Altered vision during motion: an unusual symptom of cerebellar dysfunction, quantifiable by a simple clinical test.

PURPOSE: To report a series of patients with cerebellar dysfunction and altered vision during motion, and to quantify their visual impairment in motion with a simple clinical test. METHODS: Twenty consecutive patients suffering from cerebellar dysfunction and altered vision during motion were examined between 1994 and 2007. A control group consisted of 20 age- and sex-matched healthy people. All patients had a full neuro-ophthalmic examination. Near visual acuity (NVA) was measured at rest (static NVA) and during chair rotation (dynamic NVA). Distance visual acuity (DVA) was measured at rest (static DVA) and during rotation of the patient's head (dynamic DVA). RESULTS: Only four of the 20 patients reported altered vision during motion spontaneously. The remaining 16 patients admitted this unusual visual disturbance only when asked specifically. All patients exhibited abnormal eye movements, including saccadic smooth pursuit (20/20), dysmetric saccades (15/20), nystagmus (19/20) and impaired suppression of vestibulo-ocular reflex (VOR) (20/20). During rotation of the examination chair (dynamic NVA), the drop in NVA averaged 5.6 lines (range 1-10 lines). During rotation of the patient's head (dynamic DVA), the drop in DVA averaged only 2.5 lines (range 0-10 lines). For the control group, there was no significant drop in NVA under dynamic conditions. CONCLUSION: Patients with cerebellar dysfunction rarely complain spontaneously of altered vision during motion. However, specific questioning may bring up this unusual symptom. The use of a simple clinical test, consisting of NVA measurement during rotation of the examination chair (dynamic NVA), allows practitioners to quantify the level of visual impairment in patients presenting altered VOR modulation.

The global regulator GacA of Pseudomonas fluorescens CHA0 is required for the suppression of root diseases in dicotyledons but not in Gramineae

Pseudomonas fluorescens strain CHA0 suppresses various plant diseases caused by soil-borne fungi. The pseudomonad produces the antimicrobial metabolites 2,4-diacetylphloroglucinol (Phl), pyoluteorin (Plt) and hydrogen cyanide, which are important for disease suppression, as well as the siderophores pyoverdine (Pvd), salicylic acid (Sal) and pyochelin (Pch). In the current work, a derivative of CHA0 with a mutation in the global regulator gene gacA (GacA−), which is unable to produce Phl, Plt and HCN, failed to protect the dicotyledonous plants cress and cucumber against damping-off caused by Pythium ultimum. In contrast, the GacA− mutant could still protect the Gramineae wheat and maize against damping-off mediated by the same strain of P. ultimum, and wheat against take-all caused by Gaeumannomyces graminis. However, the GacA− mutant overproduced Pch and Pvd. To gain more insight into disease protection afforded by the GacA− mutant, a GacA− Pvd− double mutant (strain CHA496) was constructed by gene replacement. Strain CHA496 overproduced Pch and Sal compared with CHA0 and protected wheat against P. ultimum and G. graminis, whereas cress and cucumber were not protected. Addition of FeCl3 repressed Pch and Sal production by strain CHA496 in vitro and impaired the protection of wheat in soil microcosms. In conclusion, a functional gacA gene was necessary for the protection of dicotyledons against root diseases, but not for that of Gramineae. Results indicated also that Pch and/or Sal were involved in the ability of the GacA− Pvd− mutant of CHA0 to suppress root diseases in Gramineae.

Carbon dioxide efflux in a rhodic hapludox as affected by tillage systems in southern Brazil

