Is the Hygiene Hypothesis an Example of Hormesis?

The “hygiene hypothesis” has been suggested to explain the rising incidence of allergic disorders in developed countries. The postulated mechanism is that infectious and/or microbial agents stimulate the immune system toward Th1 (allergy fighting) rather than Th2 (allergy promoting) response. This paper reviews the evidence related to early life infectious/microbial exposures and subsequent atopic disorders and evaluates whether these data suggest a hormetic effect. Our review indicates an insufficient and contradictory association for bacterial/viral infections, with protective effects being either absent or specific to certain infections and/or populations. Chronic, heavy parasitic burdens appear to confer protection against atopic disorders, but are associated with considerable pathology. Moreover, light parasitic burden may increase allergic responses (i.e., no “low dose” beneficial effect). In contrast, there is consistent evidence that general microbial exposures, particularly gut commensals, may be protective against allergy development, which is consistent with a hormetic effect (i.e., potentially beneficial effects at low doses and detrimental effects at high levels). Conclusion: General microbial exposures in relation to the “hygiene hypothesis” may represent a hormetic effect, although further research with more rigorous study methods (i.e., prospective designs and measurement of exposure timing, dose, route, etc.) are needed

poLCA: An R Package for Polytomous Variable Latent Class Analysis

poLCA is a software package for the estimation of latent class and latent class regression models for polytomous outcome variables, implemented in the R statistical computing environment. Both models can be called using a single simple command line. The basic latent class model is a finite mixture model in which the component distributions are assumed to be multi-way cross-classification tables with all variables mutually independent. The latent class regression model further enables the researcher to estimate the effects of covariates on predicting latent class membership. poLCA uses expectation-maximization and Newton-Raphson algorithms to find maximum likelihood estimates of the model parameters

Takeover Defense Tactics: A Comment on Two Models

One of the most important debates of current corporate law practice and scholarship is about the appropriate role of target management confronted with a takeover bid. The controversy turns on the identification of a criterion for evaluating takeovers and target management defensive tactics. An influential body of opinion contends that maximization of shareholder wealth is the appropriate criterion because, first, traditional notions of fiduciary duty generally require managers to act in the shareholders\u27 interest, and, second, shareholder wealth maximization is seen as the best available proxy for social wealth maximization. On this view, takeovers are desirable because they can increase shareholder wealth in two ways: first, by moving assets to managers who can produce the greatest economic return from them; and second, by increasing pressure on current management to maximize economic return from assets under their stewardship. From this starting point, management has only two justifiable options for responding to a takeover bid. Some argue that management should respond passively. Passivity will maximize shareholder wealth by increasing the returns to search for takeover targets, which raises the number of value-increasing bids. Others contend that management may abandon passivity, but only to the extent necessary to instigate an auction for the firm. An auction will ensure that the user who most highly values the target assets will gain control over them (without the transaction costs of successive sales) while maximizing the payoff to target shareholders. Which of these responses would in fact maximize shareholder wealth is a matter of dispute. Those who favor permitting target management responses that instigate auctions must face the problem of the divergence of shareholder and target management interests in a takeover. A successful auction means that target managers will possibly lose their jobs and certainly their autonomy. In adopting tactics that would tend to produce an auction, management may be hoping to thwart the takeover altogether. On the assumption that target management will act in a self-interested way, how should we distinguish tactics that will increase shareholder wealth from those that will not

ARAS: an automated radioactivity aliquoting system for dispensing solutions containing positron-emitting radioisotopes.

