Pressure ulcer healing with an intensive nutrition intervention in an acute setting: a pilot randomised controlled trial.

OBJECTIVE: To investigate the feasibility of recruitment, retention, intervention delivery and outcome measurement in a nutritional intervention to promote pressure ulcer healing in an acute setting. METHOD: Some 50 tertiary hospital patients with stage II or greater pressure ulcer were randomised to receive either individualised nutritional care by a dietitian, including prescription of wound healing supplements; or standard nutritional care. Relevant nutritional and pressure ulcer (PU) parameters were collected at day 5, 10, 15, 22 and then weekly or until discharge. RESULTS: The median length of hospital stay was 14 days (1-70) with 29 patients discharged by day 15. There were 24 patients discharged before their PU fully healed. Per cent change in valid PU area and score measures from baseline to day 15 were chosen for outcome data analysis to account for varying initial size and severity of the wound and length of stay. There was a larger percentage reduction in PU measures in the intervention group, but this was not statistically significant. Little difference was found in nutritional intake between the control and intervention groups indicating a requirement to focus on effective delivery of the intervention in future studies. Future studies in the acute setting need to account for length of stay and ideally follow patients until full healing. CONCLUSION: Results indicate a positive association with nutrition intervention and PU healing and that a rigorously designed and adequately powered study is feasible. DECLARATION OF INTEREST: This research was supported by a grant from the Queensland Health, Health Practitioner Research Scheme. The authors have no conflicts of interest to declare.

Evidence for Octupole Correlations in Multiple Chiral Doublet Bands.

Two pairs of positive-and negative-parity doublet bands together with eight strong electric dipole transitions linking their yrast positive- and negative-parity bands have been identified in ^{78}Br. They are interpreted as multiple chiral doublet bands with octupole correlations, which is supported by the microscopic multidimensionally-constrained covariant density functional theory and triaxial particle rotor model calculations. This observation reports the first example of chiral geometry in octupole soft nuclei.

PSTPIP2 dysregulation contributes to aberrant terminal differentiation in GATA-1-deficient megakaryocytes by activating LYN.

GATA1 mutations are tightly associated with transient myeloproliferative disorder (TMD) and acute megakaryoblstic leukemia (AMKL) in children with Down syndrome. Numerous genes are altered in GATA-1-deficient megakaryocytes, which may contribute to the hyperproliferation and abnormal terminal differentiation of these malignant cells. In this study, we demonstrate that Pstpip2 is a GATA-1-repressed gene that controls megakaryopoiesis. Ectopic expression of PSTPIP2 impaired megakaryocytic differentiation as evidenced by a decrease of CD41 expression and reduced DNA content in K562 cells. PSTPIP2 overexpression also caused enhanced activation of Src family kinases and subsequently reduced ERK phosphorylation. Consistently, PSTPIP2 knockdown showed the opposite effect on differentiation and signaling. Moreover, the W232A mutant of PSTPIP2, defective in its interaction with PEST family phosphatases that recruit c-Src terminal kinase (CSK) to suppress Src family kinases, failed to inhibit differentiation and lost its ability to enhance Src family kinases or reduce ERK phosphorylation. In fact, the W232A mutant of PSTPIP2 promoted megakaryocyte differentiation. These observations suggest that PSTPIP2 recruiting PEST phosphatases somehow blocked CSK activity and led to enhanced activation of Src family kinases and reduced ERK phosphorylation, which ultimately repressed megakaryocyte differentiation. Supporting this idea, PSTPIP2 interacted with LYN and the expression of a dominant negative LYN (LYN DN) overwhelmed the inhibitory effect of PSTPIP2 on differentiation and ERK signaling. In addition, a constitutively active LYN (LYN CA) normalized the enhanced megakaryocyte differentiation and repressed ERK signaling in PSTPIP2 knockdown cells. Finally, we found that PSTPIP2 repressed ERK signaling, differentiation, and proliferation and verified that PSTPIP2 upregulation repressed megakaryocyte development in primary mouse bone marrow cells. Our study thus reveals a novel mechanism by which dysregulation of PSTPIP2 due to GATA-1 deficiency may contribute to abnormal megakaryocyte proliferation and differentiation in pathogenesis of related diseases.

