A role for altered TLR gene expression in association with increased expression of CD200R in the induction of mucosal tissue CD4(+) Treg in aged mice following gavage with a liver extract along with intramuscular monophosphoryl lipid A (MPLA) injection.

Previous studies showed a fetal sheep liver extract (FSLE), in association with LPS, injected into aged (>20 months) mice reversed the altered polarization (increased IL-4 and IL-10 with decreased IL-2 and IFN-gamma) in cytokine production seen from ConA stimulated lymphoid cells of those mice. Aged mice show a >60% decline in numbers and suppressive function of both CD4(+)CD25(+)Foxp3(+)Treg and so-called Tr3 (CD4(+)TGFbeta(+)). Their number/function is restored to levels seen in control (8-week-old) mice by FSLE. We have reported at length on the ability of a novel pair of immunoregulatory molecules, members of the TREM family, namely CD200:CD200R, to control development of dendritic cells (DCs) which themselves regulate production of Foxp3(+) Treg. The latter express a distinct subset of TLRs which control their function. We report that a feature of the altered Treg expression following combined treatment with FSLE and monophosphoryl lipid A, MPLA (a bioactive component of lipid A of LPS) is the altered gene expression both of distinct subsets of TLRs and of CD200Rs. We speculate that this may represent one of the mechanisms by which FSLE and MPLA alter immunity in aged mice.

Postanoxic functional recovery of the developing heart is slightly altered by endogenous or exogenous nitric oxide.

Nitric oxide synthase (NOS) is strongly and transiently expressed in the developing heart but its function is not well documented. This work examined the role, either protective or detrimental, that endogenous and exogenous NO could play in the functioning of the embryonic heart submitted to hypoxia and reoxygenation. Spontaneously beating hearts isolated from 4-day-old chick embryos were either homogenized to determine basal inducible NOS (iNOS) expression and activity or submitted to 30 min anoxia followed by 100 min reoxygenation. The chrono-, dromo- and inotropic responses to anoxia/reoxygenation were determined in the presence of NOS substrate (L-arginine 10 mM), NOS inhibitor L-NIO (1-5 mM), or NO donor (DETA NONOate 10-100 microM). Myocardial iNOS was detectable by immunoblotting and its activity was specifically decreased by 53% in the presence of 5 mM L-NIO. L-Arginine, L-NIO and DETA NONOate at 10 microM had no significant effect on the investigated functional parameters during anoxia/reoxygenation. However, irrespective of anoxia/reoxygenation, DETA NONOate at 100 microM decreased ventricular shortening velocity by about 70%, and reduced atrio-ventricular propagation by 23%. None of the used drugs affected atrial activity and hearts of all experimental groups fully recovered at the end of reoxygenation. These findings indicate that (1) by contrast with adult heart, endogenously released NO plays a minor role in the early response of the embryonic heart to reoxygenation, (2) exogenous NO has to be provided at high concentration to delay postanoxic functional recovery, and (3) sinoatrial pacemaker cells are the less responsive to NO.

Cost-effectiveness analysis of immune-modulating nutritional support for gastrointestinal cancer patients.

BACKGROUND & AIM: Immune-modulating nutritional formula containing arginine, omega-3 fatty acids and nucleotides has been demonstrated to decrease complications and length of stay in surgical patients. This study aims at assessing the impact of immune-modulating formula on hospital costs in gastrointestinal cancer surgical patients in Switzerland. METHOD: Based on a previously published meta-analysis, the relative risks of overall and infectious complications with immune-modulating versus standard nutrition formula were computed. Swiss hospital costs of patients undergoing gastrointestinal cancer surgery were retrieved. A method was developed to compute the patients' severity level, not taking into account the complications from the surgery. Incremental costs of complications were computed for both treatment groups, and sensitivity analyses were carried out. RESULTS: Relative risk of complications with pre-, peri- and post-operative use of immune-modulating formula was 0.69 (95%CI 0.58-0.83), 0.62 (95%CI 0.53-0.73) and 0.73 (95%CI 0.35-0.96) respectively. The estimated average contribution of complications to the cost of stay was CHF 14,949 (euro10,901) per patient (95%CI 10,712-19,186), independently of case's severity. Based on this cost, immune-modulating nutritional support decreased costs of hospital stay by CHF 1638 to CHF 2488 per patient (euro1195-euro1814). Net hospital savings were present for baseline complications rates as low as 5%. CONCLUSION: Immune-modulating nutritional solution is a cost-saving intervention in gastrointestinal cancer patients. The additional cost of immune-modulating formula are more than offset by savings associated with decreased treatment of complications.

