Predicting AD Conversion: Comparison between Prodromal AD Guidelines and Computer Assisted PredictAD Tool

Purpose

To compare the accuracies of predicting AD conversion by using a decision support system (PredictAD tool) and current research criteria of prodromal AD as identified by combinations of episodic memory impairment of hippocampal type and visual assessment of medial temporal lobe atrophy (MTA) on MRI and CSF biomarkers.

Methods

Altogether 391 MCI cases (158 AD converters) were selected from the ADNI cohort. All the cases had baseline cognitive tests, MRI and/or CSF levels of Aβ1–42 and Tau. Using baseline data, the status of MCI patients (AD or MCI) three years later was predicted using current diagnostic research guidelines and the PredictAD software tool designed for supporting clinical diagnostics. The data used were 1) clinical criteria for episodic memory loss of the hippocampal type, 2) visual MTA, 3) positive CSF markers, 4) their combinations, and 5) when the PredictAD tool was applied, automatically computed MRI measures were used instead of the visual MTA results. The accuracies of diagnosis were evaluated with the diagnosis made 3 years later.

Results

The PredictAD tool achieved the overall accuracy of 72% (sensitivity 73%, specificity 71%) in predicting the AD diagnosis. The corresponding number for a clinician’s prediction with the assistance of the PredictAD tool was 71% (sensitivity 75%, specificity 68%). Diagnosis with the PredictAD tool was significantly better than diagnosis by biomarkers alone or the combinations of clinical diagnosis of hippocampal pattern for the memory loss and biomarkers (p≤0.037).

Conclusion

With the assistance of PredictAD tool, the clinician can predict AD conversion more accurately than the current diagnostic criteria.     

Governing the Interplay between Industrial Ecosystems and Environmental Regulation

Many scholars of industrial ecology have focused on the institutional and organizational challenges of building and maintaining regional industrial symbiosis through the synergistic integration of material and energy flows. Despite the promise that these intellectual developments hold for the future dematerialization of industrial production, they rarely address the actual regulatory obstacles of turning wastes into raw materials. In this article we introduce a potential future industrial symbiosis around the Gulf of Bothnia between Finland and Sweden, and assess the regulatory bottlenecks related to waste by‐product consideration. We find that although the Gulf of Bothnia region has technological and economic potential for industrial symbiosis, the regulatory support for this is insufficient. We suggest a common pool resource‐based governance system that could utilize market and regulatory mechanisms in a regional‐level cross‐border system of governance. Importantly, the suggested governance system would protect the users of potential raw materials from unpredictable waste regulation, market risks related to large‐scale material flows, and societal risks of hazardous waste treatment.     

Development of a New Method to Get a Reliable Powder Flow Characteristics Using Only 1 to 2 g of Powder

In powder technology, it is often important to directly measure real powder flow rate from a small amount of powder. For example, in pharmaceutical industry, a frequent problem is to determine powder flow properties of new active pharmaceutical ingredient (API) in an early stage of the development when the amount of API is limited. The purpose of this paper is to introduce a new direct method to measure powder flow when the material is poorly flowing (cohesive) and the amount of material is about 1 to 2 g. The measuring system was simple, consisting of a flow chamber and electronic balance and an automated optical detection system, and for each measurement, only 1 to 2 g of sample was required. Based on the results obtained with this testing method, three selected sugar excipients, three grades of microcrystalline cellulose, and APIs (caffeine, carbamazepine, and paracetamol) can be classified as freely flowing, intermediate flowing, and poorly flowing powders, respectively. The average relative standard deviation for the flow time determinations was not more than 2–10%. The present novel flowability testing method provides a new tool for a rapid determination of flowing characteristics of powders (e.g., inhalation powders) and granules at a small scale.     

A duplexed microsphere-based cellular adhesion assay

Interactions of integrin cellular adhesion molecules with matrix proteins play important roles in complex bidirectional signaling pathways. To investigate these interactions, a novel flow-cytometry-based cellular adhesion assay has been developed. Based on the concept of microcarrier cell culture, derivatized polystyrene microspheres (9.6 microm) are used as a substrate for the immobilization of type I collagen to which cells then adhere. Using cytometric detection, the extent of cellular adhesion can be precisely determined by comparison of adhered and nonadhered populations based on the side scatter properties of the microspheres. In combination with immunostaining, the novel format of this assay enables the correlation of adhesive function to other cellular characteristics such as surface expression. In this work, the protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate (TPA) was used to stimulate increased adhesion in Chinese hamster ovary cells stably transfected with the collagen receptor integrin alpha2beta1. Multiple clones of varying expression distributions were analyzed, and correlations of adherent populations versus receptor distributions show a threefold increase in functional cellular adhesion to collagen upon treatment with TPA. Probability binning analysis of duplexed data revealed subtle changes in adhesion versus receptor distribution mediated by TPA which otherwise would not have been detectable.     

