Characterization of cerebral glucose dynamics in vivo with a four-state conformational model of transport at the blood-brain barrier.

Determination of brain glucose transport kinetics in vivo at steady-state typically does not allow distinguishing apparent maximum transport rate (T(max)) from cerebral consumption rate. Using a four-state conformational model of glucose transport, we show that simultaneous dynamic measurement of brain and plasma glucose concentrations provide enough information for independent and reliable determination of the two rates. In addition, although dynamic glucose homeostasis can be described with a reversible Michaelis-Menten model, which is implicit to the large iso-inhibition constant (K(ii)) relative to physiological brain glucose content, we found that the apparent affinity constant (K(t)) was better determined with the four-state conformational model of glucose transport than with any of the other models tested. Furthermore, we confirmed the utility of the present method to determine glucose transport and consumption by analysing the modulation of both glucose transport and consumption by anaesthesia conditions that modify cerebral activity. In particular, deep thiopental anaesthesia caused a significant reduction of both T(max) and cerebral metabolic rate for glucose consumption. In conclusion, dynamic measurement of brain glucose in vivo in function of plasma glucose allows robust determination of both glucose uptake and consumption kinetics.

Measurement of the tree root growth using electrical impedance spectroscopy

Abstract

Selective inhibition of JNK with a peptide inhibitor attenuates pain hypersensitivity and tumor growth in a mouse skin cancer pain model.

Cancer pain significantly affects the quality of cancer patients, and current treatments for this pain are limited. C-Jun N-terminal kinase (JNK) has been implicated in tumor growth and neuropathic pain sensitization. We investigated the role of JNK in cancer pain and tumor growth in a skin cancer pain model. Injection of luciferase-transfected B16-Fluc melanoma cells into a hindpaw of mouse induced robust tumor growth, as indicated by increase in paw volume and fluorescence intensity. Pain hypersensitivity in this model developed rapidly (<5 days) and reached a peak in 2 weeks, and was characterized by mechanical allodynia and heat hyperalgesia. Tumor growth was associated with JNK activation in tumor mass, dorsal root ganglion (DRG), and spinal cord and a peripheral neuropathy, such as loss of nerve fibers in the hindpaw skin and induction of ATF-3 expression in DRG neurons. Repeated systemic injections of D-JNKI-1 (6 mg/kg, i.p.), a selective and cell-permeable peptide inhibitor of JNK, produced an accumulative inhibition of mechanical allodynia and heat hyperalgesia. A bolus spinal injection of D-JNKI-1 also inhibited mechanical allodynia. Further, JNK inhibition suppressed tumor growth in vivo and melanoma cell proliferation in vitro. In contrast, repeated injections of morphine (5 mg/kg), a commonly used analgesic for terminal cancer, produced analgesic tolerance after 1 day and did not inhibit tumor growth. Our data reveal a marked peripheral neuropathy in this skin cancer model and important roles of the JNK pathway in cancer pain development and tumor growth. JNK inhibitors such as D-JNKI-1 may be used to treat cancer pain.

Seismic Wave Velocity as a Means of In-Place Density Measurement, Part 1, HR-114

Velocity-density tests conducted in the laboratory involved small 4-inch diameter by 4.58-inch-long compacted soil cylinders made up of 3 differing soil types and for varying degrees of density and moisture content, the latter being varied well beyond optimum moisture values. Seventeen specimens were tested, 9 with velocity determinations made along two elements of the cylinder, 180 degrees apart, and 8 along three elements, 120 degrees apart. Seismic energy was developed by blows of a small tack hammer on a 5/8-inch diameter steel ball placed at the center of the top of the cylinder, with the detector placed successively at four points spaced 1/2-inch apart on the side of the specimen involving wave travel paths varying from 3.36 inches to 4.66 inches in length. Time intervals were measured using a model 217 micro-seismic timer in both laboratory and field measurements. Forty blows of the hammer were required for each velocity determination, which amounted to 80 blows on 9 laboratory specimens and 120 blows on the remaining 8 cylinders. Thirty-five field tests were made over the three selected soil types, all fine-grained, using a 2-foot seismic line with hammer-impact points at 6-inch intervals. The small tack hammer and 5/8-inch steel ball was, again, used to develop seismic wave energy. Generally, the densities obtained from the velocity measurements were lower than those measured in the conventional field testing. Conclusions were reached that: (1) the method does not appear to be usable for measurement of density of essentially fine-grained soils when the moisture content greatly exceeds the optimum for compaction, and (2) due to a gradual reduction in velocity upon aging, apparently because of gradual absorption of pore water into the expandable interlayer region of the clay, the seismic test should be conducted immediately after soil compaction to obtain a meaningful velocity value.