Monitoring network optimisation for spatial data classification using support vector machines

The paper presents a novel method for monitoring network optimisation, based on a recent machine learning technique known as support vector machine. It is problem-oriented in the sense that it directly answers the question of whether the advised spatial location is important for the classification model. The method can be used to increase the accuracy of classification models by taking a small number of additional measurements. Traditionally, network optimisation is performed by means of the analysis of the kriging variances. The comparison of the method with the traditional approach is presented on a real case study with climate data.

IowAccess Project 8 : statewide geographic information systems (GIS) support, 1998

This is the final report of the of IowAccess Project 8, which designed and implemented a geospatial data infrastructure for Iowa, including a formalized coordination body, a coordination staff, and enhanced data clearing house, and a statewide GIS training and education effort.

The thalamocortical projection systems in primate: an anatomical support for multisensory and sensorimotor interplay.

Multisensory and sensorimotor integrations are usually considered to occur in superior colliculus and cerebral cortex, but few studies proposed the thalamus as being involved in these integrative processes. We investigated whether the organization of the thalamocortical (TC) systems for different modalities partly overlap, representing an anatomical support for multisensory and sensorimotor interplay in thalamus. In 2 macaque monkeys, 6 neuroanatomical tracers were injected in the rostral and caudal auditory cortex, posterior parietal cortex (PE/PEa in area 5), and dorsal and ventral premotor cortical areas (PMd, PMv), demonstrating the existence of overlapping territories of thalamic projections to areas of different modalities (sensory and motor). TC projections, distinct from the ones arising from specific unimodal sensory nuclei, were observed from motor thalamus to PE/PEa or auditory cortex and from sensory thalamus to PMd/PMv. The central lateral nucleus and the mediodorsal nucleus project to all injected areas, but the most significant overlap across modalities was found in the medial pulvinar nucleus. The present results demonstrate the presence of thalamic territories integrating different sensory modalities with motor attributes. Based on the divergent/convergent pattern of TC and corticothalamic projections, 4 distinct mechanisms of multisensory and sensorimotor interplay are proposed.

Approximation and support theorem for a wave equation in two space dimensions

We prove a characterization of the support of the law of the solution for a stochastic wave equation with two-dimensional space variable, driven by a noise white in time and correlated in space. The result is a consequence of an approximation theorem, in the convergence of probability, for equations obtained by smoothing the random noise. For some particular classes of coefficients, approximation in the Lp-norm for p¿1 is also proved.

Altered decision-making in multiple sclerosis: a sign of impaired emotional reactivity?

We assessed decision-making capacity and emotional reactivity in 20 patients with multiple sclerosis (MS) and in 16 healthy subjects using the Gambling Task (GT), a model of real-life decision making, and the skin conductance response (SCR). Demographic, neurological, affective, and cognitive parameters were analyzed in MS patients for their effect on decision-making performance. MS patients persisted longer (slope, -3.6%) than the comparison group (slope, -6.4%) in making disadvantageous choices as the GT progressed (p < 0.001), suggesting significant slower learning in MS. Patients with higher Expanded Disability Status Scale scores (EDSS >2.0) showed a different pattern of impairment in the learning process compared with patients with lower functional impairment (EDSS </=2.0). This slower learning was associated with impaired emotional reactivity (anticipatory SCR 3.9 vs 6.1 microSiemens [microS] for patients vs the comparison group, p < 0.0001; post-choice SCR 3.9 vs 6.2 microS, p < 0.0001), but not with executive dysfunction. Impaired emotional dimensions of behavior (assessed using the Dysexecutive Questionnaire, p < 0.002) also correlated with slower learning. Given the considerable consequences that impaired decision making can have on daily life, we suggest that this factor may contribute to handicap and altered quality of life secondary to MS and is dependent on emotional experience. Ann Neurol 2004.

