The impact of preclinical irreproducibility on drug development.

The development of novel therapeutics depends and builds upon the validity and reproducibility of previously published data and findings. Yet irreproducibility is pervasive in preclinical life science research and can be traced to cumulative errors or flaws in several areas, including reference materials, study design, laboratory protocols, and data collection and analysis. The expanded development and use of consensus-based standards and well-documented best practices is needed to both enhance reproducibility and drive therapeutic innovations.

Lifetimes of antiferromagnetic magnons in two and three dimensions: experiment, theory, and numerics.

A high-resolution neutron spectroscopic technique is used to measure momentum-resolved magnon lifetimes in the prototypical two- and three-dimensional antiferromagnets Rb(2)MnF(4) and MnF(2), over the full Brillouin zone and a wide range of temperatures. We rederived theories of the lifetime resulting from magnon-magnon scattering, thereby broadening their applicability beyond asymptotically small regions of wave vector and temperature. Corresponding computations, combined with a small contribution reflecting collisions with domain boundaries, yield excellent quantitative agreement with the data. Comprehensive understanding of magnon lifetimes in simple antiferromagnets provides a solid foundation for current research on more complex magnets.

Growing cells push back under pressure.

In both plants and animals, the interplay between mechanical force generation and mechanical sensing plays a stabilizing role in many developmental processes. Uyttewaal et al. now demonstrate that cells in the Arabidopsis shoot apical meristem respond to local mechanical stresses by reorienting their growth, thereby guiding morphogenesis. Notably, the mechanism underlying such guidance is amplification--not suppression--of growth-rate heterogeneity.

Educational intervention in the management of acute procedure-related wound pain: a pilot study.

OBJECTIVE: This report describes the pilot testing of an educational intervention to manage acute pain associated with wound care in an outpatient clinic. The intervention included essential elements of pain education identified in the acute pain literature: provision of information; pain measurement; establishing expectations; treatment planning; teaching environment. METHOD: The intervention was tested on five patients attending a wound clinic for scheduled treatment. Patients were aged 65 years or older and had a history of experiencing pain during treatment procedures such as dressing changes and debridement. Before the intervention, the study nurse gave the patients information about the procedure, discussed strategies they could use to make it as comfortable as possible, and explained how they could use a rating scale to denote any physical and emotional distress. RESULTS: All patients used the intervention strategies. Three out of five reported reduced pain and/or distress following the intervention. CONCLUSION: The pilot study supported the use of education as a pain control strategy in wound care and illuminated key methodological issues for further research on this topic.

Drosophila peripodial cells, more than meets the eye?

Drosophila imaginal discs (appendage primordia) have proved invaluable for deciphering cellular and molecular mechanisms of animal development. By combining the accessibility of the discs with the genetic tractability of the fruit fly, researchers have discovered key mechanisms of growth control, pattern formation and long-range signaling. One of the principal experimental attractions of discs is their anatomical simplicity - they have long been considered to be cellular monolayers. During larval stages, however, the growing discs are 2-sided sacs composed of a columnar epithelium on one side and a squamous 'peripodial' epithelium on the other. Recent studies suggest important roles for peripodial epithelia in processes previously assumed to be confined to columnar cell monolayers.

The many faces of pain for older, dying adults.

An integration of knowledge from the fields of geriatrics, pain management, and palliative care is needed to ensure adequate pain control for the older adult who is dying. An overview is provided of the multiple factors (i.e., chronic illness, malignant disease, care procedures, emotional and cognitive status, response of others) that can cause and exacerbate pain at the end of life for the elderly. Treatment considerations are discussed and an illustrative case study is presented.

Peripodial cells regulate proliferation and patterning of Drosophila imaginal discs.

Cells employ a diverse array of signaling mechanisms to establish spatial patterns during development. Nowhere is this better understood than in Drosophila, where the limbs and eyes arise from discrete epithelial sacs called imaginal discs. Molecular-genetic analyses of pattern formation have generally treated discs as single epithelial sheets. Anatomically, however, discs comprise a columnar cell monolayer covered by a squamous epithelium known as the peripodial membrane. Here we demonstrate that during development, peripodial cells signal to disc columnar cells via microtubule-based apical extensions. Ablation and targeted gene misexpression experiments demonstrate that peripodial cell signaling contributes to growth control and pattern formation in the eye and wing primordia. These findings challenge the traditional view of discs as monolayers and provide foundational evidence for peripodial cell function in Drosophila appendage development.

Comparison of caregivers', residents', and community-dwelling spouses' opinions about expressing sexuality in an institutional setting.

Opinions regarding the appropriateness of elderly residents' sexual behaviors in a chronic care hospital and how to respond to inappropriate behaviors were surveyed. Study participation was open to all staff (N = 1,205), eligible residents (N = 182) and community-dwelling spouses (N = 103). Participation rates were 40% (residents), 42% (spouses), 34% (nursing staff), 50% (allied health staff), and 22% (support staff). Staff completed the questionnaire independently, while residents and spouses were offered self-completion or a structured interview. Almost all selected the interview. Residents and spouses were less tolerant than staff of residents' masturbating, engaging in sexual relationships, viewing sexual materials, and making sexual approaches to staff. Privacy was the primary determinant of appropriateness for behaviors for all groups. Staff and spouses were more likely to endorse counseling when behaviors were perceived as inappropriate than residents. Nurses endorsed counseling less frequently than allied health professionals and support staff. Nurses were more likely to have been approached sexually by a resident. Differences of opinion are interpreted in terms of cohort influences on values and contextual influences on behavior.