Agricultural soils can act as a source or sink of atmospheric C, according to the soil management. This long-term experiment (22 years) was evaluated during 30 days in autumn, to quantify the effect of tillage systems (conventional tillage-CT and no-till-NT) on the soil CO2-C flux in a Rhodic Hapludox in Rio Grande do Sul State, Southern Brazil. A closed-dynamic system (Flux Chamber 6400-09, Licor) and a static system (alkali absorption) were used to measure soil CO2-C flux immediately after soybean harvest. Soil temperature and soil moisture were measured simultaneously with CO2-C flux, by Licor-6400 soil temperature probe and manual TDR, respectively. During the entire month, a CO2-C emission of less than 30 % of the C input through soybean crop residues was estimated. In the mean of a 30 day period, the CO2-C flux in NT soil was similar to CT, independent of the chamber type used for measurements. Differences in tillage systems with dynamic chamber were verified only in short term (daily evaluation), where NT had higher CO2-C flux than CT at the beginning of the evaluation period and lower flux at the end. The dynamic chamber was more efficient than the static chamber in capturing variations in CO2-C flux as a function of abiotic factors. In this chamber, the soil temperature and the water-filled pore space (WFPS), in the NT soil, explained 83 and 62 % of CO2-C flux, respectively. The Q10 factor, which evaluates CO2-C flux dependence on soil temperature, was estimated as 3.93, suggesting a high sensitivity of the biological activity to changes in soil temperature during fall season. The CO2-C flux measured in a closed dynamic chamber was correlated with the static alkali adsorption chamber only in the NT system, although the values were underestimated in comparison to the other, particularly in the case of high flux values. At low soil temperature and WFPS conditions, soil tillage caused a limited increase in soil CO2-C flux.

BIO-INSPIRED COMPUTATIONAL TECHNIQUES APPLIED TO THE CLUSTERING AND VISUALIZATION OF SPATIO-TEMPORAL GEOSPATIAL DATA

The coverage and volume of geo-referenced datasets are extensive and incessantly¦growing. The systematic capture of geo-referenced information generates large volumes¦of spatio-temporal data to be analyzed. Clustering and visualization play a key¦role in the exploratory data analysis and the extraction of knowledge embedded in¦these data. However, new challenges in visualization and clustering are posed when¦dealing with the special characteristics of this data. For instance, its complex structures,¦large quantity of samples, variables involved in a temporal context, high dimensionality¦and large variability in cluster shapes.¦The central aim of my thesis is to propose new algorithms and methodologies for¦clustering and visualization, in order to assist the knowledge extraction from spatiotemporal¦geo-referenced data, thus improving making decision processes.¦I present two original algorithms, one for clustering: the Fuzzy Growing Hierarchical¦Self-Organizing Networks (FGHSON), and the second for exploratory visual data analysis:¦the Tree-structured Self-organizing Maps Component Planes. In addition, I present¦methodologies that combined with FGHSON and the Tree-structured SOM Component¦Planes allow the integration of space and time seamlessly and simultaneously in¦order to extract knowledge embedded in a temporal context.¦The originality of the FGHSON lies in its capability to reflect the underlying structure¦of a dataset in a hierarchical fuzzy way. A hierarchical fuzzy representation of¦clusters is crucial when data include complex structures with large variability of cluster¦shapes, variances, densities and number of clusters. The most important characteristics¦of the FGHSON include: (1) It does not require an a-priori setup of the number¦of clusters. (2) The algorithm executes several self-organizing processes in parallel.¦Hence, when dealing with large datasets the processes can be distributed reducing the¦computational cost. (3) Only three parameters are necessary to set up the algorithm.¦In the case of the Tree-structured SOM Component Planes, the novelty of this algorithm¦lies in its ability to create a structure that allows the visual exploratory data analysis¦of large high-dimensional datasets. This algorithm creates a hierarchical structure¦of Self-Organizing Map Component Planes, arranging similar variables' projections in¦the same branches of the tree. Hence, similarities on variables' behavior can be easily¦detected (e.g. local correlations, maximal and minimal values and outliers).¦Both FGHSON and the Tree-structured SOM Component Planes were applied in¦several agroecological problems proving to be very efficient in the exploratory analysis¦and clustering of spatio-temporal datasets.¦In this thesis I also tested three soft competitive learning algorithms. Two of them¦well-known non supervised soft competitive algorithms, namely the Self-Organizing¦Maps (SOMs) and the Growing Hierarchical Self-Organizing Maps (GHSOMs); and the¦third was our original contribution, the FGHSON. Although the algorithms presented¦here have been used in several areas, to my knowledge there is not any work applying¦and comparing the performance of those techniques when dealing with spatiotemporal¦geospatial data, as it is presented in this thesis.¦I propose original methodologies to explore spatio-temporal geo-referenced datasets¦through time. Our approach uses time windows to capture temporal similarities and¦variations by using the FGHSON clustering algorithm. The developed methodologies¦are used in two case studies. In the first, the objective was to find similar agroecozones¦through time and in the second one it was to find similar environmental patterns¦shifted in time.¦Several results presented in this thesis have led to new contributions to agroecological¦knowledge, for instance, in sugar cane, and blackberry production.¦Finally, in the framework of this thesis we developed several software tools: (1)¦a Matlab toolbox that implements the FGHSON algorithm, and (2) a program called¦BIS (Bio-inspired Identification of Similar agroecozones) an interactive graphical user¦interface tool which integrates the FGHSON algorithm with Google Earth in order to¦show zones with similar agroecological characteristics.

