The efficacy and safety of early supplementation of iron polymaltose complex in preterm infants

The purpose of this study was to examine the efficacy and safety of early nonionic iron supplementation in preterm infants. Infants with gestational age < or = 32 weeks who were fed enriched human milk were assigned concurrently to receive 5 mg/kg/d enteral iron polymaltose complex (IPC) at 2 or 4 weeks of age. The levels of hemoglobin, reticulocytes, serum iron, ferritin, and soluble transferrin receptor were recorded at 2, 4, and 8 weeks of age. The incidence of morbidities associated with prematurity and the need for red blood cell transfusions (RBCTs) were recorded. The 2-week group (n = 32) had a better iron status than the 4-week group (n = 36) at 4 weeks and at 8 weeks of age. The incidence of morbidities associated with prematurity was not different among the groups ( P = 0.26). RBCT was required in one infants of the 2-week group and in 10 infants in the 4-week group ( P = 0.045). The number needed to treat to prevent one RBCT was five. Supplementation of 5 mg/kg/d enteral IPC to preterm infants fed enriched human milk as early as 2 weeks of age was more beneficial to iron status than at 4 weeks of age, and was associated with decreased need for RBCTs and no increase in the incidence of morbidities associated with prematurity.     

Accuracy of Quadratic Versus Linear Interpolation in Noninvasive Electrocardiographic Imaging (ECGI)

Electrocardiographic Imaging (ECGI) is a cardiac functional imaging modality, noninvasively reconstructing epicardial potentials, electrograms and isochrones (activation maps) from multi-channel body surface potential recordings. The procedure involves solving Laplace’s equation in the source-free volume conductor between torso and epicardial surfaces, using Boundary Element Method (BEM). Previously, linear interpolation (LI) on three-noded triangular surface elements was used in the BEM formulation. Here, we use quadratic interpolation (QI) for potentials over six-noded linear triangles. The performance of LI and QI in ECGI is evaluated through direct comparison with measured data from an isolated canine heart suspended in a human-torso-shaped electrolyte tank. QI enhances the accuracy and resolution of ECGI reconstructions for two different inverse methods, Tikhonov regularization and Generalized Minimal Residual (GMRes) method, with the QI-GMRes combination providing the highest accuracy and resolution. QI reduces the average relative error (RE) between reconstructed and measured epicardial potentials by 25%. It preserves the amplitude (average RE reduced by 48%) and morphology of electrograms better (average correlation coefficient for QI ∼ 0.97, LI ∼ 0.92). We also applied QI to ECGI reconstructions in human subjects during cardiac pacing, where QI locates ventricular pacing sites with higher accuracy (≤ 10 mm) than LI (≤ 18 mm).     

Candidate genes associated with ageing and life expectancy in the Jerusalem longitudinal study

In an exploratory study, 11 common polymorphisms were examined for contributing to longevity including: apolipoprotein E (apoE), methylenetetrahydrofolate reductase (MTHFR), cathepsin D (CAD), superoxide dismutase 2 (SOD2), angiotensinogen (AGT) and insulin-like growth factor 2 (IGF2), Leiden factor 7, p53 oncogene, dopamine D4 receptor (DRD4) and the serotonin transporter (SERT). Genotype and allele frequencies of these genes were compared in 224 older (75 years) Jewish Jerusalem residents of Ashkenazi ethnicity to a group of 441 younger subjects (22 years). Nominally significant results provide suggestive evidence in the Ashkenazi group that apoE, MHTFR, SOD2, IGF2 ApaI, and factor VII are risk factors for a single outcome, survival to 75. Overall, the more genetically homogenous Ashkenazi ethnic group showed evidence for association in five genes examined suggesting that future studies in this population would gainfully focus on this ethnic group.     

