Motility tests for drugs preventing PolyQ aggregation in recombinant Caenorhabditis elegans.

The pathological formation of proteinaceous aggregates that accumulate into the brain cells of patients are hallmarks of neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis and the heterogeneous group of polyglutamine (polyQ) diseases. In the polyQ diseases, the most upstream events of the pathogenic cascade are the misfolding and aggregation of proteins, such as huntingtin in Huntington's disease, that contain expanded stretch of glutamine residues above 35--‐40 repeats. This expanded polyQ stretch triggers the misfolding and aggregation of cytotoxic polyQ proteins in the neurons that cause cell death through different processes, like apoptosis, excessive inflammation, formation of free radicals, eventually leading to neuronal loss and neurodegeneration. This study focuses on the cellular network of chaperone proteins that can prevent protein aggregation by binding misfolding intermediates and may, as in the case of HSP70, actively unfold misfolded proteins into refoldable non--‐toxic ones (Hinault et al., 2010; Sharma et al., 2011). The chaperones can also collaborate with the proteasome to convert stable harmful proteins into harmless amino acids. Thus, the chaperone proteins that are the most important cellular factors of prevention and curing of protein misfolding, are negatively affected by aging (Morley et al., 2002) and fail to act properly in the neurons of aged persons, which eventually may lead to neurodegenerative pathologies. The general aim of this research was to identify least toxic drugs that can upregulate the expression of chaperone genes in cells suffering from polyQ--‐ mediated protein aggregation and degeneration. The specific aim of this study was to observe the effect of ten drugs on polyQ aggregation in a recombinant nematode Caenorhabditis elegans expressing a chimeric protein containing a sequence of 35 glutamines (Q35) fused to the green fluorescent protein in muscle cells, which causes an age--‐ and temperature--‐ dependent phenotype of accelerated paralysis. The drugs were selected after having proven their causing the overexpression of chaperone proteins in a previous wide screening of 2000 drugs on the moss plant Physcomitrella patens. The screening that we performed in this study was on these ten drugs. It suggested that piroxicam and anisindione were good reducers of polyglutamine disease mediated paralysis. A hypothesis can be made that they may act as good enhancers of the heat shock response, which causes the overexpression of many HSP chaperones and thus reduce motility impairment of polyQ disease expressing nematodes. Piroxicam was found to have the greatest effect on reducing polyQ35 proteins aggregates mediated paralysis in a dose--‐dependent manner but was also found to either have a toxic effect on wild type C.elegans, either to change its natural motility behavior, eventually reducing its motility in both cases. Chloroform should be preferred over DMSO as a drug solvent as it appears to be less toxic to C.elegans.

Dynamic Tests of a Three-Span Continuous I-Beam Highway Bridge, HR-43, 1959

This paper presents the results of the static and dynamic testing of a three-span continuous I-beam highway bridge. Live load stress frequency curves for selected points are shown, and the static and dynamic load distribution to the longitudinal composite beam members are given. The bridge has four traffic lanes with a roadway width of 48 ft. Six longitudinal continuous WF beams act compositely with the reinforced concrete slab to carry the live load. The beams have partial length cover plates at the piers. Previous research has indicated that beams with partial length cover plates have a very low fatigue strength. It was found in this research that the magnitude of the stresses due to actual highway loads were very much smaller than those computed from specification loading. Also, the larger stresses which were measured occurred a relatively small number of times. These data indicate that some requirements for reduced allowable stresses at the ends of cover plates are too conservative. The load distribution to the longitudinal beams was determined for static and moving loads and includes the effect of impact on the distribution. The effective composite section was found at various locations to evaluate the load distribution data. The composite action was in negative as well as positive moment regions. The load distribution data indicate that the lateral distribution of live load is consistent with the specifications, but that there is longitudinal distribution, and therefore the specifications are too conservative.