Traumatologie de la personne âgée : une urgence nutritionnelle ? [Elderly orthopedic patients: Is nutritional support needed?]

La fracture de hanche chez la personne âgée reste un problème de santé publique. Elle est la conséquence d'une chute neuf fois sur dix et survient chez des personnes fragilisées par une ostéoporose, une sarcopénie, une dénutrition. Dans un service de traumatologie, la dénutrition protéino-énergétique est fréquente. Présente dès l'admission chez environ un patient sur deux, elle va souvent s'aggraver pendant le séjour hospitalier et favoriser la survenue de complications. Une prise en charge nutritionnelle doit impliquer une équipe multidisciplinaire qu'il faut coordonner. Elle doit être envisagée précocement pendant le séjour hospitalier et privilégier la voie orale. L'assistance nutritionnelle sous forme de CNO a prouvé son efficacité dans la réduction de la morbidité postopératoire. Son impact sur la mortalité, sur le pronostic fonctionnel et social reste discuté. Il faudra attendre l'étude de nouvelles cohortes dans lesquelles la compliance au traitement est nettement améliorée avant de conclure de manière définitive.

Individual prediction of cognitive decline in mild cognitive impairment using support vector machine-based analysis of diffusion tensor imaging data.

Although cross-sectional diffusion tensor imaging (DTI) studies revealed significant white matter changes in mild cognitive impairment (MCI), the utility of this technique in predicting further cognitive decline is debated. Thirty-five healthy controls (HC) and 67 MCI subjects with DTI baseline data were neuropsychologically assessed at one year. Among them, there were 40 stable (sMCI; 9 single domain amnestic, 7 single domain frontal, 24 multiple domain) and 27 were progressive (pMCI; 7 single domain amnestic, 4 single domain frontal, 16 multiple domain). Fractional anisotropy (FA) and longitudinal, radial, and mean diffusivity were measured using Tract-Based Spatial Statistics. Statistics included group comparisons and individual classification of MCI cases using support vector machines (SVM). FA was significantly higher in HC compared to MCI in a distributed network including the ventral part of the corpus callosum, right temporal and frontal pathways. There were no significant group-level differences between sMCI versus pMCI or between MCI subtypes after correction for multiple comparisons. However, SVM analysis allowed for an individual classification with accuracies up to 91.4% (HC versus MCI) and 98.4% (sMCI versus pMCI). When considering the MCI subgroups separately, the minimum SVM classification accuracy for stable versus progressive cognitive decline was 97.5% in the multiple domain MCI group. SVM analysis of DTI data provided highly accurate individual classification of stable versus progressive MCI regardless of MCI subtype, indicating that this method may become an easily applicable tool for early individual detection of MCI subjects evolving to dementia.

Dynamic Deflections to Determine Roadway Support Ratings, HR-245, 1983

The Benkelman Beam structural test of flexible pavements was replaced in 1976 by dynamic deflection testing with a model 400 Road Rater. The Road Rater is used to determine structural ratings of flexible pavements. New pavement construction in Iowa has decreased with a corresponding increase of restoration and rehabilitation. A method to determine structural ratings of layered systems and rigid pavements is needed to properly design overlay thickness. The objective of this research was to evaluate the feasibility of using the Road Rater to determine support values of layered systems and rigid pavements. This evaluation was accomplished by correlating the Road Rater with the Federal Highway Administration (FHWA) Thumper, a dynamic deflection testing device. Data were obtained with the Road Rater and Thumper at 411 individual test locations on 39 different structural sections ranging from 10" of PCC pavement and 25" of asphalt pavement to a newly graveled unpaved roadway. A high correlation between a 9000 pound Thumper deflection and the 1185 pound Road Rater deflection was obtained. A Road Rater modification has been completed to provide 2000 pound load inputs. The basin, defined by four sensors spaced at 1 foot intervals, resulting from the 2000 pound loading is being used to develop a graph for determining relative subgrade strengths. Road Rater deflections on rigid pavements are sufficient to support the potential for this technique.

