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There has been a resurgent interest in potential microbial etiologies of inflammatory bowel disease (IBD). Over the past decade there have been both epidemiological and tissue studies exploring the potential role of paramyxoviruses in IBD, particularly Crohn's disease. This article will review the evidence and hence plausibility of a causal association between these viruses and IBD.
Many common problems in epidemiologic and clinical research involve estimating the effect of an exposure on an outcome while blocking the exposure's effect on an intermediate variable. Effects of this kind are termed direct effects. Estimation of direct effects is typically the goal of research aimed at understanding mechanistic pathways by which an exposure acts to cause or prevent disease, as well as in many other settings. Although multivariable regression is commonly used to estimate direct effects, this approach requires assumptions beyond those required for the estimation of total causal effects. In addition, when the exposure and intermediate variables interact to cause disease, multivariable regression estimates a particular type of direct effect-the effect of an exposure on an outcome when the intermediate is fixed at a specified level. Using the counterfactual framework, we distinguish this definition of a direct effect (controlled direct effect) from an alternative definition, in which the effect of the exposure on the intermediate is blocked, but the intermediate is otherwise allowed to vary as it would in the absence of exposure (natural direct effect). We illustrate the difference between controlled and natural direct effects using several examples. We present an estimation approach for natural direct effects that can be implemented using standard statistical software, and we review the assumptions underlying our approach (which are less restrictive than those proposed by previous authors).
OBJECTIVE: To investigate the causal pathways by which age and the CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles influence progression to AIDS. DESIGN: Analysis of follow-up data from 2 cohort studies among homosexual men (n=400), having >10 years of follow-up. METHODS: The effects of the 4 cofactors on the CD4 and HIV-1 RNA trajectories after seroconversion were modeled in a random-effects model. A proportional hazards model was used to investigate their effect on the risk of AIDS after correction for CD4 cell count and RNA level. This approach allows investigation as to whether they influence AIDS progression by affecting CD4 count and RNA level or by other pathways. RESULTS: Persons of younger age or having the CCR2-64I or SDF-1 3'A mutation have significantly higher CD4 levels. Persons with the CCR5-Delta32 deletion or CCR2-64I mutation have significantly lower RNA levels. After correction for both CD4 count and RNA level, only the SDF-1 3'A mutation significantly increases the AIDS risk. CONCLUSIONS: Age and the CCR5-Delta32 deletion and CCR2-64I mutation influence AIDS progression by affecting CD4 and HIV-1 RNA. The SDF-1 3'A allele increases the AIDS risk, but this effect is countered by its effect on CD4 and HIV-1 RNA level.
Neuroimaging studies have implicated the left supramarginal gyrus in short-term auditory memory processing, including memory for pitch. The present study investigated the causal role of the left supramarginal gyrus in short-term pitch memory by comparing the effects of cathodal transcranial direct current stimulation when applied over the left or right supramarginal gyrus with sham transcranial direct current stimulation. Only cathodal transcranial direct current stimulation over the left supramarginal gyrus had a detrimental effect on short-term pitch-memory performance in 11 adult participants. These results provide support for the important role of the left supramarginal gyrus in short-term memory for pitch information, and they further demonstrate the potential of transcranial direct current stimulation to modulate the functional contribution of a brain area to a particular cognitive process.
A proposed causal model based upon Lazarus' theory of psychological stress and coping was tested in a sample of 75 persons disabled by stroke. Coping constraints such as demographic and stroke factors were hypothesized to affect resources (perceived availability of social support, perceived effectiveness of social support, social contact), stress appraisal, coping behavior and coping effectiveness. Although the model did not fit the data, several path coefficients within the model were statistically significant. Functional status was positively related to resources and negatively related to the stressor. Resources were negatively related to the stressor and positively related to coping effectiveness. It was noted that the buffering effect of social support was related to the level of disability of the stroke person. Persons with functional disability following stroke also had decreased social contact, perceived less availability of social resources and increased threat to physical well-being, and had reduced coping effectiveness.
Present technology is characterized by complexity, rapid change and growing size of technical systems. This has caused increasing concern with the human involvement in system safety. Analyses of the major accidents during recent decades have concluded that human errors on part of operators, designers or managers have played a major role. There are, however, several basic problems in analysis of accidents and identification of human error. This paper addresses the nature of causal explanations and the ambiguity of the rules applied for identification of the events to include in analysis and for termination of the search for 'causes'. In addition, the concept of human error is analysed and its intimate relation with human adaptation and learning is discussed. It is concluded that identification of errors as a separate class of behaviour is becoming increasingly difficult in modern work environments. The influence of this change on the control of safety of large-scale industrial systems is discussed.