Methods for the analysis of two dimensional measurement data of paper web

This work is devoted to the problem of reconstructing the basis weight structure at paper web with black{box techniques. The data that is analyzed comes from a real paper machine and is collected by an o®-line scanner. The principal mathematical tool used in this work is Autoregressive Moving Average (ARMA) modelling. When coupled with the Discrete Fourier Transform (DFT), it gives a very flexible and interesting tool for analyzing properties of the paper web. Both ARMA and DFT are independently used to represent the given signal in a simplified version of our algorithm, but the final goal is to combine the two together. Ljung-Box Q-statistic lack-of-fit test combined with the Root Mean Squared Error coefficient gives a tool to separate significant signals from noise.

Measurement of a Structured Backflow in an Open Small Channel Induced by Surface-Tension Gradients

We present experiments in which the laterally confined flow of a surfactant film driven by controlled surface tension gradients causes the subtended liquid layer to self-organize into an inner upstream microduct surrounded by the downstream flow. The anomalous interfacial flow profiles and the concomitant backflow are a result of the feedback between two-dimensional and three-dimensional microfluidics realized during flow in open microchannels. Bulk and surface particle image velocimetry data combined with an interfacial hydrodynamics model explain the dependence of the observed phenomena on channel geometry.

Aortic blood pressure measured via EIT: investigation of different measurement settings.

Electrical impedance tomography (EIT) allows the measurement of intra-thoracic impedance changes related to cardiovascular activity. As a safe and low-cost imaging modality, EIT is an appealing candidate for non-invasive and continuous haemodynamic monitoring. EIT has recently been shown to allow the assessment of aortic blood pressure via the estimation of the aortic pulse arrival time (PAT). However, finding the aortic signal within EIT image sequences is a challenging task: the signal has a small amplitude and is difficult to locate due to the small size of the aorta and the inherent low spatial resolution of EIT. In order to most reliably detect the aortic signal, our objective was to understand the effect of EIT measurement settings (electrode belt placement, reconstruction algorithm). This paper investigates the influence of three transversal belt placements and two commonly-used difference reconstruction algorithms (Gauss-Newton and GREIT) on the measurement of aortic signals in view of aortic blood pressure estimation via EIT. A magnetic resonance imaging based three-dimensional finite element model of the haemodynamic bio-impedance properties of the human thorax was created. Two simulation experiments were performed with the aim to (1) evaluate the timing error in aortic PAT estimation and (2) quantify the strength of the aortic signal in each pixel of the EIT image sequences. Both experiments reveal better performance for images reconstructed with Gauss-Newton (with a noise figure of 0.5 or above) and a belt placement at the height of the heart or higher. According to the noise-free scenarios simulated, the uncertainty in the analysis of the aortic EIT signal is expected to induce blood pressure errors of at least ± 1.4 mmHg.

Two-dimensional probabilistic inversion of plane-wave electromagnetic data: Methodology, model constraints and joint inversion with electrical resistivity data