AKT is a therapeutic target in myeloproliferative neoplasms.

The majority of patients with BCR-ABL1-negative myeloproliferative neoplasms (MPN) harbor mutations in JAK2 or MPL, which lead to constitutive activation of the JAK/STAT, PI3K and ERK signaling pathways. JAK inhibitors by themselves are inadequate in producing selective clonal suppression in MPN and are associated with hematopoietic toxicities. MK-2206 is a potent allosteric AKT inhibitor that was well tolerated, including no evidence of myelosuppression, in a phase I study of solid tumors. Herein, we show that inhibition of PI3K/AKT signaling by MK-2206 affected the growth of both JAK2V617F- or MPLW515L-expressing cells via reduced phosphorylation of AKT and inhibition of its downstream signaling molecules. Moreover, we demonstrate that MK-2206 synergizes with ruxolitinib in suppressing the growth of JAK2V617F-mutant SET2 cells. Importantly, MK-2206 suppressed colony formation from hematopoietic progenitor cells in patients with primary myelofibrosis and alleviated hepatosplenomegaly and reduced megakaryocyte burden in the bone marrows, livers and spleens of mice with MPLW515L-induced MPN. Together, these findings establish AKT as a rational therapeutic target in the MPNs.

AKT collaborates with ERG and Gata1s to dysregulate megakaryopoiesis and promote AMKL.

The requirement that leukemic Gata1 mutations be present in cells harboring trisomy 21 led to the discovery that overexpression of ERG drives aberrant megakaryopoiesis. Given that constitutive PI3K/AKT signaling is a frequent component of hematologic malignancies and the relationship between AKT and Notch in this lineage, we studied the crosstalk between AKT signaling and ERG in megakaryopoiesis. We discovered that constitutive AKT signaling is associated with a dramatic increase in apoptosis of WT megakaryocytes (MKs), but that overexpression of ERG blocks AKT-induced death. We further found that Gata1 mutations protect MKs from activated AKT-induced apoptosis. As a consequence, however, the enhanced signaling inhibits differentiation of Gata1 mutant, but not WT, MKs. Gata1 mutant cells that overexpress ERG with hyperactive AKT are characterized by diminished FOXO1/3a expression and an increased dependency on the c-Jun pathway similar to that seen in acute megakaryoblastic leukemia (AMKL) cell lines, acute myeloid leukemia (AML) with knockdown of FOXO3a, or AML with expression of myristoylated Akt. Additionally, we found that the AKT allosteric inhibitor MK2206 caused reduced cell viability and proliferation of AMKL cell lines. The contribution of aberrant AKT signaling during the ontogeny of Down syndrome-transient myeloproliferative disorder/AMKL indicates that AKT is a therapeutic target in this form of AML.

Induction of immune responses in sheep by vaccination with liposome-entrapped DNA complexes encoding Toxoplasma gondii MIC3 gene.

Toxoplasma gondii is a parasite that has been extensively studied due to its medical and veterinary importance in terminating pregnancies. Consequently, a satisfactory vaccine is required to control its adverse effects on pregnant animals. The microneme protein, MIC3, is a major adhesion protein that binds to the surface of host cells and parasites, and is therefore a potential vaccine against T. gondii. The viability of MIC3 as a vaccine is investigated in this study. Sheep were injected twice, intramuscularly, with plasmids containing DNA encoding for the mature form of MIC3 protein formulated into liposomes. Control sheep were injected with an empty vector or received no injections. The injection of sheep with DNA plasmids encoding for MIC3 elicited an immune response after the first and second injections as indicated by antibody responses and the production of IFN-gamma. The immune response, as measured by the IgG2 and IgG1 serum levels, was boosted after the injection of the MIC3 DNA vaccine together with high anti-MIC3 antibodies. The results demonstrate that the intramuscular injection of sheep with a plasmid containing DNA coding for MIC3 protein induces a significant and effective immune response against T. gondii.

Immunological response of sheep to injections of plasmids encoding Toxoplasma gondii SAG1 and ROP1 genes.

