The discovery of a potent, intracellular, orally bioavailable, long duration inhibitor of human neutrophil elastase--GW311616A a development candidate

The discovery of a potent intracellular inhibitor of human neutrophil elastase which is orally active and has a long duration of action is described. The pharmacodynamic and pharmacokinetic properties of a trans-lactam development candidate, GW311616A, are described.     

Carry-over effects from passage regions are more important than breeding climate in determining the breeding phenology and performance of three avian migrants of conservation concern

Long distance migrants are declining more rapidly than residents, with birds that breed in Europe and winter in tropical Africa providing particularly clear examples. Causal mechanisms may include climate change, but are poorly understood partly because carry-over effects from non-breeding ranges can influence breeding performance. Using long-term data spanning four decades we assess how climatic variation in migrants’ winter, passage and breeding ranges determine timing of breeding and reproductive success. We do so for three Afro-European avian migrants of regional conservation concern (redstart, spotted flycatcher and wood warbler). We find that carry-over effects from passage regions consistently had stronger impacts on breeding phenology than breeding climate. Warm Mediterranean passage conditions promoted earlier breeding in all species, and redstarts also bred earlier following higher Sahel rainfall. Warmer springs on the breeding grounds promoted slightly earlier breeding in redstart and wood warbler, but not spotted flycatcher. Carry-over effects also typically influenced breeding performance to a greater extent than weather on the breeding grounds. Greater rainfall in the Sahel increased redstart brood size, warmer Mediterranean passage conditions increased spotted flycatcher brood size and, to a lesser extent, the number of wood warbler fledglings. In contrast to the concern regarding climate change impacts on migrants’ breeding grounds we found no evidence that warmer temperatures on the breeding grounds were associated with reduced reproductive performance. We thus find that climatic variation on the non-breeding grounds, especially passage regions, typically influenced migrants’ breeding phenology and demography more strongly than equivalent variation on the breeding sites. Such carry-over effects should be considered when assessing the causes of migrants’ marked population declines.     

Kdm3a lysine demethylase is an Hsp90 client required for cytoskeletal rearrangements during spermatogenesis

The lysine demethylase Kdm3a (Jhdm2a, Jmjd1a) is required for male fertility, sex determination, and metabolic homeostasis through its nuclear role in chromatin remodeling. Many histone-modifying enzymes have additional nonhistone substrates, as well as nonenzymatic functions, contributing to the full spectrum of events underlying their biological roles. We present two Kdm3a mouse models that exhibit cytoplasmic defects that may account in part for the globozoospermia phenotype reported previously. Electron microscopy revealed abnormal acrosome and manchette and the absence of implantation fossa at the caudal end of the nucleus in mice without Kdm3a demethylase activity, which affected cytoplasmic structures required to elongate the sperm head. We describe an enzymatically active new Kdm3a isoform and show that subcellular distribution, protein levels, and lysine demethylation activity of Kdm3a depended on Hsp90. We show that Kdm3a localizes to cytoplasmic structures of maturing spermatids affected in Kdm3a mutant mice, which in turn display altered fractionation of β-actin and γ-tubulin. Kdm3a is therefore a multifunctional Hsp90 client protein that participates directly in the regulation of cytoskeletal components.     

Using Information from the Electronic Health Record to Improve Measurement of Unemployment in Service Members and Veterans with mTBI and Post-Deployment Stress

Objective

The purpose of this pilot study is 1) to develop an annotation schema and a training set of annotated notes to support the future development of a natural language processing (NLP) system to automatically extract employment information, and 2) to determine if information about employment status, goals and work-related challenges reported by service members and Veterans with mild traumatic brain injury (mTBI) and post-deployment stress can be identified in the Electronic Health Record (EHR).

Design

Retrospective cohort study using data from selected progress notes stored in the EHR.

Setting

Post-deployment Rehabilitation and Evaluation Program (PREP), an in-patient rehabilitation program for Veterans with TBI at the James A. Haley Veterans'' Hospital in Tampa, Florida.

Participants

Service members and Veterans with TBI who participated in the PREP program (N = 60).

Main Outcome Measures

Documentation of employment status, goals, and work-related challenges reported by service members and recorded in the EHR.

Results

Two hundred notes were examined and unique vocational information was found indicating a variety of self-reported employment challenges. Current employment status and future vocational goals along with information about cognitive, physical, and behavioral symptoms that may affect return-to-work were extracted from the EHR. The annotation schema developed for this study provides an excellent tool upon which NLP studies can be developed.

Conclusions

Information related to employment status and vocational history is stored in text notes in the EHR system. Information stored in text does not lend itself to easy extraction or summarization for research and rehabilitation planning purposes. Development of NLP systems to automatically extract text-based employment information provides data that may improve the understanding and measurement of employment in this important cohort.     

Localization of monoamine oxidase A and B in human pancreas, thyroid, and adrenal glands.