Probabilistic inversion methods based on Markov chain Monte Carlo (MCMC) simulation are well suited to quantify parameter and model uncertainty of nonlinear inverse problems. Yet, application of such methods to CPU-intensive forward models can be a daunting task, particularly if the parameter space is high dimensional. Here, we present a 2-D pixel-based MCMC inversion of plane-wave electromagnetic (EM) data. Using synthetic data, we investigate how model parameter uncertainty depends on model structure constraints using different norms of the likelihood function and the model constraints, and study the added benefits of joint inversion of EM and electrical resistivity tomography (ERT) data. Our results demonstrate that model structure constraints are necessary to stabilize the MCMC inversion results of a highly discretized model. These constraints decrease model parameter uncertainty and facilitate model interpretation. A drawback is that these constraints may lead to posterior distributions that do not fully include the true underlying model, because some of its features exhibit a low sensitivity to the EM data, and hence are difficult to resolve. This problem can be partly mitigated if the plane-wave EM data is augmented with ERT observations. The hierarchical Bayesian inverse formulation introduced and used herein is able to successfully recover the probabilistic properties of the measurement data errors and a model regularization weight. Application of the proposed inversion methodology to field data from an aquifer demonstrates that the posterior mean model realization is very similar to that derived from a deterministic inversion with similar model constraints.

A Population-Based Model to Consider the Effect of Seasonal Variation on Serum 25(OH)D and Vitamin D Status.

Background. We elaborated a model that predicts the centiles of the 25(OH)D distribution taking into account seasonal variation. Methods. Data from two Swiss population-based studies were used to generate (CoLaus) and validate (Bus Santé) the model. Serum 25(OH)D was measured by ultra high pressure LC-MS/MS and immunoassay. Linear regression models on square-root transformed 25(OH)D values were used to predict centiles of the 25(OH)D distribution. Distribution functions of the observations from the replication set predicted with the model were inspected to assess replication. Results. Overall, 4,912 and 2,537 Caucasians were included in original and replication sets, respectively. Mean (SD) 25(OH)D, age, BMI, and % of men were 47.5 (22.1) nmol/L, 49.8 (8.5) years, 25.6 (4.1) kg/m(2), and 49.3% in the original study. The best model included gender, BMI, and sin-cos functions of measurement day. Sex- and BMI-specific 25(OH)D centile curves as a function of measurement date were generated. The model estimates any centile of the 25(OH)D distribution for given values of sex, BMI, and date and the quantile corresponding to a 25(OH)D measurement. Conclusions. We generated and validated centile curves of 25(OH)D in the general adult Caucasian population. These curves can help rank vitamin D centile independently of when 25(OH)D is measured.

Visual Measurement and Modelling of Tool Wear in Rough Turning

Huolimatta korkeasta automaatioasteesta sorvausteollisuudessa, muutama keskeinen ongelma estää sorvauksen täydellisen automatisoinnin. Yksi näistä ongelmista on työkalun kuluminen. Tämä työ keskittyy toteuttamaan automaattisen järjestelmän kulumisen, erityisesti viistekulumisen, mittaukseen konenäön avulla. Kulumisen mittausjärjestelmä poistaa manuaalisen mittauksen tarpeen ja minimoi ajan, joka käytetään työkalun kulumisen mittaukseen. Mittauksen lisäksi tutkitaan kulumisen mallinnusta sekä ennustamista. Automaattinen mittausjärjestelmä sijoitettiin sorvin sisälle ja järjestelmä integroitiin onnistuneesti ulkopuolisten järjestelmien kanssa. Tehdyt kokeet osoittivat, että mittausjärjestelmä kykenee mittaamaan työkalun kulumisen järjestelmän oikeassa ympäristössä. Mittausjärjestelmä pystyy myös kestämään häiriöitä, jotka ovat konenäköjärjestelmille yleisiä. Työkalun kulumista mallinnusta tutkittiin useilla eri menetelmillä. Näihin kuuluivat muiden muassa neuroverkot ja tukivektoriregressio. Kokeet osoittivat, että tutkitut mallit pystyivät ennustamaan työkalun kulumisasteen käytetyn ajan perusteella. Parhaan tuloksen antoivat neuroverkot Bayesiläisellä regularisoinnilla.

