Visual analytics for the interpretation of fluency tests during Alzheimer evaluation

International audienceA possible way to evaluate the progress of Alzheimer disease is to conduct the Isaac set test [13, 14]. In this activity, patients are asked to cite the largest possible number of city names within a minute. Since the city names are handwritten very quickly by a medical practitioner some cities are abbreviated or poorly written. In order to analyze such data, medical practitioners need to digitize the notes first and clean the dataset. Because these tasks are intricate and error prone we propose a novel set of tools, involving interactive visualization techniques, to help medical practitioners in the digitization and data-cleaning process. This system will be tested as part of an ongoing longitudinal study involving 9500 patients

Electrosprayed Minocycline-loaded PLGA Microparticles for the Treatment of Glioblastoma

Background: Around 12,340 patients in the US are diagnosed with glioblastoma multiforme (GBM) yearly, and despite the current treatment options, such as chemotherapy, radiotherapy, surgical resection, or a combination of them, the median survival is only about 15 months after initial diagnosis. Minocycline, a tetracycline antibiotic, has shown to inhibit U87 glioblastoma cell death and inhibit angiogenesis, or the creation of new blood vessels as is often needed by the tumor to grow. The utilization of biomaterials such as poly lactic-co-glycolic acid (PLGA) can better sustain the release and bioactivity of loaded drugs. The use of polyethylene glycol (PEG), a hydrophilic polymer, may improve the encapsulation of minocycline into the PLGA microparticles, given its hydrophilic nature. Electrospraying may be a promising method to fabricate drug loaded PLGA microparticles with high drug loading and loading efficiency. Therefore, the objective of this project was to develop electrosprayed minocycline-loaded PLGA microparticles for the treatment of GBM. Methods: Minocycline-loaded PLGA microparticles were fabricated through electrospraying utilizing an 18 cm needle-tip to glass plate distance, 0.9 ml/hr flowrate, and 14 kV voltage. The solution consisted of 1 ml of chloroform as the solvent and 70 mg of PLGA as the polymer with different minocycline amounts and with or without polyethylene glycol (PEG). The amount of drug loaded into the microparticles was determined by dissolving the microparticles in 1 mL of dimethylsulfoxide and then measuring the absorbance of minocycline at 350 nm. Release kinetics studies were performed by placing the microparticles in phosphate-buffered saline and reading minocycline absorbance of the supernatant at various timepoint. Scanning Electron Microscopy (SEM) was used to determine size and morphology of the minocycline-loaded PLGA microparticles. Results: The amount of drug loading and loading efficiency increased with the addition of PEG (3.23 ± 0.29 vs. 4.02 ± 0.34 and 49.40 ± 4.49 vs. 64.30 ± 5.47%, respectively) and the utilization of higher amount of drug (4.02 ± 0.34 vs. 9.93 ± 0.64 and 64.30 ± 5.47 vs. 70.76 ± 4.57%, respectively). The release kinetics study demonstrated that the different microparticles experienced a burst release within the first hour (67-80%). The microparticles were spherical in shape and ranged between 4-11 μm in size. The addition of PEG resulted in the aggregation of the microparticles, as observed in SEM imaging. Conclusions: This study demonstrated that electrosprayed minocycline-loaded PLGA microparticles can be successfully fabricated with high drug loading and loading efficiency and have a spherical shape within the micron size range. PEG was able to increase drug loading of the lipophilic drug by increasing the solubility of the drug in the polymer/chloroform solution. However, the utilization of PEG affected the collection of the particles and therefore, further optimization of the electrospraying parameters needs to be done to improve the collection of non-aggregated microparticles. In addition, given their burst release of minocycline, the microparticles may need to be further encapsulated in a scaffold or depot to prolong their release of drug

The plasma membrane-actin linking protein, ezrin, is a glomerular epithelial cell marker in glomerulogenesis, in the adult kidney and in glomerular injury