Ionizing radiation enhances immunogenicity of cells expressing a tumor-specific T-cell epitope.

BACKGROUND: p53 point mutations represent potential tumor-specific cytolytic T lymphocyte (CTL) epitopes. Whether ionizing radiation (IR) alters the immunological properties of cells expressing mutant p53 in respect of the CTL epitope generated by a defined point mutation has not been evaluated. METHODS: Mutant p53-expressing syngeneic, nontumor forming BALB/c 3T3 fibroblasts, tumor forming ras-transfected BALB/c 3T3 sarcomas, and DBA/2-derived P815 mastocytoma cells, which differ at the level of minor histocompatibility antigens, were used as cellular vaccines. Cells were either injected with or without prior IR into naive BALB/c mice. Cellular cytotoxicity was assessed after secondary restimulation of effector spleen cells in vitro. RESULTS: Injection of P815 mastocytoma cells expressing the mutant p53 induced mutation-specific CTL in BALB/c mice irrespective of prior irradiation. However, syngeneic fibroblasts or fibrosarcomas endogenously expressing mutant p53 were able to induce significant mutation-specific CTL only when irradiated prior to injection into BALB/c mice. IR of fibroblasts did not detectably alter the expression of cell surface molecules involved in immune response induction, nor did it alter the short-term in vitro viability of the fibroblasts. Interestingly, radioactively-labeled fibroblasts injected into mice after irradiation showed altered organ distribution, suggesting that the in vivo fate of these cells may play a crucial role in their immunogenicity. CONCLUSIONS: These findings indicate that IR can alter the immunogenicity of syngeneic normal as well as tumor forming fibroblasts in vivo, and support the view that ionizing radiation enhances immunogenicity of cellular tumor vaccines.

High dose chemotherapy with autologous hematopoietic stem cell support for solid tumors other than breast cancer in adults.

Since the early 1980s high dose chemotherapy with autologous hematopoietic stem cell support was adopted by many oncologists as a potentially curative option for solid tumors, supported by a strong rationale from laboratory studies and apparently convincing results of early phase II studies. As a result, the number and size of randomized trials comparing this approach with conventional chemotherapy initiated (and often abandoned before completion) to prove or disprove its value was largely insufficient. In fact, with the possible exception of breast carcinoma, the benefit of a greater escalation of dose of chemotherapy with stem cell support in solid tumors is still unsettled and many oncologists believe that this approach should cease. In this article, we critically review and comment on the data from studies of high dose chemotherapy so far reported in adult patients with small cell lung cancer, ovarian cancer, germ cell tumors and sarcomas.

Support for a colleague

As collaborators of Anders Pape Møller, we were shocked and surprised to read that he was accused of data fabrication ("Ecologists roiled by misconduct case," G. Vogel, F. Proffitt, R. Stone, News of the Week, 30 Jan., p. 606). We have never had cause to be concerned about any aspect of our collaborations with Møller. He is an amazing scientist, and his great organizational skills are a model for how to be productive in the face of competing time demands. Most of us are capable of much more than we actually accomplish, but we lack the dedication and self-discipline to follow through like Anders Møller. This is the secret of his phenomenal effectiveness that has been so puzzling to the scientific community. His achievements may have caused negative responses from some of his competitors. We would like to see a full, objective, and independent inquiry into the allegations. Our experience tells us that Anders Møller has an exceptionally complete focus on any task at hand, be it fieldwork, data analysis, or paper writing; this, combined with more than a little natural talent, is sufficient to explain his exceptional productivity. We have worked with him on a variety of projects, including collecting data, sometimes under arduous conditions, and in all our dealings with him, his behavior has been beyond reproach. We would ask colleagues to restrain from further public condemnation until such time as any allegations have been proven beyond doubt.