p53 and Ki-ras as prognostic factors for Dukes' stage B colorectal cancer.

Mutations of the TP53 and Ki-ras genes have been reported to be of prognostic importance in colorectal carcinomas. An increased intracellular concentration of the p53 protein, although not identical to, is sometimes seen in tumours with TP53 mutation and has been correlated with poor prognosis in some tumour types. Previous colorectal cancer studies, addressing the prognostic importance of Ki-ras mutation and TP53 aberrations, yielded contradictory results. The aim of this study was to determine in a clinically and therapeutically homogeneous group of 122 sporadic Dukes' B colorectal carcinomas with a median follow-up of 67 months (3-144 months) whether or not p53 protein expression, TP53 mutation and K-ras mutation correlated with prognosis. p53 staining was performed by immunohistochemistry, using the monoclonal antibody DO7 on paraffin-embedded tissue. Mutations in exons 5-8 of the TP53 gene and in codons 12 and 13 of the K-ras gene were assayed in paraffin-embedded tissue by the single-strand conformation polymorphism (SSCP) assay. Nuclear p53 staining was found in 57 (47%) tumours. Aberrant migration patterns indicating mutation of the TP53 gene were found in 39 (32%) tumours. Forty-six carcinomas (38%) showed a mutation of the Ki-ras codons 12 or 13. In a univariate analysis, patients with wild-type TP53 status showed a trend towards better survival, compared with those with mutated TP53 (log-rank test, P = 0.051). Likewise, tumours immunohistochemically positive for p53 showed a worse prognosis than p53-negative tumours (P = 0.010). The presence or absence of mutations in Ki-ras did not correlate with prognosis (P = 0.703). In multivariate analysis, only p53 immunoreactivity emerged as an independent marker for prognosis hazard ratio (HR) = 2.16, 95% confidence interval (CI) 1.12-4.11, P = 0.02). Assessment of p53 protein expression is more discriminative than TP53 mutation to predict the outcome of Dukes' stage B tumours and could be a useful tool to identify patients who might benefit from adjuvant therapy.

Clinical and molecular characterization of Diastrophic Dysplasia in the Portuguese population.

SLC26A2-related dysplasias encompass a spectrum of diseases: from lethal achondrogenesis type 1B (ACG1B; MIM #600972) and atelosteogenesis type 2 (AO2; MIM #256050) to classical diastrophic dysplasia (cDTD; MIM #222600) and recessive multiple epiphyseal dysplasia (rMED; MIM #226900). This study aimed at characterizing clinically, radiologically and molecularly 14 patients affected by non-lethal SLC26A2-related dysplasias and at evaluating genotype-phenotype correlation. Phenotypically, eight patients were classified as cDTD, four patients as rMED and two patients had an intermediate phenotype (mild DTD - mDTD, previously 'DTD variant'). The Arg279Trp mutation was present in all patients, either in homozygosity (resulting in rMED) or in compound heterozygosity with the known severe alleles Arg178Ter or Asn425Asp (resulting in DTD) or with the mutation c.727-1G>C (causing mDTD). The 'Finnish mutation', c.-26+2T>C, and the p.Cys653Ser, both frequent mutations in non-Portuguese populations, were not identified in any of the patients of our cohort and are probably very rare in the Portuguese population. A targeted mutation analysis for p.Arg279Trp and p.Arg178Ter in the Portuguese population allows the identification of approximately 90% of the pathogenic alleles.