The plasma membrane-actin linking protein, ezrin, is a glomerular epithelial cell marker in glomerulogenesis, in the adult kidney and in glomerular injury.BackgroundEzrin belongs to a family of plasma membrane-cytoskeleton linking, actin binding proteins (Ezrin-radixin-Moesin family) involved in signal transduction, growth control, cell-cell adhesion, and microvilli formation.MethodsThe expression of ezrin was examined in glomerular cells in culture, during kidney development, in the mature kidney, and in five different experimental kidney disease models in the rat.ResultsEzrin was specifically expressed in glomerular epithelial cells in developing glomeruli in mature glomeruli and in glomerular epithelial cells in culture. Distinct from its other family members, moesin and radixin, which are predominantly expressed in glomerular endothelial and mesangial areas, ezrin protein (by immunohistochemistry) was specifically and exclusively modulated during podocyte injury and regeneration. Ezrin immunohistochemistry was able to visualize cell body attenuation, pseudocysts, and in particular vacuolation of injured podocytes, a feature that usually has to be identified at the ultrastructural level, and was strikingly increased in binucleated podocytes or podocytes that were partially or completely detached from the underlying GBM (frequently also binucleated). Infiltrating macrophages also express ezrin, but can easily be differentiated from podocytes by their round shape and higher level of expression.ConclusionsEzrin likely has a role in the cytoskeletal organization, such as reassembling of actin filaments accompanying podocyte injury and regeneration. Since suitable light microscopic markers for the identification of glomerular epithelial cells are rare, ezrin may also be a useful marker for podocytes in normal and injured glomeruli

APOE genotype and cognitive change in young, middle-aged, and older adults living in the community.

We examined whether the apolipoprotein E (APOE) ε4 allele was associated with cognitive benefits in young adulthood and whether it reversed to confer cognitive deficits in later life ("antagonistic pleiotropy") in the absence of dementia-related neuropathology. We also tested whether the ε2 allele was associated with disadvantages in early adulthood but offered protection against cognitive decline in early old age. Eight-year cognitive change was assessed in 2,013 cognitively normal community-dwelling adults aged 20-24, 40-44, or 60-64 years at baseline. Although cognitive decline was associated with age, multilevel models contrasting the ε2 and ε4 alleles provided no evidence that the APOE genotype was related to cognitive change in any of the age groups. The findings suggest that in the absence of clinically salient dementia pathology, APOE ε2 and ε4 alleles do not exhibit antagonistic pleiotropy in relation to cognition between the ages of 20 and 72 years

Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans

Peer reviewedPreprin

Apolipoprotein E ε4 and Later-Life Decline in Cognitive Function and Grip Strength.

Objectives: Presence of the apolipoprotein E (APOE) ε4 allele is a risk factor for dementia, whereas the ε2 allele offers protection against dementia. There is also evidence for a relationship between APOE genotype and changes in cognitive function. It is not clear, however, whether this relationship stems from undetected disease in persons genetically more vulnerable to dementia. This study examined whether APOE genotype was associated with either initial performance or change in performance on a range of cognitive and noncognitive tasks, after accounting for possible preclinical dementia. Design: A population-based cohort was assessed up to four times over 12 years. Participants: The sample was an Australian cohort of 590 participants age 70 years and older who were genotyped for APOE. Measurements: The outcomes were processing speed, verbal fluency, episodic memory, word recognition, face recognition, grip strength, and reaction time. Results: Adjusted latent growth models indicated that ε4 carriers had significantly poorer initial memory performance and greater declines in processing speed and word recognition than ε2 and ε3 carriers. In addition, ε2 carriers exhibited significantly less decline in right grip strength than ε3 carriers. However, after excluding 125 participants with low global cognition scores, all genotype effects became nonsignificant. Conclusions: Over a 12-year period, findings indicate that APOE ε4-related cognitive decline in older community-dwelling populations is due to a higher likelihood of preclinical dementia among ε4 carriers. When possible dementia cases are removed from the analyses, ε4 associations with cognitive decline become statistically unreliable

Location of Pathogenic Bacteria during Persistent Infections: Insights from an Analysis Using Game Theory

Bacterial persistent infections are responsible for a significant amount of the human morbidity and mortality. Unlike acute bacterial infections, it is very difficult to treat persistent bacterial infections (e.g. tuberculosis). Knowledge about the location of pathogenic bacteria during persistent infection will help to treat such conditions by designing novel drugs which can reach such locations. In this study, events of bacterial persistent infections were analyzed using game theory. A game was defined where the pathogen and the host are the two players with a conflict of interest. Criteria for the establishment of Nash equilibrium were calculated for this game. This theoretical model, which is very simple and heuristic, predicts that during persistent infections pathogenic bacteria stay in both intracellular and extracellular compartments of the host. The result of this study implies that a bacterium should be able to survive in both intracellular and extracellular compartments of the host in order to cause persistent infections. This explains why persistent infections are more often caused by intracellular pathogens like Mycobacterium and Salmonella. Moreover, this prediction is in consistence with the results of previous experimental studies

Caveolin-1 protects B6129 mice against Helicobacter pylori gastritis.

