-1) and a validation AUC of 0.90 in preclinical AD prediction. CONCLUSIONS: Plasma isoprostanoids could be useful biomarkers in preclinical diagnosis for AD. However, these results would require a further validation with an external cohort.

Plasma alterations in cholinergic and serotonergic systems in early Alzheimer Disease: Diagnosis utility.

BACKGROUND: Alzheimer Disease (AD) is the most common cause of dementia and it involves a high social and economic cost worldwide, and the health system still does not count with an effective treatment. This may be explained by the lack of a reliable early diagnosis and the complex physiological mechanisms involved in the disease development. In this sense, the cholinergic and serotonergic systems may be altered in the disease course. METHODS: In this study, metabolites from these pathways were determined in order to develop a non-invasive and early diagnosis model, as well as to advance in the knowledge of the physiopathological mechanisms of the disease. For this, plasma samples from mild cognitive impairment due to AD patients (MCI-AD, n = 25) and healthy controls (n = 25) were analysed. RESULTS: choline and tryptophan pathways were deregulated in MCI-AD. Therefore, a model based on betaine, cytidine, uridine, choline, acetylcholine, serotonin and tryptophan was developed, showing an AUC-ROC of 0.862, and sensitivity and specificity of 96% and 72%, respectively. CONCLUSION: Alterations in metabolites from these pathways are related to cognitive impairment and neurodegeneration, and they could be useful in AD diagnosis. Nevertheless, further research is required in order to validate this diagnosis model.

I Cannot Read Your Eye Expression: Suicide Attempters Have Difficulties in Interpreting Complex Social Emotions.

Background: The ability to differentiate emotions in social contexts is important for dealing with challenging social situations. Suicide attempters show some difficulties in emotion recognition that may result in hypersensitivity to social stress. However, other studies on the recognition of social complex emotions found that suicide attempters have similar performances as depressed non-attempters. Objectives: To investigate differences in social emotion recognition in patients with current Major Depressive Episode (MDE) with and without history of suicide attempt. Methods: Two hundred and ten patients with MDE were recruited among whom 115 had lifetime history of suicide attempt (suicide attempters, SA) and 95 did not (affective controls, AC). Recognition of complex social emotions was assessed using the Reading the Mind in the Eyes Test (RMET). Emotions were separated in three valence categories: positive, negative, and neutral. Verbal intelligence quotient (IQ) and attention were measured with the National Adult Reading Task (NART) and the d2 test, respectively. Results: Mixed logistic regression models adjusted for sex, lifetime bipolar disorder, verbal IQ and attention showed that the RMET performance for neutral emotions was worse in the SA than AC group (OR = 0.87 [0.75, 0.99]). Furthermore, when violent/serious SA were compared to non-violent/non-serious SA and AC, the RMET neutral valence category showed a trend for group factor (p < 0.059) and RMET scores were lower in the violent/serious SA than AC group (OR = 0.79 [0.64, 0.96]). Conclusion: Recognition of neutral emotions is poor in SA and this may complicate their daily life. Interventions to improve the understanding of complex emotions may be helpful to prevent suicidal risk in patients with depression.

Early neurotransmission impairment in non-invasive Alzheimer Disease detection.

Alzheimer Disease (AD) is a pathology suffered by millions of people worldwide and it has a great social and economic impact. Previous studies reported a relationship between alterations in different amino acids and derivatives involved in neurotransmission systems and cognitive impairment. Therefore, in this study the neurotransmission impairment associated to early AD has been evaluated. For this purpose, different amino acids and derivatives were determined in saliva samples from AD patients and healthy subjects, by means of an analytical method based on chromatography coupled to tandem mass spectrometry. Results showed statistically significant differences in salivary levels for the compounds myo-inositol, creatine and acetylcholine; and other compounds (myo-inositol, glutamine, creatine, acetylcholine) showed significant correlations with some cognitive tests scores. Therefore, these compounds were included in a multivariate analysis and the corresponding diagnosis model showed promising indices (AUC 0.806, sensitivity 61%, specificity 92%). In conclusion, some amino acids and derivatives involved in neurotransmission impairment could be potential biomarkers in early and non-invasive AD detection.

Ultrasonic Molding Technology: Recent Advances and Potential Applications in the Medical Industry.

Recently, ultrasonic molding (USM) has emerged as a promising replication technique for low and medium volume production of miniature and micro-scale parts. In a relatively short time cycle, ultrasonic molding can process a wide variety of polymeric materials without any noticeable thermal degradation into cost-effective molded parts. This research work reviews recent breakthroughs of the ultrasonic injection molding and ultrasonic compression molding process regarding the equipment and tooling development, materials processing and potential applications in the medical industry. The discussion is centered on the challenges of industrializing this technology, pointing out the need for improvement of the current process's robustness and repeatability. Among the most important research areas that were identified are the processing of novel engineered and nanomaterials, the understanding and control of the ultrasonic plasticization process and the tooling and equipment development.

New screening approach for Alzheimer's disease risk assessment from urine lipid peroxidation compounds.