Soil infiltration based on bp neural network and grey relational analysis

Soil infiltration is a key link of the natural water cycle process. Studies on soil permeability are conducive for water resources assessment and estimation, runoff regulation and management, soil erosion modeling, nonpoint and point source pollution of farmland, among other aspects. The unequal influence of rainfall duration, rainfall intensity, antecedent soil moisture, vegetation cover, vegetation type, and slope gradient on soil cumulative infiltration was studied under simulated rainfall and different underlying surfaces. We established a six factor-model of soil cumulative infiltration by the improved back propagation (BP)-based artificial neural network algorithm with a momentum term and self-adjusting learning rate. Compared to the multiple nonlinear regression method, the stability and accuracy of the improved BP algorithm was better. Based on the improved BP model, the sensitive index of these six factors on soil cumulative infiltration was investigated. Secondly, the grey relational analysis method was used to individually study grey correlations among these six factors and soil cumulative infiltration. The results of the two methods were very similar. Rainfall duration was the most influential factor, followed by vegetation cover, vegetation type, rainfall intensity and antecedent soil moisture. The effect of slope gradient on soil cumulative infiltration was not significant.

Association of ECG abnormalities and incident heart failure events

Background: With the aging of the population, the heart failure (HF) incidence and prevalence trends are expected to significantly worsen unless concentrated prevention efforts are undertaken. ECG abnormalities are common in the elderly but data are limited for their association with HF risk. Objective: To assess whether baseline ECG abnormalities or dynamic changes are associated with an increased risk of HF. Method: A prospective cohort study of 2915 participants aged 70 to 79 years without a preexisting HF followed for a median period of 11.4 (IQR 7.0-11.7) years from the Health Aging and Body Composition study. The Minnesota Code was used to define major and minor ECG abnormalities at baseline and at 4-year. Main outcome measure was adjudicated incident HF events. Using Cox models, the (1) the association between ECG abnormalities and incident HF and (2) incremental value of adding ECG to the Health ABC HF Risk Score, was assessed. Results: At baseline, 380 participants (13.0%) had minor and 620 (21.3%) had major ECG abnormalities. During follow-up, 485 (16.6%) participants developed incident HF. After adjusting for the eight clinical variables in the Health ABC HF Risk Score, the hazard ratio (HR) was 1.27 (95% confidence interval [CI] 0.96-1.68) for minor and 1.99 (CI 1.61-2.44) for major ECG abnormalities (P for trend <0.001) compared to no ECG abnormalities. The association did not change according to presence of baseline CHD. At 4-year, 263 participants developed new and 549 had persistent abnormalities and both were associated with increased HF risk (HR = 1.94, CI 1.38-2.72 for new and HR=2.35, CI 1.82-3.02 for persistent compared to no ECG abnormalities). Baseline ECG correctly reclassified 10.6% of overall participants across the categories of the Health ABC HF Risk Score. Conclusion: Among older adults, baseline ECG abnormalities and changes in them over time are common; both are associated with an increased risk of HF. Whether ECG should be incorporated in routine screening of older adults should be evaluated in randomized controlled trials.

Non-viral gene therapy for GDNF production in RCS rat: the crucial role of the plasmid dose.

Glial cell line-derived neurotrophic factor (GDNF) is one of the candidate molecules among neurotrophic factors proposed for a potential treatment of retinitis pigmentosa (RP). It must be administered repeatedly or through sustained releasing systems to exert prolonged neuroprotective effects. In the dystrophic Royal College of Surgeon's (RCS) rat model of RP, we found that endogenous GDNF levels dropped during retinal degeneration time course, opening a therapeutic window for GDNF supplementation. We showed that after a single electrotransfer of 30 μg of GDNF-encoding plasmid in the rat ciliary muscle, GDNF was produced for at least 7 months. Morphometric, electroretinographic and optokinetic analyses highlighted that this continuous release of GDNF delayed photoreceptors (PRs) as well as retinal functions loss until at least 70 days of age in RCS rats. Unexpectedly, increasing the GDNF secretion level accelerated PR degeneration and the loss of electrophysiological responses. This is the first report: (i) demonstrating the efficacy of GDNF delivery through non-viral gene therapy in RP; (ii) establishing the efficacy of intravitreal administration of GDNF in RP associated with a mutation in the retinal pigment epithelium; and (iii) warning against potential toxic effects of GDNF within the eye/retina.