Hedgehog is required for activation of engrailed during regeneration of fragmented Drosophila imaginal discs.

Surgically fragmented Drosophila appendage primordia (imaginal discs) engage in wound healing and pattern regulation during short periods of in vivo culture. Prothoracic leg disc fragments possess exceptional regulative capacity, highlighted by the ability of anterior cells to convert to posterior identity and establish a novel posterior compartment. This anterior/posterior conversion violates developmental lineage restrictions essential for normal growth and patterning of the disc, and thus provides an ideal model for understanding how cells change fate during epimorphic pattern regulation. Here we present evidence that the secreted signal encoded by hedgehog directs anterior/posterior conversion by activating the posterior-specific transcription factor engrailed in regulating anterior cells. In the absence of hedgehog activity, prothoracic leg disc fragments fail to undergo anterior/posterior conversion, but can still regenerate missing anterior pattern elements. We suggest that hedgehog-independent regeneration within the anterior compartment (termed integration) is mediated by the positional cues encoded by wingless and decapentaplegic. Taken together, our results provide a novel mechanistic interpretation of imaginal disc pattern regulation and permit speculation that similar mechanisms could govern appendage regeneration in other organisms.

The art and science of a behavioural approach to care.

Behavioural psychology has much to offer residents, families and staff. Properly developed, a behavioural approach to care is at once humane, scientific and practical. In our experience, the dedication of resources and expertise to implementation of a behavioural approach to care has been truly beneficial for all concerned.

Comparison of noncancer risk assessment approaches for use in deriving drinking water criteria.

The development and promulgation of drinking water regulations to protect exposed human populations from contaminants that may occur in public drinking water supplies has been a major regulatory concern and effort of the United States Environmental Protection Agency for decades. Risk assessment, as applied in the development of drinking water regulations, involves the quantification of the level below which adverse health effects are not expected to occur. Traditionally, the oral reference dose (RfD) has been the preferred approach for characterizing these noncancer health risks. The benchmark dose approach to derive RfDs has increasingly gained scientific and regulatory acceptance as a risk assessment methodology since its introduction in 1984. Similarly, the use of categorical regression techniques were introduced at about the same time. The objective of this paper is to present an evaluation of the strengths and weaknesses of each risk assessment method as related to the development of drinking water criteria for noncarcinogenic chemicals. The data base requirements, performance record, mathematical or statistical basis, and other parameters are described and compared.

Absence of exogenous satellite cell contribution to regeneration of frozen skeletal muscle.

Rat extensor digitorum longus (EDL) muscles were repeatedly frozen and thawed to kill completely all cellular constituents. Within four days, blood vessels and phagocytic cells invaded the muscle. Migrating or circulating myoblasts were not among the invading cells, and could be induced to invade the frozen muscle only when a physical bridge was created with an adjacent intact muscle. A further requirement for migration was that the connective tissue investments of both the frozen EDL and adjacent muscle had to be disrupted. This study demonstrates that regeneration of a muscle is primarily dependent upon the intrinsic satellite cell population, although under some circumstances recruitment of extrinsic cells is possible.

Age-related differences in absolute numbers of skeletal muscle satellite cells.

The absolute number of satellite cells (SC) in young and adult rat skeletal muscle was estimated by correlating data from light and electron microscopic quantitation of myofiber nuclei (myonuclei and satellite cell nuclei) with biochemical assays for determining total muscle DNA content. Expressed both as a proportion of total myofiber nuclei and as absolute numbers, satellite cells are more numerous in the predominantly oxidative soleus muscle than in the mixed glycolytic/oxidative extensor digitorum longus (EDL) muscle at 1, 12, and 24 months of age. Satellite cell proportions decline gradually in both muscles with advancing age, but absolute numbers increase significantly in the soleus between 1 and 12 months, while EDL exhibits a continuous significant decline in satellite cells between each of the ages examined.

The distribution of satellite cells and their relationship to specific fiber types in soleus and extensor digitorum longus muscles.

Fiber type classification of p-phenylene-diamine-stained transverse sections of rat skeletal muscle correlated with electron microscopic observations demonstrate that satellite cells are not equally distributed among the various fiber types in either the EDL or soleus at 1 and 12 months of age. Of the three fiber types in the EDL, satellite cells are observed most frequently on Type IIA fibers, and at approximately equal frequencies on Type IIB and Type I fibers. Satellite cells in the soleus, in contrast to the EDL, are not often encountered on Type IIA fibers, but are preferentially associated with Type I fibers in that muscle. The frequency with which satellite cells are found on specific fiber types is distinct for the soleus and EDL and appears to correspond with their growth characteristics. The distribution of satellite cells according to fiber type does not provide an explanation for the differences in the percentage of satellite cell nuclei between the EDL and soleus.

Satellite cells are mitotically quiescent in mature mouse muscle: an EM and radioautographic study.

Normal adult mouse tibialis anterior muscles were perfused continuously with 3H-thymidine for nine days. Quantitation of the satellite cell population in these muscles reveals that not only is the frequency of satellite cell nuclei low, but that those present are mitotically quiescent.