Mental Causation : Investigating the mind's powers in a natural world

4.6 Summary and Conclusion In this chapter, we have first tried to make precise the distinctions between the concepts of parthood and coincidence and the concepts of causation and causal influence. These distinc-tions had never been made entirely explicit in the debate on mental causation before, despite the fact that they constantly figure in its background. Section 4.2 then demonstrated that the at-tained definitions are both compatible with all the solutions elaborated in chapters 2 and 3 and that they are even of great help in clarifying both what precisely the mentioned accounts are claiming respectively and what their mutual connections are. In sections 4.3. and 4.4, we have then tried to explore two possible solutions to the problem of mental causation that, at least in these particular versions, have not been explicitly defended in the literature. These solutions we dubbed "overdeteiminationism lite" and "plural determinism". We found the accounts both to bear impressive explanatory capabilities and to be vulnerable to far fewer problems than is commonly supposed. We also found out that they have many corresponding aspects and that their theoretical costs stand in a relation of a relative mutual balance. Our final discussion in section 4.5 revealed, however, that overdetenninationism lite should probably be considered the more successful theory. The fact that it needs to endorse the existence of two kinds of causation, although not unproblematic itself, did not appear as a commitment as strong as that of an ontological hierarchy that extends over all time, which at least the broad version of plural determinism was forced to make.

Feasibility Study of Dynamic Overload and Ultimate Load Tests of Full-Scale Highway Bridges, HR-160, 1973

As a result of the construction of the Saylorville Dam and Reservoir on the Des Moines River, six highway bridges are scheduled for removal. Five of these are old high-truss single-lane bridges, each bridge having several simple spans. The other bridge is a fairly modern (1955) double 4-span continuous beam-and-slab composite highway bridge. The availability of these bridges affords an unusual opportunity for study of the behavior of full-scale bridges. Because of the magnitude of the potential testing program, a feasibility study was initiated and the results are presented in this two-part final report. Part I summarizes the findings and Part II presents the supporting detailed information.

Tests diagnostiques rapides (TDR): la panacée pour le praticien [Rapid diagnostic tests (RDT): the cure-all for the practitioner?].

Many rapid diagnostic tests (RDT) for the diagnosis of infectious diseases have been developed over the last 20 years. These allow (1) administering a treatment immediately in case of a potentially fatal disease, (2) prescribing a specific rather than presumptive treatment, (3) quickly introducing measures aimed at interrupting the transmission of the disease, (4) avoiding useless antibiotic treatments and (5) implementing a sequential diagnostic strategy to avoid extensive investigations. Using the example of malaria, a new strategy that includes a RDT as first-line emergency diagnostic tool and, when negative, delayed microscopy at the laboratory opening time is implemented in Lausanne since 1999. This strategy has been shown to be safe. Each TDR has its own characteristics that imperatively need to be known by the practitioner if he/she wants to use it in a rational way.

The importance of environmental exposures to physical, mental and social well-being

"Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity" states the WHO. However, the current focus in this important area seems to be on reducing diseases, while less attention is paid on aspects how to increase the well-being of populations. This paper reviews three examples where well-being has drawn attention of the public and policy makers, and compares the policies of two wealthy countries. The first example is noise. Noise can reduce sleep quality and cause physiological, mental, and social effects. In Switzerland, noise receives a lot of attention by the public. Swiss laws are extensive, e.g., they prohibit trucks and planes from traveling at night. In the USA, there is little public attention and no national strategy against environmental noise. The second example is aesthetics and recreation. Many humans seek contact with the beauty of nature. The USA and Switzerland have similar strategies for achieving clear waters, while the protection of scenic views is approached very differently. Lifestyle is the last example. In the USA, the desire for individual freedom is a leading cause for suburban sprawl, a car-dependent sedentary lifestyle resulting in obesity, asthma and loss of community spirit. In Switzerland, a strict land use planning seeks to balance individual and public interests and stresses public transportation, which seems to be a more promising approach. Paying attention to aspects of well-being while developing political strategies might be a promising model to tackle environmental problems. Successful strategies employed so far seem to include the public, local authorities, politicians and scientists in this process, which might have been a key for their success. [Authors]