Infection with the intracellular protozoan parasite Toxoplasma gondii (T. gondii) causes health problems to both humans and livestock and has a large economic impact worldwide. The immune response in sheep following infection with T. gondii was evaluated using six different combinations of plasmid DNA, recombinant antigen and adjuvant. Sheep were generally vaccinated twice by intramuscular injection with plasmid DNA containing gene sequences for either the surface antigen (SAG1) or the rhoptry protein (ROP1) of T. gondii. Two of the groups injected with plasmid DNA SAG1 were boosted with recombinant protein (SAG1). We investigated the efficacy of including oligodeoxynucleotides (ODN) that contain CG motifs (CpG) and the gene coding for ovine granulocyte-macrophage colony stimulating factor (GM-CSF) as potential adjuvants. Administration of the plasmid encoding the ROP1 gene significantly enhanced both IFN-gamma production from peripheral blood cells when cultured in vitro with Toxoplasma antigen, and ROP1-specific IgG1 and IgG2 antibody levels present in serum. However, injection with SAG1 did not stimulate IFN-gamma production. These results indicate the potential of ROP1, given as plasmid DNA, as a potential vaccine candidate to protect sheep against T. gondii infection.

Event-by-event fluctuations of azimuthal particle anisotropy in Au+Au collisions at square root(sNN) = 200 GeV.

This Letter presents the first measurement of event-by-event fluctuations of the elliptic flow parameter v(2) in Au+Au collisions at square root(s(NN))=200 GeV as a function of collision centrality. The relative nonstatistical fluctuations of the v(2) parameter are found to be approximately 40%. The results, including contributions from event-by-event elliptic flow fluctuations and from azimuthal correlations that are unrelated to the reaction plane (nonflow correlations), establish an upper limit on the magnitude of underlying elliptic flow fluctuations. This limit is consistent with predictions based on spatial fluctuations of the participating nucleons in the initial nuclear overlap region. These results provide important constraints on models of the initial state and hydrodynamic evolution of relativistic heavy ion collisions.

High transverse momentum triggered correlations over a large pseudorapidity acceptance in Au + Au collisions at square root(s(NN)) = 200 GeV.

A measurement of two-particle correlations with a high transverse momentum trigger particle (p(T)(trig) > 2.5 GeV/c) is presented for Au+Au collisions at square root(s(NN)) = 200 GeV over the uniquely broad longitudinal acceptance of the PHOBOS detector (-4 < Delta eta < 2). A broadening of the away-side azimuthal correlation compared to elementary collisions is observed at all Delta eta. As in p+p collisions, the near side is characterized by a peak of correlated partners at small angle relative to the trigger particle. However, in central Au+Au collisions an additional correlation extended in Delta eta and known as the "ridge" is found to reach at least |Delta eta| approximately = 4. The ridge yield is largely independent of Delta eta over the measured range, and it decreases towards more peripheral collisions. For the chosen (p(T)(trig) cut, the ridge yield is consistent with zero for events with less than roughly 100 participating nucleons.

System size, energy, and centrality dependence of pseudorapidity distributions of charged particles in relativistic heavy-ion collisions.

We present the first measurements of the pseudorapidity distribution of primary charged particles in Cu+Cu collisions as a function of collision centrality and energy, sqrt[s_{NN}]=22.4, 62.4, and 200 GeV, over a wide range of pseudorapidity, using the PHOBOS detector. A comparison of Cu+Cu and Au+Au results shows that the total number of produced charged particles and the rough shape (height and width) of the pseudorapidity distributions are determined by the number of nucleon participants. More detailed studies reveal that a more precise matching of the shape of the Cu+Cu and Au+Au pseudorapidity distributions over the full range of pseudorapidity occurs for the same N{part}/2A rather than the same N_{part}. In other words, it is the collision geometry rather than just the number of nucleon participants that drives the detailed shape of the pseudorapidity distribution and its centrality dependence at RHIC energies.

Protein supply influences the nutritional penalty associated with the development of immunity in lambs infected with Trichostrongylus colubriformis.