Failure to thrive in a girl born into a family affected by familial dysalbuminemic hyperthyroxinemia

Autosomal dominant familial dysalbuminemic hyperthyroxinemia (FDH)is characterized by modified human serum albumin (HSA) inducing asubstantially higher affinity for thyroxine (T4). Histidin or prolinsubstitution on residue R218 produces localized conformationalchanges of HSA creating additional room for T4 binding, leadingto 14-20 fold normal total T4 (TT4) levels. Affected individuals areconsidered euthyroid. Our patient is an 18 months-old swiss girl bornto a mother known for the rare R218P mutation in the HSA gene.She presented with severe failure to thrive (height -2.92 SD, weight-3.6 SD), habitual hip dislocation without anatomical anomaly, latefontanelle closing and protruding ears. Psychomotor development isslightly retarded. Thyroid function testing confirmed extremely high TT4(1446.0 nmol/l) levels, which are similar to her brother's values (1534.4nmol/l and 1757.6 nmol/l respectively). Free T4 seems slightly elevated(26 pmol/l), probably due to methodological reasons. TSH (0.92 mU/l),free T3 (4.4 pmol/l) and thyroxin binding globulin (32 mg/l) are withinthe normal range. Her two half-brothers, affected by the samemutation, are now 18.7 (P1) and 16.6 (P2) years old and wereoriginally described by S. Pannain et al. in 2000. Both werecharacterized by growth retardation (-2.1 and -2.2 SD) before the ageof 4 years. P1 has reached a normal adult height (-0.4 SD) and P2has caught up to normal growth (-0.68 SD) with moderate bonematuration delay. Pubertal development and anterior pituitary functionare adequate. Primary growth and developmental retardation in thefirst years of life with adequate catch-up seem to be a distinctcharacteristic in FDH with R218P mutation. Hip dislocation is typicallyseen in other situations associated to thyroid disorders, like Downsyndrome. These findings might be explained by altered early thyroidhormone utilization in children with FDH.

Practice guidelines for evaluation of Fever in returning travelers and migrants.

BACKGROUND: Fever upon return from tropical or subtropical regions can be caused by diseases that are rapidly fatal if left untreated. The differential diagnosis is wide. Physicians often lack the necessary knowledge to appropriately take care of such patients. OBJECTIVE: To develop practice guidelines for the initial evaluation of patients presenting with fever upon return from a tropical or subtropical country in order to reduce delays and potential fatal outcomes and to improve knowledge of physicians. TARGET AUDIENCE: Medical personnel, usually physicians, who see the returning patients, primarily in an ambulatory setting or in an emergency department of a hospital and specialists in internal medicine, infectious diseases, and travel medicine. METHOD: A systematic review of the literature--mainly extracted from the National Library of Medicine database--was performed between May 2000 and April 2001, using the keywords fever and/or travel and/or migrant and/or guidelines. Eventually, 250 articles were reviewed. The relevant elements of evidence were used in combination with expert knowledge to construct an algorithm with arborescence flagging the level of specialization required to deal with each situation. The proposed diagnoses and treatment plans are restricted to tropical or subtropical diseases (nonautochthonous diseases). The decision chart is accompanied with a detailed document that provides for each level of the tree the degree of evidence and the grade of recommendation as well as the key points of debate. PARTICIPANTS AND CONSENSUS PROCESS: Besides the 4 authors (2 specialists in travel/tropical medicine, 1 clinical epidemiologist, and 1 resident physician), a panel of 11 European physicians with different levels of expertise on travel medicine reviewed the guidelines. Thereafter, each point of the proposed recommendations was discussed with 15 experts in travel/tropical medicine from various continents. A final version was produced and submitted for evaluation to all participants. CONCLUSION: Although the quality of evidence was limited by the paucity of clinical studies, these guidelines established with the support of a large and highly experienced panel should help physicians to deal with patients coming back from the Tropics with fever.