When engaged by a stimulus, different nodes of a neural circuit respond in a coordinated fashion. We often ask whether there is a cause and effect in such interregional interactions. This paper proposes that we can infer causality in functional connectivity by employing a 'perturb and measure' approach. In the human brain, this has been achieved by combining transcranial magnetic stimulation (TMS) with positron emission tomography (PET), functional magnetic resonance imaging or electroencephalography. Here, I will illustrate this approach by reviewing some of our TMS/PET work, and will conclude by discussing a few methodological and theoretical challenges facing those studying neural connectivity using a perturbation.
The sequences of several cDNA clones of pear blister canker viroid (PBCVd) P1914T and P47A isolates have been determined. Seven out of eight P1914T clones analysed have a constant sequence which differs at six positions from that of the P2098T isolate reported previously. The remaining P1914T clone (8) has a single nucleotide substitution. The same six changes have been also observed in most of the ten P47A clones sequenced. However, some P47A clones show additional variability in positions on both strands of the central conserved region (CCR) and in another conserved sequence at the left-terminal region. This is the first report of a change affecting the upper strand of a viroid CCR. Reasons why such a change is tolerated are discussed. Infectivity bioassays have demonstrated that PBCVd is the causal agent of PBC disease.
A long-term cell line (SHK-1) supporting replication of the causal virus of infectious salmon anaemia (ISA) has been established. The cell line was developed from a culture of Atlantic salmon (Salmo salar L.) head kidney cells. CPE was observed in SHK-1 cells 12-14 days after inoculation with ISA-infective tissue material. The time for CPE to develop decreased after repeated passages of medium from infected cell cultures to new cultures. Transmission trials demonstrated that Atlantic salmon parr developed ISA after intraperitoneal injection of preparations made from infected cells and growth medium. The ISA infectivity of the cell preparations increased with incubation time of inoculated cells. Cell cultures in a second passage were found to have a higher infectivity than the primary inoculated cultures. Virus particles with a diameter of approximately 100-120 nm, and which contained an external envelope and granules were seen in electron micrographs of thin sections of infected cells. Most of the virus particles were located extracellularly close to the cell surface, and in some cases, a connection between virus and plasma membrane could be observed. This indicates that virus particles were released by budding. Enveloped virus particles of 45-140 nm in diameter were seen in abundance in electron micrographs of a negatively stained purified virus preparation. Large, highly pleomorphic particles up to 700 nm in the longest dimension were occasionally observed in unpurified preparations. The evidence is therefore strong that the virus isolated in SHK-1 cells is the aetiological agent of ISA.
A full-length in vivo infectious cDNA clone of strawberry mild yellow edge-associated potexvirus (SMYEaV) was constructed and used to inoculate Fragaria vesca 'Alpine' seedlings and Rubus rosifollus. Both host plants could be infected using particle bombardment or agroinoculation, but not by mechanical inoculation. A method that used potted strawberry plants for particle bombardment resulted in high survival and infection rates. The plants developed systemic infection and virus particles were detected by ELISA and immunoelectron microscopy. Mechanical inoculation of Chenopodium quinoa and C. foetidum with the 35S construct resulted in localized infections. F. vesca 'Alpine' indicator plants produced symptoms that were indistinguishable from control plants inoculated with a naturally occurring isolate of strawberry mild yellow edge by graft or aphid transmission. These results suggest that SMYE potexvirus is the causal agent of strawberry mild yellow edge disease. As this virus is capable of causing the disease, we propose the name strawberry mild yellow edge potexvirus, with the acronym SMYEPV, to replace the name strawberry mild yellow edge-associated potexvirus.
The difficulty of fine localizing the polymorphisms responsible for genotype-phenotype correlations is emerging as an important constraint in the implementation and interpretation of genetic association studies, and calls for the definition of protocols for the follow-up of associated variants. One recent example is the 3435C>T polymorphism in the multidrug transporter gene ABCB1, associated with protein expression and activity, and with several clinical conditions. Available data suggest that 3435C>T may not directly cause altered transport activity, but may be associated with one or more causal variants in the poorly characterized stretch of linkage disequilibrium (LD) surrounding it. Here we describe a strategy for the follow-up of reported associations, including a Bayesian formalization of the associated interval concept previously described by Goldstein. We focus on the region of high LD around 3435C>T to compile an exhaustive list of variants by (1) using a relatively coarse set of marker typings to assess the pattern of LD, and (2) resequencing derived and ancestral chromosomes at 3435C>T through the associated interval. We identified three intronic sites that are strongly associated with the 3435C>T polymorphism. One of them is associated with multidrug resistance in patients with epilepsy (chi2 = 3.78, P = 0.052), and sits within a stretch of significant evolutionary conservation. We argue that these variants represent additional candidates for influencing multidrug resistance due to P-glycoprotein activity, with the IVS 26+80 T>C being the best candidate among the three intronic sites. Finally, we describe a set of six haplotype tagging single-nucleotide polymorphisms that represent common ABCB1 variation surrounding 3435C>T in Europeans.