The influence of dietary protein supply on the nutritional penalty associated with the acquisition phase of the immune response to gastrointestinal nematodes in lambs was investigated. Groups of lambs were offered either a low-protein diet (L; 62 g metabolizable protein (MP)/kg dry matter (DM)) or high-protein diet (H; 95 g MP/kg DM) while being either infected with the equivalent of 2.000 L3 Trichostrongylus colubriformis/day (IF), similarly infected and concurrently immuno-suppressed with methylprednisolone acetate (ISIF), immuno-suppressed only (IS) or kept as uninfected controls (C). Body composition of all animals was measured on days -8 and 76 of infection using X-ray computed tomography. Temporal changes in serum phosphate and serum albumin concentrations, which provided an indicator of pathological damage, in addition to patterns of total daily nematode egg excretion and comparative worm burdens at slaughter indicated that a protective immune response was developed in H-IF, but not L-IF, H-ISIF or L-ISIF groups. Compared to their respective non-infected controls, the gross efficiency of use of metabolizable energy (ME) for net energy (NE) deposition in the carcass was reduced by 0.23 in H-IF (P < 0.05), 0.13 in H-ISIF (P > 0.05), 0.49 in L-IF (P < 0.01) and 0.23 in L-ISIF (P > 0.05). It is concluded that the reduction in ME utilization and reduced performance, which can be attributed to the immunological response, are lessened in animals offered a high-protein diet. Furthermore, evidence is presented to indicate a possible association between T. colubriformis L3 IgA antibody production and loss of performance in lambs infected with this nematode.

The effect of corticosteroid treatment on local immune responses, intake and performance in lambs infected with Teladorsagia circumcincta.

The nutritional cost of, and the sequential cellular changes associated with the developing immune response to the abomasal parasite Teladorsagia circumcincta were investigated using corticosteroid-induced immune-suppression. Six-month-old lambs with minimal nematode experience were either infected with 4000 L3 T. circumcincta per day (group IF), similarly infected and concurrently immune-suppressed with methylprednisolone acetate (group ISIF), immune-suppressed only (group IS) or remained as controls (group C). Food intake, faecal egg count (FEC) and antibody titres in plasma were recorded weekly, worm burden at necropsy on day 63 p.i. and body composition by X-ray computed tomography on days -2 and 62 p.i. Furthermore, sequential immunological changes at the site of parasite infestation in the abomasal mucosa were measured from serial biopsy tissue samples taken from additional animals that were fitted with an abomasal cannula and either infected with the same regime as IF animals above (group CnIF) or concurrently infected and immune-suppressed as above (group CnISIF). Corticosteroid treatment resulted in greater FECs (P<0.01) and worm burdens (P<0.01) in both ISIF and CnISIF compared with IF and CnIF sheep, respectively. Infection reduced feed intake by 17% between 14 and 28 days p.i. (P<0.05) and efficiency of energy utilisation by 20% (P=0.07) in IF animals but not in ISIF animals. Mast cells, globule leukocytes and IgA in tissue biopsy samples were elevated in CnIF from 42 days p.i., all of which were abrogated by corticosteroid treatment. The ability to regulate the worm population appeared to be associated with a rise in tissue IgA concentration and numbers of globule leucocytes (GL). The results support the hypothesis that a majority of the production losses that occur during infection of lambs with T. circumcincta in lambs are a consequence of the host immune response. These findings may have implications for regimes that promote the development of a strong host immune reaction to gastrointestinal parasites in lambs.

Does suckling offer protection to the lamb against Teladorsagia circumcincta infection?