The Measurement Invariance of Schizotypy in Europe

The short version of the Oxford-Liverpool Inventory of Feelings and Experiences (sO-LIFE) is a widely used measure assessing schizotypy. There is limited information, however, on how sO-LIFE scores compare across different countries. The main goal of the present study is to test the measurement invariance of the sO-LIFE scores in a large sample of non-clinical adolescents and young adults from four European countries (UK, Switzerland, Italy, and Spain). The scores were obtained from validated versions of the sO-LIFE in their respective languages. The sample comprised 4190 participants (M = 20.87 years; SD = 3.71 years). The study of the internal structure, using confirmatory factor analysis, revealed that both three (i.e., positive schizotypy, cognitive disorganisation, and introvertive anhedonia) and four-factor (i.e., positive schizotypy, cognitive disorganisation, introvertive anhedonia, and impulsive nonconformity) models fitted the data moderately well. Multi-group confirmatory factor analysis showed that the three-factor model had partial strong measurement invariance across countries. Eight items were non-invariant across samples. Significant statistical differences in the mean scores of the s-OLIFE were found by country. Reliability scores, estimated with Ordinal alpha ranged from 0.75 to 0.87. Using the Item Response Theory framework, the sO-LIFE provides more accuracy information at the medium and high end of the latent trait. The current results show further evidence in support of the psychometric proprieties of the sO-LIFE, provide new information about the cross-cultural equivalence of schizotypy and support the use of this measure to screen for psychotic-like features and liability to psychosis in general population samples from different European countries.

Creatine deficiency syndomes : a new model of partial GAMT deficiency affecting brain cell development

Les syndromes de déficiences cérébrales en créatine (CCDS) sont dus à des mutations dans les gènes GATM et G AMT (codant pour les enzymes AGAT et G AMT de la voie de synthèse de créatine) ainsi que SLC6A8 (transporteur de créatine), et génèrent une absence ou une très forte baisse de créatine (Cr) dans le cerveau, mesurée par spectroscopic de résonance magnétique. Les patients CCDS développent des handicaps neurologiques sévères. Les patients AGAT et GAMT peuvent être traités avec des doses importantes de Cr, mais gardent dans la plupart des cas des séquelles neurologiques irréversibles. Aucun traitement efficace n'existe à ce jour pour la déficience en SLC6A8. Bien que de nombreux modèles aient été développés pour comprendre la Cr cérébrale en conditions physiologiques, les pathomécanismes des CCDS ne sont pas encore compris. Des souris transgéniques pour les gènes Gatm, Gamt et Slc6a8 ont été générées, mais elles ne miment que partiellement la pathologie humaine. Parmi les CCDS, la déficience en GAMT est la plus sévère, en raison de l'accumulation cérébrale de l'intermédiaire guanidinoacétate (GAA). Alors que la toxicité cérébrale du GAA a été étudiée par exposition directe au GAA d'animaux adultes sains, les mécanismes de la toxicité du GAA en condition de déficience en GAMT dans le cerveau en développement sont encore inconnus. Le but de ce projet était donc de développer un modèle de déficience en GAMT dans des cultures 3D primaires de cellules nerveuses de rat en agrégats par knock-down du gène GAMT, en utilisant un virus adéno-associé (AAV) induisant le mécanisme d'interférence à l'ARN (RNAi). Le virus scAAV2, à la multiplicité d'infection de 1000, s'est révélé le plus efficace pour transduire tous les types de cellules nerveuses des cultures (neurones, astrocytes, oligodendrocytes), et générer un knock-down maximal de la protéine GAMT de 85% (jour in vitro 18). Cette déficience partielle en GAMT s'est révélée insuffisante pour générer une déficience en Cr, mais a causé l'accumulation attendue de GAA, à des doses comparables aux niveaux observés dans le LCR des patients GAMT. Le GAA a induit une croissance axonale anarchique accompagnée d'une baisse de l'apoptose naturelle, suivis par une induction tardive de mort cellulaire non-apoptotique. Le co-traitement par la Cr a prévenu tous les effets toxiques du GAA. Ce travail montre que l'accumulation de GAA en absence de déficience en Cr est suffisante pour affecter le développement du tissu nerveux, et suggère que des formes de déficiences en GAMT supplémentaires, ne présentant pas de déficiences en Cr, pourraient être découvertes par mesure du GAA, en particulier à travers les programmes récemment proposés de dépistage néonatal de la déficience en GAMT. -- Cerebral creatine deficiency syndromes (CCDS) are caused by mutations in the genes GATM and GAMT (respectively coding for the two enzymes of the creatine synthetic pathway, AGAT and GAMT) as well as SLC6A8 (creatine transporter), and lead to the absence or very strong decrease of creatine (Cr) in the brain when measured by magnetic resonance spectroscopy. Affected patients show severe neurological impairments. While AGAT and GAMT deficient patients can be treated with high dosages of Cr, most remain with irreversible brain sequelae. No treatment has been successful so far for SLC6A8 deficiency. While many models have helped understanding the cerebral Cr pathways in physiological conditions, the pathomechanisms underlying CCDS are yet to be elucidated. Transgenic mice carrying mutations in the Gatm, Gamt and Slc6a8 genes have been developed, but only partially mimic the human pathology. Among CCDS, GAMT deficiency is the most severe, due to the CNS accumulation of the guanidinoacetate (GAA) intermediate. While brain toxicity of GAA has been explored through direct GAA exposure of adult healthy animals, the mechanisms underlying GAA toxicity in GAMT deficiency conditions on the developing CNS are yet unknown. The aim of this project was thus to develop and characterize a GAMT deficiency model in developing brain cells by gene knockdown, by adeno-associated virus (AAV)-driven RNA interference (RNAi) in rat 3D organotypic primary brain cell cultures in aggregates. scAAV2 with a multiplicity of infection of 1000 was shown as the most efficient serotype, was able to transduce all brain cell types (neurons, astrocytes, oligodendrocytes) and to induce a maximal GAMT protein knockdown of 85% (day in vitro 18). Metabolite analysis showed that partial GAMT knockdown was insufficient to induce Cr deficiency but generated the awaited GAA accumulation at concentrations comparable to the levels observed in cerebrospinal fluid of GAMT-deficient patients. Accumulated GAA induced axonal hypersprouting paralleled with inhibition of natural apoptosis, followed by a later induction in non-apoptotic cell death. Cr supplementation led to the prevention of all GAA-induced toxic effects. This work shows that GAA accumulation without Cr deficiency is sufficient to affect CNS development, and suggests that additional partial GAMT deficiencies, which may not show the classical brain Cr deficiency, may be discovered through GAA measurement including by recently proposed neonatal screening programs for GAMT deficiency.

Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants.

BACKGROUND: Underweight and severe and morbid obesity are associated with highly elevated risks of adverse health outcomes. We estimated trends in mean body-mass index (BMI), which characterises its population distribution, and in the prevalences of a complete set of BMI categories for adults in all countries. METHODS: We analysed, with use of a consistent protocol, population-based studies that had measured height and weight in adults aged 18 years and older. We applied a Bayesian hierarchical model to these data to estimate trends from 1975 to 2014 in mean BMI and in the prevalences of BMI categories (<18·5 kg/m(2) [underweight], 18·5 kg/m(2) to <20 kg/m(2), 20 kg/m(2) to <25 kg/m(2), 25 kg/m(2) to <30 kg/m(2), 30 kg/m(2) to <35 kg/m(2), 35 kg/m(2) to <40 kg/m(2), ≥40 kg/m(2) [morbid obesity]), by sex in 200 countries and territories, organised in 21 regions. We calculated the posterior probability of meeting the target of halting by 2025 the rise in obesity at its 2010 levels, if post-2000 trends continue. FINDINGS: We used 1698 population-based data sources, with more than 19·2 million adult participants (9·9 million men and 9·3 million women) in 186 of 200 countries for which estimates were made. Global age-standardised mean BMI increased from 21·7 kg/m(2) (95% credible interval 21·3-22·1) in 1975 to 24·2 kg/m(2) (24·0-24·4) in 2014 in men, and from 22·1 kg/m(2) (21·7-22·5) in 1975 to 24·4 kg/m(2) (24·2-24·6) in 2014 in women. Regional mean BMIs in 2014 for men ranged from 21·4 kg/m(2) in central Africa and south Asia to 29·2 kg/m(2) (28·6-29·8) in Polynesia and Micronesia; for women the range was from 21·8 kg/m(2) (21·4-22·3) in south Asia to 32·2 kg/m(2) (31·5-32·8) in Polynesia and Micronesia. Over these four decades, age-standardised global prevalence of underweight decreased from 13·8% (10·5-17·4) to 8·8% (7·4-10·3) in men and from 14·6% (11·6-17·9) to 9·7% (8·3-11·1) in women. South Asia had the highest prevalence of underweight in 2014, 23·4% (17·8-29·2) in men and 24·0% (18·9-29·3) in women. Age-standardised prevalence of obesity increased from 3·2% (2·4-4·1) in 1975 to 10·8% (9·7-12·0) in 2014 in men, and from 6·4% (5·1-7·8) to 14·9% (13·6-16·1) in women. 2·3% (2·0-2·7) of the world's men and 5·0% (4·4-5·6) of women were severely obese (ie, have BMI ≥35 kg/m(2)). Globally, prevalence of morbid obesity was 0·64% (0·46-0·86) in men and 1·6% (1·3-1·9) in women. INTERPRETATION: If post-2000 trends continue, the probability of meeting the global obesity target is virtually zero. Rather, if these trends continue, by 2025, global obesity prevalence will reach 18% in men and surpass 21% in women; severe obesity will surpass 6% in men and 9% in women. Nonetheless, underweight remains prevalent in the world's poorest regions, especially in south Asia. FUNDING: Wellcome Trust, Grand Challenges Canada.