In vivo 13C NMR spectroscopy and metabolic modeling in the brain: a practical perspective.

In vivo 13C NMR spectroscopy has the unique capability to measure metabolic fluxes noninvasively in the brain. Quantitative measurements of metabolic fluxes require analysis of the 13C labeling time courses obtained experimentally with a metabolic model. The present work reviews the ingredients necessary for a dynamic metabolic modeling study, with particular emphasis on practical issues.

A realistic Computed Tomography simulator for small motion analysis of cerebral aneurysms.

This paper describes a realistic simulator for the Computed Tomography (CT) scan process for motion analysis. In fact, we are currently developing a new framework to find small motion from the CT scan. In order to prove the fidelity of this framework, or potentially any other algorithm, we present in this paper a simulator to simulate the whole CT acquisition process with a priori known parameters. In other words, it is a digital phantom for the motion analysis that can be used to compare the results of any related algorithm with the ground-truth realistic analytical model. Such a simulator can be used by the community to test different algorithms in the biomedical imaging domain. The most important features of this simulator are its different considerations to simulate the best the real acquisition process and its generality.

Stochastic inversion of tracer test and electrical geophysical data to estimate hydraulic conductivities.

Quantifying the spatial configuration of hydraulic conductivity (K) in heterogeneous geological environments is essential for accurate predictions of contaminant transport, but is difficult because of the inherent limitations in resolution and coverage associated with traditional hydrological measurements. To address this issue, we consider crosshole and surface-based electrical resistivity geophysical measurements, collected in time during a saline tracer experiment. We use a Bayesian Markov-chain-Monte-Carlo (McMC) methodology to jointly invert the dynamic resistivity data, together with borehole tracer concentration data, to generate multiple posterior realizations of K that are consistent with all available information. We do this within a coupled inversion framework, whereby the geophysical and hydrological forward models are linked through an uncertain relationship between electrical resistivity and concentration. To minimize computational expense, a facies-based subsurface parameterization is developed. The Bayesian-McMC methodology allows us to explore the potential benefits of including the geophysical data into the inverse problem by examining their effect on our ability to identify fast flowpaths in the subsurface, and their impact on hydrological prediction uncertainty. Using a complex, geostatistically generated, two-dimensional numerical example representative of a fluvial environment, we demonstrate that flow model calibration is improved and prediction error is decreased when the electrical resistivity data are included. The worth of the geophysical data is found to be greatest for long spatial correlation lengths of subsurface heterogeneity with respect to wellbore separation, where flow and transport are largely controlled by highly connected flowpaths.

Modification of the monomer composition of polyhydroxyalkanoate synthesized in Saccharomyces cerevisiae expressing variants of the beta-oxidation-associated multifunctional enzyme.

Expression by Saccharomyces cerevisiae of a polyhydroxyalkanoate (PHA) synthase modified at the carboxy end by the addition of a peroxisome targeting signal derived from the last 34 amino acids of the Brassica napus isocitrate lyase (ICL) and containing the terminal tripeptide Ser-Arg-Met resulted in the synthesis of PHA. The ability of the terminal peptide Ser-Arg-Met and of the 34-amino-acid peptide from the B. napus ICL to target foreign proteins to the peroxisome of S. cerevisiae was demonstrated with green fluorescent protein fusions. PHA synthesis was found to be dependent on the presence of both the enzymes generating the beta-oxidation intermediate 3-hydroxyacyl-coenzyme A (3-hydroxyacyl-[CoA]) and the peroxin-encoding PEX5 gene, demonstrating the requirement for a functional peroxisome and a beta-oxidation cycle for PHA synthesis. Using a variant of the S. cerevisiae beta-oxidation multifunctional enzyme with a mutation inactivating the B domain of the R-3-hydroxyacyl-CoA dehydrogenase, it was possible to modify the PHA monomer composition through an increase in the proportion of the short-chain monomers of five and six carbons.