This study tested the hypothesis that milk has a direct effect on the establishment of infection with Teladorsagia circumcincta, and provides information on the effects of suckling on resilience to infection in young lambs. Of 46 six-week-old twin-born lambs, one from each twin was allowed to continue suckling (S-) and its twin-weaned (W-) while both were concurrently infected with an average of either 0 (-0; n=7/group), 250 (-250; n=8/group) or 1000 (-1000; n=8/group) third stage infective larvae (L3) of T. circumcincta per day, providing six treatment groups. All groups grazed minimally contaminated pasture, and after 42 days were slaughtered for necropsy. Low pasture larval contamination was confirmed in W0 and S0 lambs by faecal egg counts (FEC) of less than 30 eggs per gram (EPG) and burdens of less than 140 worms. There was no difference in FEC between weaned and suckled lambs. Within infection regime, total worm burdens were 55-60% greater in the weaned compared with their suckled counterparts (P=0.05), and represented 27 and 17%, respectively, net establishment of larvae. The greater worm burdens of both groups of weaned animals, which compared with their suckled counterparts, and of those infected with 1000 compared with 250 larvae per day, were associated with shorter female adults that had fewer eggs in utero, perhaps indicating intra-worm population regulation, but highlighting the limitation of FEC in assessing nematode burdens of such young lambs. There was no effect of infection on live weight gain of either weaned or suckled groups and the possibility was raised that, in such young lambs, immune unresponsiveness may be responsible. The major benefit of continued milk consumption appears to lie more in providing nutrients for enhanced growth rather than in improving resilience of the lambs to infection.

System size, energy, pseudorapidity, and centrality dependence of elliptic flow.

This Letter presents measurements of the elliptic flow of charged particles as a function of pseudorapidity and centrality from Cu-Cu collisions at 62.4 and 200 GeV using the PHOBOS detector at the Relativistic Heavy Ion Collider. The elliptic flow in Cu-Cu collisions is found to be significant even for the most central events. For comparison with the Au-Au results, it is found that the detailed way in which the collision geometry (eccentricity) is estimated is of critical importance when scaling out system-size effects. A new form of eccentricity, called the participant eccentricity, is introduced which yields a scaled elliptic flow in the Cu-Cu system that has the same relative magnitude and qualitative features as that in the Au-Au system.

Association of a new SNP in promoter region of the porcine FABP3 gene with fatness traits in a polish synthetic line.

Associations between FABP3 (alternatively named H-FABP) gene polymorphisms and fatness traits were tested in two pig breeds (Polish Large White and Polish Landrace) and one synthetic line - 990. Three known single nucleotide polymorphisms, detected by HinfI, MspI and HaeIII restriction enzymes, were analyzed. Moreover, three new polymorphisms in the 5' regulatory region were identified: C(-221)T, C(-160)G and T(-158)G, but only the third one was widely distributed and correlated with backfat thickness in line 990. The obtained results suggest that the FABP3 gene is linked with an unknown gene directly affecting backfat thickness, but the analyzed polymorphisms do not influence fatness traits.

Peptides of arachnid venoms with insecticidal activity targeting sodium channels.

Arachnids have a venom apparatus and secrete a complex chemical mixture of low molecular mass organic molecules, enzymes and polypeptide neurotoxins designed to paralyze or kill their prey. Most of these toxins are specific for membrane voltage-gated sodium channels, although some may also target calcium or potassium channels and other membrane receptors. Scorpions and spiders have provided the greatest number of the neurotoxins studied so far, for which, a good number of primary and 3D structures have been obtained. Structural features, comprising a folding that determines a similar spatial distribution of charged and hydrophobic side chains of specific amino acids, are strikingly common among the toxins from spider and scorpion venoms. Such similarities are, in turn, the key feature to target and bind these proteins to ionic channels. The search for new insecticidal compounds, as well as the study of their modes of action, constitutes a current approach to rationally design novel insecticides. This goal tends to be more relevant if the resistance to the conventional chemical products is considered. A promising alternative seems to be the biotechnological approach using toxin-expressing recombinant baculovirus. Spider and scorpion toxins having insecticidal activity are reviewed here considering their structures, toxicities and action mechanisms in sodium channels of excitable membranes.

Usefulness of Toxoplasma gondii recombinant antigens (GRA1, GRA7 and SAG1) in an immunoglobulin G avidity test for the serodiagnosis of toxoplasmosis.

The precise diagnosis of an acute and recent Toxoplasma infection in pregnant women and the newborn child is important before treatment. This study describes a new Toxoplasma gondii IgG avidity test based on a combination of recombinant GRA1, GRA7 and SAG1 antigens and shows that this test is useful for diagnostic purposes and may replace the lysed, whole-cell antigens. Although more sera need to be tested, the results obtained here suggest that the IgG avidity test performed with rec-antigens correlated more with the stage of a T. gondii infection than the IgG avidity results obtained with the lysed, whole-cell antigen test, the VIDAS Toxo IgG avidity (bioMérieux).