Troubles psychiques et épilepsies [Mental disorders and epilepsies]

Mental disorders in patients having difficulties to treat their epilepsy are without a doubt more frequent than those presented by patients with controlled epilepsies or within a general population. These problems are especially affective disorders; clinical presentations of these troubles are often particular and difficult to classify through the current admitted classification guidelines. We speak generally about an interictal dysphoric disorder. The relationship between observed troubles in seizures is in some cases very particular: postictal depressions and psychosis are very peculiar disorders, self limited, difficult to detect and to treat. Some considerations are made about certain topics related to severe epilepsies: suicide, pseudo seizures and therapeutic attitude.

Allergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests.

To cite this article: Ponvert C, Perrin Y, Bados-Albiero A, Le Bourgeois M, Karila C, Delacourt C, Scheinmann P, De Blic J. Allergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests. Pediatr Allergy Immunol 2011; 22: 411-418. ABSTRACT: Studies based on skin and challenge tests have shown that 12-60% of children with suspected betalactam hypersensitivity were allergic to betalactams. Responses in skin and challenge tests were studied in 1865 children with suspected betalactam allergy (i) to confirm or rule out the suspected diagnosis; (ii) to evaluate diagnostic value of immediate and non-immediate responses in skin and challenge tests; (iii) to determine frequency of betalactam allergy in those children, and (iv) to determine potential risk factors for betalactam allergy. The work-up was completed in 1431 children, of whom 227 (15.9%) were diagnosed allergic to betalactams. Betalactam hypersensitivity was diagnosed in 50 of the 162 (30.9%) children reporting immediate reactions and in 177 of the 1087 (16.7%) children reporting non-immediate reactions (p < 0.001). The likelihood of betalactam hypersensitivity was also significantly higher in children reporting anaphylaxis, serum sickness-like reactions, and (potentially) severe skin reactions such as acute generalized exanthematic pustulosis, Stevens-Johnson syndrome, and drug reaction with systemic symptoms than in other children (p < 0.001). Skin tests diagnosed 86% of immediate and 31.6% of non-immediate sensitizations. Cross-reactivity and/or cosensitization among betalactams was diagnosed in 76% and 14.7% of the children with immediate and non-immediate hypersensitivity, respectively. The number of children diagnosed allergic to betalactams decreased with time between the reaction and the work-up, probably because the majority of children with severe and worrying reactions were referred for allergological work-up more promptly than the other children. Sex, age, and atopy were not risk factors for betalactam hypersensitivity. In conclusion, we confirm in numerous children that (i) only a few children with suspected betalactam hypersensitivity are allergic to betalactams; (ii) the likelihood of betalactam allergy increases with earliness and/or severity of the reactions; (iii) although non-immediate-reading skin tests (intradermal and patch tests) may diagnose non-immediate sensitizations in children with non-immediate reactions to betalactams (maculopapular rashes and potentially severe skin reactions especially), the diagnostic value of non-immediate-reading skin tests is far lower than the diagnostic value of immediate-reading skin tests, most non-immediate sensitizations to betalactams being diagnosed by means of challenge tests; (iv) cross-reactivity and/or cosensitizations among betalactams are much more frequent in children reporting immediate and/or anaphylactic reactions than in the other children; (v) age, sex and personal atopy are not significant risk factors for betalactam hypersensitivity; and (vi) the number of children with diagnosed allergy to betalactams (of the immediate-type hypersensitivity especially) decreases with time between the reaction and allergological work-up. Finally, based on our experience, we also propose a practical diagnostic approach in children with suspected betalactam hypersensitivity.