We studied monoamine oxidase (MAO) A and B localization in human pancreas, thyroid gland, and adrenal gland by immunohistochemistry. The primary antibodies used were mouse monoclonal anti-human MAO-A (6G11/E1) and anti-human MAO-B (3F12/G10/2E3). Samples were obtained from six routine autopsy cases and fixed in 2% paraformaldehyde. Exocrine pancreas showed a widespread distribution of MAO-A, whereas MAO-B was present only in centroacinar cells and epithelial cells of pancreatic ducts. In endocrine pancreas, MAO-A was observed in around 50% of islet cells, whereas MAO-B was less abundant and was restricted to the periphery of islets. Thyroid gland showed strong MAO-A immunoreactivity in all cell types and was MAO-B-negative. In adrenal gland, the capsule displayed MAO-A but not MAO-B immunoreactivity, whereas the cortex showed widespread MAO-A staining but was MAO-B-negative in interstitial cells. Finally, in the medulla only a few scattered cells showed either MAO-A or MAO-B immunoreactivity. To our knowledge, these data represent the first study of the cellular distribution of MAO-A and MAO-B in the three human tissues included.     

Identification of the Escherichia coli recN gene product as a major SOS protein.

The recA+ lexA+-dependent induction of four Escherichia coli SOS proteins was readily observed by two-dimensional gel analysis. In addition to the 38-kilodalton (kDa) RecA protein, which was induced in the greatest amounts and was readily identified, three other proteins of 115, 62, and 12 kDa were seen. The 115-kDa protein is the product of the uvrA gene, which is required for nucleotide excision repair and has previously been shown to be induced in the SOS response. The 62-kDa protein, which was induced to high intracellular levels, is the product of recN, a gene required for recBC-independent recombination. The recA and recN genes were partially derepressed in a recBC sbcB genetic background, a phenomenon which might account for the recombination proficiency of such strains. The 12-kDa protein has yet to be identified.     

Elevated Density of [3H]Imipramine Binding in Aged Human Brain

Aging was associated with an increase in the density of specific binding sites for [3H]imipramine in postmortem specimens of human hypothalamus, frontal cortex, and parietal cortex. In general, [3H]imipramine binding was not affected by factors considered difficult to control in postmortem studies, i.e., time from death to autopsy and cause of death. The in vitro regulation of [3H]imipramine binding by sodium was impaired with age in hypothalamic homogenates. In vitro regulation of [3H]imipramine binding by chloride was intact. Determination of the concentrations of 5-hydroxytryptamine (serotonin) and 5-hydroxyindoleacetic acid in hypothalamus and frontal cortex indicated no apparent age-related changes in indole metabolism. The age-related increase in brain [3H]imipramine binding and impairment in the in vitro regulation of binding by ions are similar to changes observed previously in aged mouse brain. The increase in brain antidepressant binding sites is discussed in relationship to other indices of brain serotonergic function in aging and to the relationship of [3H]imipramine binding and depression.     

Comparison of animal infectivity, excystation, and fluorogenic dye as measures of Giardia muris cyst inactivation by ozone.

Giardia muris cyst viability after ozonation was compared by using fluorescein diacetate-ethidium bromide staining, the C3H/HeN mouse-G. muris model, and in vitro excystation. Bench-scale batch experiments were conducted under laboratory conditions (pH 6.7, 22 degrees C) in ozone-demand-free phosphate buffer. There was a significant difference between fluorogenic staining and infectivity (P less than or equal to 0.05), with fluorogenic staining overestimating viability compared with infectivity estimates of viability. This suggests that viable cysts as indicated by fluorogenic dyes may not be able to complete the life cycle and produce an infection. No significant differences between infectivity and excystation and between fluorogenic staining and excystation (P less than or equal to 0.05) were detected for inactivations up to 99.9%. Only animal infectivity had the sensitivity to detect inactivations greater than 99.9%. Therefore, the animal model is the best method currently available for detecting high levels of G. muris cyst inactivation.     

The Swedish version of the Normalization Process Theory Measure S-NoMAD: translation,adaptation, and pilot testing

Background

The original British instrument the Normalization Process Theory Measure (NoMAD) is based on the four core constructs of the Normalization Process Theory: Coherence, Cognitive Participation, Collective Action, and Reflexive Monitoring. They represent ways of thinking about implementation and are focused on how interventions can become part of everyday practice.

Aim

To translate and adapt the original NoMAD into the Swedish version S-NoMAD and to evaluate its psychometric properties based on a pilot test in a health care context including in-hospital, primary, and community care contexts.

Methods

A systematic approach with a four-step process was utilized, including forward and backward translation and expert reviews for the test and improvement of content validity of the S-NoMAD in different stages of development. The final S-NoMAD version was then used for process evaluation in a pilot study aimed at the implementation of a new working method for individualized care planning. The pilot was executed in two hospitals, four health care centres, and two municipalities in a region in northern Sweden. The S-NoMAD pilot results were analysed for validity using confirmatory factor analysis, i.e. a one-factor model fitted for each of the four constructs of the S-NoMAD. Cronbach’s alpha was used to ascertain the internal consistency reliability.

Results

In the pilot, S-NoMAD data were collected from 144 individuals who were different health care professionals or managers. The initial factor analysis model showed good fit for two of the constructs (Coherence and Cognitive Participation) and unsatisfactory fit for the remaining two (Collective Action and Reflexive Monitoring) based on three items. Deleting those items from the model yielded a good fit and good internal consistency (alphas between 0.78 and 0.83). However, the estimation of correlations between the factors showed that the factor Reflexive Monitoring was highly correlated (around 0.9) with the factors Coherence and Collective Action.

Conclusions

The results show initial satisfactory psychometric properties for the translation and first validation of the S-NoMAD. However, development of a highly valid and reliable instrument is an iterative process, requiring more extensive validation in various settings and populations. Thus, in order to establish the validity and reliability of the S-NoMAD, additional psychometric testing is needed.