Bone Morphogenetic Protein-2 Is a Regulator of Cell Adhesion

Bone morphogenetic proteins (BMPs) are a group of peptide growth factors closely related to transforming growth factors-β. The BMPs are suggested to play an essential role in bone development and they are strong candidate molecules to be used clinically to improve fracture healing. BMPs are also involved in the differentiation of several other tissues during embryogenesis. Here, we show that human recombinant BMP-2 regulates cell–matrix interactions by modifying the expression of integrin-type receptors. The synthesis of α3 integrin was down-regulated by BMP-2 in two osteogenic sarcoma-derived cell lines, Saos-2 and HOS, and also in human fetal chondrocytes. BMP-2 had no effect on the expression of α1, α2, α5, α6, and αV integrins. BMP-2 reduced the expression of α3 integrin subunit at mRNA level. Laminin-5 was shown to be the ligand for α3β1 integrin on Saos cells and BMP-2 decreased the ability of Saos cells to attach to it. These results suggest that BMP-2 has a specific effect on the α3β1 integrin-mediated cell adhesion to laminin-5. Given the fact that BMP-2 is expressed in osteosarcomas, in addition to in bone, this mechanism is putatively important especially in bone development and tumors. We also studied the effect of BMP-2 on a human keratinocyte cell line, HaCaT. In HaCaT cells, the expression of α2 integrin was strongly down-regulated by BMP-2, whereas its effect on the expression of α3 integrin was smaller. We suggest that the effects of BMP-2 may be partially mediated by specifically altered cell adhesion.     

Effects of abiotic factors on movements of pikeperch during pre-spawning and spawning season in a Baltic archipelago

The effects of temperature, water level and moon phase on the movements of pikeperch (Sander lucioperca) were studied during pre-spawning and spawning season from April to June. Trends in catches and temperature were removed with linear regression. Cross-correlation analysis showed that temperature change one and two days earlier had the strongest effect on catches. Close to the new moon, pikeperch catches increased, whereas changes in water level had no effects on movements. Handling editor: J. A. Cambray     

Effects of Spray Drying on Physicochemical Properties of Chitosan Acid Salts

The effects of spray-drying process and acidic solvent system on physicochemical properties of chitosan salts were investigated. Chitosan used in spray dryings was obtained by deacetylation of chitin from lobster (Panulirus argus) origin. The chitosan acid salts were prepared in a laboratory-scale spray drier, and organic acetic acid, lactic acid, and citric acid were used as solvents in the process. The physicochemical properties of chitosan salts were investigated by means of solid-state CP-MAS ¹³C nuclear magnetic resonance (NMR), X-ray powder diffraction (XRPD), differential scanning calorimetry, and Fourier transform infrared spectrometry (FTIR) and near-infrared spectroscopy. The morphology of spray-dried chitosan acid salts showed tendency toward higher sphericity when higher temperatures in a spray-drying process were applied. Analysis by XRPD indicated that all chitosan acid salts studied were amorphous solids. Solid-state ¹³C NMR spectra revealed the evidence of the partial conversion of chitosan acetate to chitin and also conversion to acetyl amide form which appears to be dependent on the spray-drying process. The FTIR spectra suggested that the organic acids applied in spray drying may interact with chitosan at the position of amino groups to form chitosan salts. With all three chitosan acid salts, the FTIR bands at 1,597 and 1,615 cm⁻¹ were diminished suggesting that –NH groups are protonated. The FTIR spectra of all chitosan acid salts exhibited ammonium and carboxylate bands at 1,630 and 1,556 cm⁻¹, respectively. In conclusion, spray drying is a potential method of preparing acid salts from chitosan obtained by deacetylation of chitin from lobster (P. argus) origin.     

Calpain 1 and 2 are required for RNA replication of echovirus 1

Calpains are calcium-dependent cysteine proteases that degrade cytoskeletal and cytoplasmic proteins. We have studied the role of calpains in the life cycle of human echovirus 1 (EV1). The calpain inhibitors, including calpeptin, calpain inhibitor 1, and calpain inhibitor 2 as well as calpain 1 and calpain 2 short interfering RNAs, completely blocked EV1 infection in the host cells. The effect of the inhibitors was not specific for EV1, because they also inhibited infection by other picornaviruses, namely, human parechovirus 1 and coxsackievirus B3. The importance of the calpains in EV1 infection also was supported by the fact that EV1 increased calpain activity 3 h postinfection. Confocal microscopy and immunoelectron microscopy showed that the EV1/caveolin-1-positive vesicles also contain calpain 1 and 2. Our results indicate that calpains are not required for virus entry but that they are important at a later stage of infection. Calpain inhibitors blocked the production of EV1 particles after microinjection of EV1 RNA into the cells, and they effectively inhibited the synthesis of viral RNA in the host cells. Thus, both calpain 1 and calpain 2 are essential for the replication of EV1 RNA.     

Radiochemical high-performance liquid chromatographic assay for the determination of catechol O-methyltransferase activity towards various substrates

A new chromatographic catechol O-methyltransferase (COMT) assay based on S-adenosyl- -[methyl-¹⁴C]methionine and on-line radioactivity detection was developed. With minor modifications in the mobile phase composition the methylation velocities for 30 structurally diverse compounds including simple catechols, neurotransmitters, catecholestrogens and catecholic drugs could be measured using human and rat recombinant soluble COMT. The enzymes showed very similar substrate selectivities. The radiochemical method was validated using 3,4-dihydroxybenzoic acid as a model substrate and it was shown that accurate and reproducible methylation velocity values could be achieved for both of the catecholic hydroxyls. The method proved to be suited for determining the enzyme kinetic parameters and can probably be further used for gathering enzyme kinetic data on differentially substituted catechols in order to construct proper structure-activity relationships for COMT.