Alzheimer Disease (AD) standard biological diagnosis is based on expensive or invasive procedures. Recent research has focused on some molecular mechanisms involved since early AD stages, such as lipid peroxidation. Therefore, a non-invasive screening approach based on new lipid peroxidation compounds determination would be very useful. Well-defined early AD patients and healthy participants were recruited. Lipid peroxidation compounds were determined in urine using a validated analytical method based on liquid chromatography coupled to tandem mass spectrometry. Statistical studies consisted of the evaluation of two different linear (Elastic Net) and non-linear (Random Forest) regression models to discriminate between groups of participants. The regression models fitted to the data from some lipid peroxidation biomarkers (isoprostanes, neuroprostanes, prostaglandines, dihomo-isoprostanes) in urine as potential predictors of early AD. These prediction models achieved fair validated area under the receiver operating characteristics (AUC-ROCs > 0.68) and their results corroborated each other since they are based on different analytical principles. A satisfactory early screening approach, using two complementary regression models, has been obtained from urine levels of some lipid peroxidation compounds, indicating the individual probability of suffering from early AD.

Process Parameter Effects on Biocompatible Thermoplastic Sheets Produced by Incremental Forming.

There has been increasing interest in the processes that enable part customization and small-batch production in recent years. The prosthetic sector, in which biocompatible materials are used, is one of the areas that requires these types of processes; Incremental Sheet Forming (ISF) technology can meet these requirements. However, the biocompatible thermoplastic polymers formed by this technology have not yet been tested. Hence, the aim of this paper is to cover this gap in our knowledge by analyzing the effects of process parameters on the ISF process with the aim of optimizing these parameters before the actual production of, in this case, customized prostheses. Tests with polycaprolactone (PCL) and ultra-high molecular weight polyethylene (UHMWPE) were performed. Maximum force, surface roughness and maximum depth were statistically analyzed by means of response surface methodology and survival analysis. Spindle speed and tool diameter were shown to be the most influential process parameters in terms of maximum forming force and surface roughness for both materials. In contrast, survival analysis applied to maximum depth showed a greater influence of tool diameter in PCL sheets and a greater influence of spindle speed in the case of UHMWPE.

Effect of the main process parameters on the mechanical strength of polyphenylsulfone (PPSU) in ultrasonic micro-moulding process.

Ultrasonic micro-moulding technology was used to process high performance polymer polyphenylsulfone (PPSU) due to investigate mechanical and chemical characteristics of manufacturing parts. Both the processing window and dependence between the main input parameters, in this case amplitude, plunger velocity and ultrasonic exposure time and their influence on the mechanical properties were appointed. The experiments showed that each available amplitude level (58 µm, 52.2 µm, 46.4 µm, 40.6 µm) are suitable to produce specimens characterised by high mechanical strength but only when combined with the appropriate values of the rest of the parameters. The parameter, which influenced the most on the part degradation is the ultrasonic vibration time. Samples from the combination of parameters, where the amplitude and velocity had the highest value but time of sonication is one of the lowest are less exposed for degradation. Cavitation bubbles makes polymer falling apart which decreases mechanical strength of the manufacturing parts. Degradation was observed via FTIR analysis even if it was not visually visible. Finally, the model as a tool for selecting the appropriate values for the input process parameters when using the novel ultrasonic micro-moulding technology required to produce PPSU parts characterised by their high mechanical strength was developed.

Plasma lipid peroxidation biomarkers for early and non-invasive Alzheimer Disease detection.

INTRODUCTION: Alzheimer Disease (AD) standard diagnosis is based on evaluations and biomarkers that are non-specific, expensive, or requires invasive sampling. Therefore, an early, and non-invasive diagnosis is required. As regards molecular mechanisms, recent research has shown that lipid peroxidation plays an important role. METHODS: Well-defined participants groups were recruited. Lipid peroxidation compounds were determined in plasma using a validated analytical method. Statistical studies consisted of an elastic-net-penalized logistic regression adjustment. RESULTS: The regression model fitted to the data included six variables (lipid peroxidation biomarkers) as potential predictors of early AD. This model achieved an apparent area under the receiver operating characteristics (AUC-ROCs) of 0.883 and a bootstrap-validated AUC-ROC of 0.817. Calibration of the model showed very low deviations from real probabilities. CONCLUSION: A satisfactory early diagnostic model has been obtained from plasma levels of 6 lipid peroxidation compounds, indicating the individual probability of suffering from early AD.

On the Rule of Mixtures for Predicting Stress-Softening and Residual Strain Effects in Biological Tissues and Biocompatible Materials.

In this work, we use the rule of mixtures to develop an equivalent material model in which the total strain energy density is split into the isotropic part related to the matrix component and the anisotropic energy contribution related to the fiber effects. For the isotropic energy part, we select the amended non-Gaussian strain energy density model, while the energy fiber effects are added by considering the equivalent anisotropic volumetric fraction contribution, as well as the isotropized representation form of the eight-chain energy model that accounts for the material anisotropic effects. Furthermore, our proposed material model uses a phenomenological non-monotonous softening function that predicts stress softening effects and has an energy term, derived from the pseudo-elasticity theory, that accounts for residual strain deformations. The model's theoretical predictions are compared with experimental data collected from human vaginal tissues, mice skin, poly(glycolide-co-caprolactone) (PGC25 3-0) and polypropylene suture materials and tracheal and brain human tissues. In all cases examined here, our equivalent material model closely follows stress-softening and residual strain effects exhibited by experimental data.