BackgroundAutomated protocols for measuring and dispensing solutions containing radioisotopes are essential not only for providing a safe environment for radiation workers but also to ensure accuracy of dispensed radioactivity and an efficient workflow. For this purpose, we have designed ARAS, an automated radioactivity aliquoting system for dispensing solutions containing positron-emitting radioisotopes with particular focus on fluorine-18 ((18)F).MethodsThe key to the system is the combination of a radiation detector measuring radioactivity concentration, in line with a peristaltic pump dispensing known volumes.ResultsThe combined system demonstrates volume variation to be within 5 % for dispensing volumes of 20 μL or greater. When considering volumes of 20 μL or greater, the delivered radioactivity is in agreement with the requested amount as measured independently with a dose calibrator to within 2 % on average.ConclusionsThe integration of the detector and pump in an in-line system leads to a flexible and compact approach that can accurately dispense solutions containing radioactivity concentrations ranging from the high values typical of [(18)F]fluoride directly produced from a cyclotron (~0.1-1 mCi μL(-1)) to the low values typical of batches of [(18)F]fluoride-labeled radiotracers intended for preclinical mouse scans (~1-10 μCi μL(-1))

Convergence of the restricted Nelder-Mead algorithm in two dimensions

The Nelder-Mead algorithm, a longstanding direct search method for unconstrained optimization published in 1965, is designed to minimize a scalar-valued function f of n real variables using only function values, without any derivative information. Each Nelder-Mead iteration is associated with a nondegenerate simplex defined by n+1 vertices and their function values; a typical iteration produces a new simplex by replacing the worst vertex by a new point. Despite the method's widespread use, theoretical results have been limited: for strictly convex objective functions of one variable with bounded level sets, the algorithm always converges to the minimizer; for such functions of two variables, the diameter of the simplex converges to zero, but examples constructed by McKinnon show that the algorithm may converge to a nonminimizing point. This paper considers the restricted Nelder-Mead algorithm, a variant that does not allow expansion steps. In two dimensions we show that, for any nondegenerate starting simplex and any twice-continuously differentiable function with positive definite Hessian and bounded level sets, the algorithm always converges to the minimizer. The proof is based on treating the method as a discrete dynamical system, and relies on several techniques that are non-standard in convergence proofs for unconstrained optimization.Comment: 27 page

Imaging the deep structure of the San Andreas Fault south of Hollister with joint analysis of fault zone head and direct P arrivals

Author Posting. © Blackwell, 2007. This article is posted here by permission of Blackwell for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 169 (2007): 1028–1042, doi:10.1111/j.1365-246X.2006.03319.x.We perform a joint inversion of arrival time data generated by direct P and fault zone (FZ) head waves in the San Andreas Fault south of Hollister, CA, to obtain a high-resolution local velocity structure. The incorporation of head waves allows us to obtain a sharp image of the overall velocity contrast across the fault as a function of depth, while the use of near-fault data allows us to resolve internal variations in the FZ structure. The data consist of over 9800 direct P and over 2700 head wave arrival times from 450 events at up to 54 stations of a dense temporary seismic array and the permanent northern California seismic network in the area. One set of inversions is performed upon the whole data set, and five inversion sets are performed on various data subsets in an effort to resolve details of the FZ structure. The results imply a strong contrast of P-wave velocities across the fault of ~50 per cent in the shallow section, and lower contrasts of 10–20 per cent below 3 km, with the southwest being the side with faster velocities. The presence of a shallow low velocity zone around the fault, which could corresponds to the damage structures imaged in trapped wave studies, is detected by inversions using subsets of the data made up of only stations close to the fault. The faster southwest side of the fault shows the development of a shallow low velocity FZ layer in inversions using instruments closer and closer to the fault (<5 and <2 km). Such a feature is not present in results of inversions using only stations at greater distances from the fault. On the slower northeast side of the fault, the presence of a low velocity shallow layer is only detected in the inversions using the stations within 2 km of the fault. We interpret this asymmetry across the fault as a possible indication of a preferred propagation direction of earthquake ruptures in the region. Using events from different portions of the fault, the head wave inversions also resolve small-scale features of the fault visible in the surface geology and relocated seismicity

Bioresorbable Polylactide Interbody Implants in an Ovine Anterior Cervical Discectomy and Fusion Model: Three-Year Results