Mobile Subscription Acquisition and Retention Costs - An Actvity-Based Model

The objective of this master’s thesis was to develop a model for mobile subscription acquisition cost, SAC, and mobile subscription retention cost, SRC, by applying activity-based cost accounting principles. The thesis was conducted as a case study for a telecommunication company operating on the Finnish telecommunication market. In addition to activity-based cost accounting there were other theories studied and applied in order to establish a theory framework for this thesis. The concepts of acquisition and retention were explored in a broader context with the concepts of customer satisfaction, loyalty and profitability and eventually customer relationship management to understand the background and meaning of the theme of this thesis. The utilization of SAC and SRC information is discussed through the theories of decision making and activity-based management. Also, the present state and future needs of SAC and SRC information usage at the case company as well as the functions of the company were examined by interviewing some members of the company personnel. With the help of these theories and methods it was aimed at finding out both the theory-based and practical factors which affect the structure of the model. During the thesis study it was confirmed that the existing SAC and SRC model of the case company should be used as the basis in developing the activity-based model. As a result the indirect costs of the old model were transformed into activities and the direct costs were continued to be allocated directly to acquisition of new subscriptions and retention of old subscriptions. The refined model will enable managing the subscription acquisition, retention and the related costs better through the activity information. During the interviews it was found out that the SAC and SRC information is also used in performance measurement and operational and strategic planning. SAC and SRC are not fully absorbed costs and it was concluded that the model serves best as a source of indicative cost information. This thesis does not include calculating costs. Instead, the refined model together with both the theory-based and interview findings concerning the utilization of the information produced by the model will serve as a framework for the possible future development aiming at completing the model.

Defining a Performance Measurement System for Technology Marketing Team by Using the Balanced Scorecard Method

This thesis was produced for the Technology Marketing unit at the Nokia Research Center. Technology marketing was a new function at Nokia Research Center, and needed an established framework with the capacity to take into account multiple aspects for measuring the team performance. Technology marketing functions had existed in other parts of Nokia, yet no single method had been agreed upon for measuring their performance. The purpose of this study was to develop a performance measurement system for Nokia Research Center Technology Marketing. The target was that Nokia Research Center Technology Marketing had a framework for separate metrics; including benchmarking for starting level and target values in the future planning (numeric values were kept confidential within the company). As a result of this research, the Balanced Scorecard model of Kaplan and Norton, was chosen for the performance measurement system for Nokia Research Center Technology Marketing. This research selected the indicators, which were utilized in the chosen performance measurement system. Furthermore, performance measurement system was defined to guide the Head of Marketing in managing Nokia Research Center Technology Marketing team. During the research process the team mission, vision, strategy and critical success factors were outlined.