Caveolin-1 (Cav1) is a scaffold protein and pathogen receptor in the mucosa of the gastrointestinal tract. Chronic infection of gastric epithelial cells by Helicobacter pylori (H. pylori) is a major risk factor for human gastric cancer (GC) where Cav1 is frequently down-regulated. However, the function of Cav1 in H. pylori infection and pathogenesis of GC remained unknown. We show here that Cav1-deficient mice, infected for 11 months with the CagA-delivery deficient H. pylori strain SS1, developed more severe gastritis and tissue damage, including loss of parietal cells and foveolar hyperplasia, and displayed lower colonisation of the gastric mucosa than wild-type B6129 littermates. Cav1-null mice showed enhanced infiltration of macrophages and B-cells and secretion of chemokines (RANTES) but had reduced levels of CD25+ regulatory T-cells. Cav1-deficient human GC cells (AGS), infected with the CagA-delivery proficient H. pylori strain G27, were more sensitive to CagA-related cytoskeletal stress morphologies ("humming bird") compared to AGS cells stably transfected with Cav1 (AGS/Cav1). Infection of AGS/Cav1 cells triggered the recruitment of p120 RhoGTPase-activating protein/deleted in liver cancer-1 (p120RhoGAP/DLC1) to Cav1 and counteracted CagA-induced cytoskeletal rearrangements. In human GC cell lines (MKN45, N87) and mouse stomach tissue, H. pylori down-regulated endogenous expression of Cav1 independently of CagA. Mechanistically, H. pylori activated sterol-responsive element-binding protein-1 (SREBP1) to repress transcription of the human Cav1 gene from sterol-responsive elements (SREs) in the proximal Cav1 promoter. These data suggested a protective role of Cav1 against H. pylori-induced inflammation and tissue damage. We propose that H. pylori exploits down-regulation of Cav1 to subvert the host's immune response and to promote signalling of its virulence factors in host cells

Hierarchical Hidden Markov Model in Detecting Activities of Daily Living in Wearable Videos for Studies of Dementia

International audienceThis paper presents a method for indexing activities of daily living in videos obtained from wearable cameras. In the context of dementia diagnosis by doctors, the videos are recorded at patients' houses and later visualized by the medical practitioners. The videos may last up to two hours, therefore a tool for an efficient navigation in terms of activities of interest is crucial for the doctors. The specific recording mode provides video data which are really difficult, being a single sequence shot where strong motion and sharp lighting changes often appear. Our work introduces an automatic motion based segmentation of the video and a video structuring approach in terms of activities by a hierarchical two-level Hidden Markov Model. We define our description space over motion and visual characteristics of video and audio channels. Experiments on real data obtained from the recording at home of several patients show the difficulty of the task and the promising results of our approach

Detection of early Alzheimer's disease in MCI patients by the combination of MMSE and an episodic memory test

BACKGROUND: Mild cognitive impairment (MCI) is a heterogeneous clinical entity that comprises the prodromal phase of Alzheimer's disease (Pr-AD). New biomarkers are useful in detecting Pr-AD, but they are not universally available. We aimed to investigate baseline clinical and neuropsychological variables that might predict progression from MCI to AD dementia. METHODS: All patients underwent a complete clinical and neuropsychological evaluation at baseline and every 6 months during a two-year follow-up period, with 54 out of 109 MCI patients progressing to dementia (50 of them progressed to AD dementia), and 55 remaining as stable MCI (S-MCI). RESULTS: A combination of MMSE and California Verbal Learning Test Long Delayed Total Recall (CVLT-LDTR) constituted the best predictive model: subjects scoring above 26/30 on MMSE and 4/16 on CVLT-LDTR had a negative predictive value of 93.93% at 2 years, whereas those subjects scoring below both of these cut-off scores had a positive predictive value of 80.95%. CONCLUSIONS: Pr-AD might be distinguished from S-MCI at baseline using the combination of MMSE and CVLT-LDTR. These two neuropsychological predictors are relatively brief and may be readily completed in non-specialist clinical settings