Study Design. In vivo study of anterior discectomy and fusion using a bioresorbable 70:30 poly(l-lactide-co-d,l-lactide) interbody implant in an ovine model. Objective. To evaluate the efficacy of the polylactide implant to function as an interbody fusion device, and to assess the tissue reaction to the material during the resorption process. Summary of Background Data. The use of polylactide as a cervical interbody implant has several potential advantages when compared with traditional materials. Having an elastic modulus very similar to bone minimizes the potential for stress shielding, and as the material resorbs additional loading is transferred to the developing fusion mass. Although preclinical and clinical studies have demonstrated the suitability of polylactide implants for lumbar interbody fusion, detailed information on cervical anterior cervical discectomy and fusion (ACDF) with polylactide devices is desirable. Methods. Single level ACDF was performed in 8 skeletally mature ewes. Bioresorbable 70:30 poly (l-lactide-co-d,l-lactide) interbody implants packed with autograft were used with single-level metallic plates. Radiographs were made every 3 months up to 1 year, and yearly thereafter. The animals were killed at 6 months (3 animals), 12 months (3 animals), and 36 months (2 animals). In addition to the serial plain radiographs, the specimens were evaluated by nondestructive biomechanical testing and undecalcified histologic analysis. Results. The bioresorbable polylactide implants were effective in achieving interbody fusion. The 6-month animals appeared fused radiographically and biomechanically, whereas histologic sections demonstrated partial fusion (in 3 of 3 animals). Radiographic fusion was confirmed histologically and biomechanically at 12 months (3 of 3 animals) and 36 months (2 of 2 animals). A mild chronic inflammatory response to the resorbing polylactide implant was observed at both 6 months and 12 months. At 36 months, the operative levels were solidly fused and the implants were completely resorbed. No adverse tissue response was observed in any animal at any time period. Conclusion. Interbody fusion was achieved using bioresorbable polylactide implants, with no evidence of implant collapse, extrusion, or adverse tissue response to the material. The use of polylactide as a cervical interbody device appears both safe and effective based on these ACDF animal model results

Fire in Southern Appalachians: Fuels, Stand Structure and Oaks

Managers responsible for maintaining the diversity and productivity of Southern Appalachian forests are increasingly turning to prescribed fire as an important management tool in oak dominated forests. The decision to use fire with increasing frequency and spatial extent is based, in part, on an emerging sense of the prehistoric significance of fire in this landscape and its potential to control the proliferation of fire-sensitive competitors in contemporary forests. While it is well documented that fire has been an important ecological force in Southern Appalachian forests for a very long time, there has been little research to demonstrate that prescribed fire effectively controls fire-sensitive competitors, promotes regeneration of desirable species, or maintains and promotes healthy forest stands. In the face of increased management burning there is a need to address these questions, and to quantify the role of existing and residual fuels in fire management following repeated fire of differing intervals. Two studies were initiated in 1995 and 2002 in upland forests on the Cumberland Plateau of Kentucky to examine the effectiveness of prescribed fire to maintain oak dominance by altering stand structure and enhancing oak seedling establishment and development. We hypothesized that fire would: (1) reduce midstory stem density, and that these changes to stand structure and light availability would lead to improved performance of oak seedlings; and (2) control oak competitors. On ridgetop sites on the escarpment of the Cumberland Plateau, we measured stand structure and tree regeneration on 48 plots in 6 treatment areas over an 11-year period. Four units were burned 3-4 times and two units serve as fire-excluded references. On the topographically-dissected landscape of the Cumberland Plateau we recorded stand structure and multiple aspects of the tree regeneration process on 9 study sites (93 plots), with three sites burned four times, three sites burned twice, and three fire-excluded sites. Prescribed fire reduced midstory stem density and basal area, and increased light availability which was transitory due to understory sprouting. Seedling population studies revealed that oaks and maple seedlings responded to stem kill by re-sprouting, with increased height and diameter. However, red maple seedlings grew more than oaks after burning. Burning reduced seedling density of potential competitor species, yet high fecundity of some species (e.g., red maple) and strong sprouting response of others (e.g., sassafras), suggests that multiple fires have provided neither the stand structural changes nor competition control that would lead to the development of more competitive oak advance reproduction. An oak mast event revealed a potentially positive role for fire in reducing the depth of the litter layer and enhancing oak seedling establishment and growth. Overall, our results suggest a modest role for prescribed fire in enhancing the establishment, growth and persistence of oak advance regeneration