The effect of vaccinating infection during pregnancy and dietary protein supply on the peri-parturient immune response of sheep to infection with Teladorsagia circumcincta and Trichostrongylus colubriformis larvae.

It is well established that dietary protein supply can influence the peri-parturient breakdown of immunity to nematode parasites but there is no information on the importance of exposure to nematode larvae during pregnancy for this response. We investigated this by exposing housed pregnant sheep, scanned as carrying two lambs, to a vaccinating infection with a trickle mixed infection of Teladorsagia circumcincta and Trichostrongylus colubriformis larvae (L3) or to no infection during weeks - 9 to - 4 relative to parturition. At the beginning of week - 3 all sheep were treated with anthelmintic to remove any vaccinating worm burden and from week - 2 to week +6 received a trickle challenge infection with the same nematodes. Within each vaccinating treatment there were two nutritional treatments (no. = 20 per subgroup) designed to provide 1.5 or 1.0 and 1.3 or 0.8 of metabolisable protein (MP) requirement during pregnancy and lactation, respectively. Five ewes were necropsied during weeks +1 and +3 to measure worm burdens and mucosal inflammatory cells and the remainder maintained until week +6. Serum levels of total, IgA and IgE antibodies against L3 antigen of each nematode were measured.Scanning errors and lamb losses resulted in some ewes carrying and/or rearing only one lamb. Numbers of lambs reared was therefore introduced as a treatment effect. Vaccinating infection delayed the peri-parturient rise in faecal egg count (FEC) by an average of 2 weeks but its effect on FEC during the first 6 weeks of lactation was smaller and less persistent than that of dietary MP supply and single- v. twin-suckling.Populations of both nematodes were lower in association with high MP supply, vaccination and single suckling. These changes were associated with increases in numbers of mucosal mast cells (MMC) as a result of both increased MP supply and vaccination. Evidence for a more rapid return of host ability to limit populations of the abdominal nematode T. circumcincta than of the intestinal nematode T. colubriformis was associated with fewer eosinophils and more globule leucocytes (GL) in abomasal than in intestinal tissue.None of the serum antibody isotypes was affected by dietary protein supply. Total and IgA antibodies were maintained by a current larval (vaccinating) intake. IgA titres, however, increased progressively during pregnancy, especially in twin-bearing ewes. IgE titres appeared to be sensitive primarily to the reproductive cycle itself, peaking around parturition.This work supports the conclusion that availability of MP supply influences the recruitment and activity of cells of the immune armoury of the gastro-intestinal tract to nematode parasites. The precise outcome may differ with site and/or nematode species.

System size and centrality dependence of charged hadron transverse momentum spectra in Au + Au and Cu + Cu collisions at square root of SNN = 62.4 and 200 GeV.

We present transverse momentum distributions of charged hadrons produced in Cu + Cu collisions at square root of SNN = 62.4 and 200 GeV. The spectra are measured for transverse momenta of 0.25 < pT < 5.0 GeV/c at square root of SNN = 62.4 GeV and 0.25 < pT < 7.0 GeV/c at square root of SNN = 200 GeV, in a pseudorapidity range of 0.2 < eta < 1.4. The nuclear modification factor R(AA) is calculated relative to p + p data at both collision energies as a function of collision centrality. At a given collision energy and fractional cross section, R(AA) is observed to be systematically larger in Cu + Cu collisions compared to Au + Au. However, for the same number of participating nucleons, R(AA) is essentially the same in both systems over the measured range of pT, in spite of the significantly different geometries of the Cu + Cu and Au + Au systems.

Centrality dependence of charged hadron transverse momentum spectra in Au+Au collisions from sqrt[s(NN)]=62.4 to 200 GeV.

We have measured transverse momentum distributions of charged hadrons produced in Au+Au collisions at sqrt[s(NN)]=62.4 GeV. The spectra are presented for transverse momenta 0.25