Systemic hypoxia mimicry enhances axonal regeneration and functional recovery following peripheral nerve injury.

Despite the ability of peripheral nerves to regenerate after injury, failure occurs due to an inability of supporting cells to maintain growth, resulting in long-term consequences such as sensorimotor dysfunction and neuropathic pain. Here, we investigate the potential of engaging the cellular adaptive response to hypoxia, via inhibiting its negative regulators, to enhance the regenerative process. Under normoxic conditions, prolyl hydroxylase domain (PHD) proteins 1, 2, and 3 hydroxylate the key metabolic regulator hypoxia inducible factor 1α (HIF1α), marking it for subsequent proteasomal degradation. We inhibited PHD protein function systemically via either individual genetic deletion or pharmacological pan-PHD inhibition using dimethyloxalylglycine (DMOG). We show enhanced axonal regeneration after sciatic nerve crush injury in PHD1-/- mice, PHD3-/- mice, and in DMOG-treated mice, and in PHD1-/- and DMOG-treated mice a reduction in hypersensitivity to cooling after permanent sciatic ligation. Electromyographically, PHD1-/- and PHD3-/- mice showed an increased CMAP amplitude one-month post-injury, probably due to protection against denervation induced muscle atrophy, while DMOG-treated and PHD2+/- mice showed reduced latencies, indicating improved motor axon function. DMOG treatment did not affect the growth of dorsal root ganglion neurites in vitro, suggesting a lack of direct effects of DMOG on axonal regrowth. Enhanced regeneration in vivo was concurrent with an increase in macrophage density, and a shift in macrophage polarization state ratios (from M1-like toward M2-like) in DMOG-treated animals. These results indicate PHD proteins as a novel therapeutic target to improve regenerative and functional outcomes after peripheral nerve injury without manipulating molecular O2.

HpARI Protein Secreted by a Helminth Parasite Suppresses Interleukin-33.

Infection by helminth parasites is associated with amelioration of allergic reactivity, but mechanistic insights into this association are lacking. Products secreted by the mouse parasite Heligmosomoides polygyrus suppress type 2 (allergic) immune responses through interference in the interleukin-33 (IL-33) pathway. Here, we identified H. polygyrus Alarmin Release Inhibitor (HpARI), an IL-33-suppressive 26-kDa protein, containing three predicted complement control protein (CCP) modules. In vivo, recombinant HpARI abrogated IL-33, group 2 innate lymphoid cell (ILC2) and eosinophilic responses to Alternaria allergen administration, and diminished eosinophilic responses to Nippostrongylus brasiliensis, increasing parasite burden. HpARI bound directly to both mouse and human IL-33 (in the cytokine's activated state) and also to nuclear DNA via its N-terminal CCP module pair (CCP1/2), tethering active IL-33 within necrotic cells, preventing its release, and forestalling initiation of type 2 allergic responses. Thus, HpARI employs a novel molecular strategy to suppress type 2 immunity in both infection and allergy.

Subcellular metabolite and lipid analysis of Xenopus laevis eggs by LAESI mass spectrometry.

Xenopus laevis eggs are used as a biological model system for studying fertilization and early embryonic development in vertebrates. Most methods used for their molecular analysis require elaborate sample preparation including separate protocols for the water soluble and lipid components. In this study, laser ablation electrospray ionization (LAESI), an ambient ionization technique, was used for direct mass spectrometric analysis of X. laevis eggs and early stage embryos up to five cleavage cycles. Single unfertilized and fertilized eggs, their animal and vegetal poles, and embryos through the 32-cell stage were analyzed. Fifty two small metabolite ions, including glutathione, GABA and amino acids, as well as numerous lipids including 14 fatty acids, 13 lysophosphatidylcholines, 36 phosphatidylcholines and 29 triacylglycerols were putatively identified. Additionally, some proteins, for example thymosin ß4 (Xen), were also detected. On the subcellular level, the lipid profiles were found to differ between the animal and vegetal poles of the eggs. Radial profiling revealed profound compositional differences between the jelly coat vitelline/plasma membrane and egg cytoplasm. Changes in the metabolic profile of the egg following fertilization, e.g., the decline of polyamine content with the development of the embryo were observed using LAESI-MS. This approach enables the exploration of metabolic and lipid changes during the early stages of embryogenesis.