Presentación de REICESMA - Red Española de Investigación en Cuidados de Enfermería de Salud Mental y Adicciones

La Red Española de Investigación en Cuidados de Enfermería de Salud Mental y Adicciones (REICESMA) es una estructura formada por grupos enfermeros de investigación que desarrollan su actividad científica en el ámbito de los cuidados de la enfermería de salud mental y adicciones. REICESMA es un proyecto de larga evolución: como es sabido, no se puede crear una red de forma espontánea sino que se requieren unas bases y unos requisitos previos imprescindibles. Si revisamos esos requisitos en plan descendente, el paso previo y el que se mantiene en todo el proceso de construcción y desarrollo de una red de investigación es la existencia de Grupos de Investigación. Podríamos aceptar que a partir de la existencia de dos Grupos de Investigación ya se podría configurar una Red. Seguramente es posible, pero en nuestra visión de REICESMA la estructura ha de ser mucho más amplia. Nuestro punto de referencia (aunque no necesariamente tiene que ser el punto de llegada) son las convocatorias oficiales de reconocimiento de redes /los criterios de definición de Red en los que se detalla que una Red deberá estar formada por al menos 10 grupos de investigación de cuatro más comunidades autónomas.

Polyphenol-rich foods in the Mediterranean diet are associated with better cognitive function in elderly subjects at high cardiovascular risk

Brain oxidative processes play a major role in age-related cognitive decline, thus consumption of antioxidant-rich foods might help preserve cognition. Our aim was to assess whether consumption of antioxidant-rich foods in the Mediterranean diet relates to cognitive function in the elderly. In asymptomatic subjects at high cardiovascular risk (n = 447; 52% women; age 5580 y) enrolled in the PREDIMED study, a primary prevention dietary-intervention trial, we assessed food intake and cardiovascular risk profile, determined apolipoprotein E genotype, and used neuropsychological tests to evaluate cognitive function.We also measured urinary polyphenols as an objective biomarker of intake. Associations between energy-adjusted food consumption, urinary polyphenols, and cognitive scores were assessed by multiple linear regression models adjusted for potential confounders. Consumption of some foods was independently related to better cognitive function. The specific associations [regression coefficients (95% confidence intervals)] were: total olive oil with immediate verbal memory [0.755 (0.1511.358)]; virgin olive oil and coffee with delayed verbal memory [0.163 (0.0100.316) and 0.294 (0.0550.534), respectively];walnuts with working memory [1.191 (0.0612.322)]; and wine with Mini-Mental State Examination scores [0.252 (0.0060.496)]. Urinary polyphenols were associated with better scores in immediate verbal memory [1.208 (0.2362.180)]. Increased consumption of antioxidant-rich foods in general and of polyphenols in particular is associated with better cognitive performance in elderly subjects at high cardiovascular risk. The results reinforce the notion that Mediterranean diet components might counteract age-related cognitive decline.

Out-of-sample forecast tests robust to the choice of window size

This paper proposes new methodologies for evaluating out-of-sample forecastingperformance that are robust to the choice of the estimation window size. The methodologies involve evaluating the predictive ability of forecasting models over a wide rangeof window sizes. We show that the tests proposed in the literature may lack the powerto detect predictive ability and might be subject to data snooping across differentwindow sizes if used repeatedly. An empirical application shows the usefulness of themethodologies for evaluating exchange rate models' forecasting ability.

Is diagnosis enough to guide interventions in mental health? Using case formulation in clinical practice.

ABSTRACT: While diagnosis has traditionally been viewed as an essential concept in medicine, particularly when selecting treatments, we suggest that the use of diagnosis alone may be limited, particularly within mental health. The concept of clinical case formulation advocates for collaboratively working with patients to identify idiosyncratic aspects of their presentation and select interventions on this basis. Identifying individualized contributing factors, and how these could influence the person's presentation, in addition to attending to personal strengths, may allow the clinician a deeper understanding of a patient, result in a more personalized treatment approach, and potentially provide a better clinical outcome.