The optical properties of a homogeneous slab of material characterized by causal permittivity epsilon (f) , and permeability mu (f) are investigated through finite difference time domain simulations. Lorentzian epsilon (f) and mu (f) are used to produce values of interest in the resulting index n (f) , namely, n<0 , 0<n<1 , and n approximately 0 . Negative refraction of both cw and pulsed waves is observed when operated in the left-handed medium (LHM) regime. In particular, we examined materials having both an impedance matched to free space and an impedance not matched to free space, as is the case of a split-ring resonator structure, and find it to exhibit LHM behavior, in agreement with previously published claims. Spherical aberration and channeling are observed as the magnitude of the negative index is increased beyond -1 . Critical angle phenomena are seen for indices in the range 0<n<1 , and a spatial filter effect is identified in the n approximately 0 region. A transmission bandpass in the vicinity of n approximately 0 is identified as a "ferromagnetic antiresonance," where the material acts as both a frequency and a spatial filter.
In this work we propose a general nonparametric test of causality for weakly dependent time series. More precisely, we study the problem of attribution, i.e., the proper comparison of the relative influence that two or more external dynamics trigger on a given system of interest. We illustrate the possible applications of the proposed methodology in very different fields like physiology and climate science.
A dispute about the existence of an additional time associated with the Goos-Hänchen shift has recently arisen. By analyzing light propagation in an optical planar waveguide with both the zigzag-ray model and the electromagnetic theory, we show in this paper that the Goos-Hänchen time really exists, and the total time delay upon total reflection is the sum of the group delay time and the Goos-Hänchen time. The causality paradox of total reflection of a TM wave upon an ideal nonabsorbing plasma mirror is also solved with the consideration of a negative Goos-Hänchen shift.
A classical and quantum mechanical generalized second law of thermodynamics in cosmology implies constraints on the effective equation of state of the universe in the form of energy conditions, obeyed by many known cosmological solutions, forbids certain cosmological singularities, and is compatible with entropy bounds. This second law is based on the conjecture that causal boundaries and not only event horizons have geometric entropies proportional to their area. In string cosmology the second law provides new information about nonsingular solutions.
Causal Dynamical Triangulations in four dimensions provide a background-independent definition of the sum over geometries in nonperturbative quantum gravity, with a positive cosmological constant. We present evidence that a macroscopic four-dimensional world emerges from this theory dynamically.
The data reported indicate that the oxidation-reduction balance of the ascorbic acid system is not causally related to the auxin-regulation of cell elongation. There was no shift in the ascorbic acid (AA) to dehydroascorbic acid (DHA) ratio with growth-promoting concentration of auxin in several plant tissues. The AA to DHA ratio was experimentally increased without altering the growth rate. Inhibition of growth by supra-optimal auxin was associated with a decrease in the AA to DHA ratio. Since the AA to DHA ratio was lowered by EDTA treatment without altering growth, it seems unlikely that the decrease in the AA to DHA ratio related to the inhibition of growth by high levels of auxin.
Photosynthesis and the Warburg effect (O(2) inhibition of photosynthesis) were evaluated in preparations of intact spinach chloroplasts enriched with varying amounts of lysed chloroplasts. Increasing the ratio of broken to intact plastids resulted in decreased rates of CO(2) assimilation.Hydrogen peroxide when added at 10 or more micromolar also inhibited photosynthesis in these preparations. Inhibition of the photosynthetic rate by both factors was eliminated by addition of catalase. These findings indicate that H(2)O(2) presumably generated by the broken chloroplasts was the causal agent of this inhibition.The Warburg effect also became more pronounced by increasing the level of broken to intact chloroplasts. This effect was examined as a function of added catalase, pH, and O(2) concentration. At 21% O(2) and 0.44 to 0.68 millimolar CO(2), catalase relieved the effect almost completely at pH 7.5, but at pH 8.3, the rate was restored only to about half or less of the control. At pH 7.6, 0.44 millimolar CO(2), and 100% O(2), the effect was only slightly overcome by catalase.A rise in glycolate synthesis by the isolated spinach chloroplast has been shown previously to be coupled to an increase in pH and O(2) (Kow, Robinson, Gibbs 1977 Plant Physiol 60: 492-495; Robinson, Gibbs, Cotler 1977 Plant Physiol 59: 530-534). At 21% O(2), glycolate synthesis was not affected by the addition of catalase at pH 7.5 or 8.3. It is proposed that at 21% O(2) and without some means of removing H(2)O(2), that portion of the Warburg effect attributed to glycolate synthesis has been overestimated at pH values in the order of 7.5. In contrast, that portion of the Warburg effect which was, at alkaline pH, insensitive to catalase represented the stress placed upon the photosynthetic carbon reduction cycle which resulted from an enhanced synthesis of glycolate. At 100% O(2) aeration and pH 7.5 to 8.5, the Warburg effect may also represent O(2)-mediated inhibition of a Calvin cycle enzyme within the intact plastid.