Reproductive endocrine disruption in smallmouth bass (Micropterus dolomieu) in the Potomac River basin: spatial and temporal comparisons of biological effects.

A high prevalence of intersex or testicular oocytes (TO) in male smallmouth bass within the Potomac River drainage has raised concerns as to the health of the river. Studies were conducted to document biomarker responses both temporally and spatially to better understand the influence of normal physiological cycles, as well as water quality and land-use influences. Smallmouth bass were collected over a 2-year period from three tributaries of the Potomac River: the Shenandoah River, the South Branch Potomac and Conococheague Creek, and an out-of-basin reference site on the Gauley River. The prevalence of TO varied seasonally with the lowest prevalence observed in July, post-spawn. Reproductive maturity and/or lack of spawning the previous spring, as well as land-use practices such as application of manure and pesticides, may influence the seasonal observations. Annual, seasonal, and site differences were also observed in the percentage of males with measurable concentrations of plasma vitellogenin, mean concentration of plasma vitellogenin in females, and plasma concentrations of 17ß-estradiol and testosterone in both sexes. Bass collected in the South Branch Potomac (moderate to high prevalence of TO) had less sperm per testes mass with a lower percentage of those sperm being motile when compared to those from the Gauley River (low prevalence of TO). An inverse relationship was noted between TO severity and sperm motility. An association between TO severity and wastewater treatment plant flow, percent of agriculture, total number of animal feeding operations, the number of poultry houses, and animal density within the catchment was observed.

Librarians collaborating with nurses.

Nurses have the potential to be one of the largest groups of users a medical library can serve. In recognition of this fact, librarians at St. John's Health System embarked on a journey to collaborate with nurses and increase this group's use of the medical library. In 2004, a nursing outreach plan was developed by librarians, with input from non-physician health care employees. The nursing outreach plan will be reviewed along with the barriers and successes encountered during implementation of the plan. Innovative strategies for reaching nursing personnel were accomplished by partnering with nurses to reach nurses.

Water incident related hospital activity across England between 1997/8 and 2003/4: a retrospective descriptive study.

BACKGROUND: No one has ever reported or investigated the number of people who have been admitted to hospital for a water related incident. The purpose of this paper is to examine, the hospital activity resulting from such incidents including to length of stay, gender, age and cause. METHODS: The data was extracted from the Hospital Episode Statistics (HES) for episodes with a mention of ICD 10 (V90-94, W15-16, W65-74, X38, X92, Y21) for the years 1997/8 to 2003/4. Population based rates and relative risk were calculated using the most recent Census data for England (2001). RESULTS: The 6,793 episodes resulted in a total of 32,520 bed days with an average of length of stay of 5.0 days. Males made up 73.7% (n = 5,006) of episodes and females 26.1% (n = 1,787). Annual trends peaked in 1999-2000 at a rate of 2.4 per 100,000 and have fluctuated on alternate years there after. In terms of relative risk males are at a 2.3 to 3.0 increased annual risk of being admitted compared to females, relating to a water event. The highest annual rates were observed within the 0 - 14 age group, ranging from 3.1 to 4.2 episodes per 100,000. CONCLUSION: Based on these findings, for every one drowning that occurs per year there are three hospital episodes. Each of the age groups identified within the study reported an increase in hospital episodes between 2002 - 2003 and 2003 - 2004, when considering the fatality information available it would appear that although fatalities are decreasing in the similar time period, hospital episodes are increasing. For the 0-14 age group, the cause of the injury had changed over the years, moving away from bath tub and swimming pool, to watercraft incidents (V91 - 93). For the 15 - 59 age group there had been a decline in the frequency of watercraft and water transport episodes, however, an increase in diving and jumping injury and incidents. In the over 60 age group water transport episodes remained the most frequent, with swimming pool related episodes declining and other specified drowning and submersion increasing. More work needs to be undertaken in regard to who is admitted to hospital, when where, and how to fill gaps in knowledge and highlight information that is critical to prevention strategies.

From depths of despair to heights of recovery.

While disclosure of my personal experience with mental illness and recovery is not without some concern regarding its reception by others, I feel it's important I tell my story. This is because I wish to challenge the misunderstanding and stigma that surely surround mental illness. Also, I want to hold out hope to anyone presently struggling in the direction of recovery. I know life has its ups and downs--it does for everyone. But I feel better able to cope and for now, for me, life is good; I hope this article is of help in making this possible for others.