Enhanced excitability compensates for high-pressure-induced depression of cortical inputs to the hippocampus

High pressure (>1.0 MPa) induces the high-pressure neurological syndrome (HPNS) characterized by increased excitability of the CNS and cognitive impairments involving memory disorders. The perforant-path transfer of cortical information to the hippocampal formation is important for memory acquisition. High pressure may alter information transfer in this connection. We used rat corticohippocampal slices for studying the effect of pressure on the transfer function between synaptic inputs from the medial perforant path (MPP) and spike generation by granule cells (GC) of the dentate gyrus. High pressure (10.1 MPa) reduced single MPP field excitatory postsynaptic potential (fEPSP) amplitude and slope by nearly 50%. Field antidromic action potentials (AAPs) elicited by stimulation of GC axons, and population spike (PS) generation by the pressure-depressed MPP fEPSP were not significantly altered at hyperbaric conditions. Nevertheless the relationship PS/fEPSP increased at high pressure, indicating dendritic hyperexcitability in the GC. PSs elicited by paired-pulse MPP fEPSPs at 10- to 200-ms interstimulus intervals and PS generated by trains of five fEPSPs at 25 Hz were also not affected in spite of severe pressure-induced synaptic depression. Similarly, trains of AAPs at 25-50 Hz were not significantly changed. Trains of fEPSPs at higher frequency (50 Hz), however, induced additional spikes at high pressure, indicating pressure disruption of the regular low-pass filter properties of the DG. Such effect was closely mimicked by partial blockade of GABAA inhibition. High pressure depresses synaptic activity while increases excitability in the neuronal dendrites but not in the axons. This mechanism, allowing neuronal communication at low input signals, may partially cope with pressure effects at the low frequency range (<25 Hz) but losses reliability at higher frequencies (>50 Hz).     

ZnT-1 protects HL-1 cells from simulated ischemia–reperfusion through activation of Ras–ERK signaling

Activation of ERK signaling may promote cardioprotection from ischemia-reperfusion (I/R) injury. ZnT-1, a protein that confers resistance from zinc toxicity, was found to interact with Raf-1 kinase through its C-terminal domain, leading to downstream activation of ERK. In the present study, we evaluated the effects of ZnT-1 in cultured murine cardiomyocytes (HL-1 cells) that were exposed to simulated-I/R. Cellular injury was evaluated by lactate dehydrogenase (LDH) release and by staining for pro-apoptotic caspase activation. Overexpression of ZnT-1 markedly reduced LDH release and caspase activation following I/R. Knockdown of endogenous ZnT-1 augmented the I/R-induced release of LDH and increased caspase activation following I/R. Phospho-ERK levels were significantly increased following I/R in cells overexpressing ZnT-1, while knockdown of ZnT-1 reduced phospho-ERK levels. Pretreatment of cells with the MEK inhibitor PD98059 abolished the protective effect of ZnT-1 following I/R. Accordingly, a truncated form of ZnT-1 lacking the C-terminal domain failed to induce ERK activation and did not protect the cells from I/R injury. In contrast, expression of the C-terminal domain by itself was sufficient to induce ERK activation and I/R protection. Interestingly, the C-terminal of the ZnT-1 did not have protective effect against the toxicity of zinc. In the isolated rat heart, global ischemic injury rapidly increased the endogenous levels of ZnT-1. However, following reperfusion ZnT-1 levels were found to be decreased. Our findings indicate that ZnT-1 may have important role in the ischemic myocardium through its ability to interact with Raf-1 kinase.     

Attitudes of significant others of people with Ménière's disease vary from coping to victimization

Objective: To explore the impact, reactions and coping methods of the significant others (SOs) of people with Ménière's disease (MD). Design: SOs of people with MD were asked to answer open-ended questions reporting the ‘life effects’ and ‘positive experiences’ they have had as a result of the partner's condition. The replies to the ‘life effects’ question was categorized using the WHO-ICF framework. The responses of ‘life effects’ from this study and the ‘positive experiences’ reported in a recent study (Manchaiah et al, 2013 Manchaiah V.K.C., Pyykkö, I., Kentala E., Levo H. &; Stephens D. 2013. Positive impact of Ménière's disorder on significant others as well as on patients: Our experience from eighty-eight respondents. Clin Otol, 38, 550–554.[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]) were evaluated with K-means clustering analysis. Study sample: Eighty-eight SOs (42 male, 42 female, and four did not state gender). Results: While the SOs mainly listed their own problems, a significant number of responses related to the problems of their partner. Personal perspectives tended to focus on the consequences of their partner's condition, whereas in perspectives of their partner they focussed on his/her symptoms. Further, replies from 81 SOs were used in evaluation of responses and were classified into four categories: constrained life attitude; disease burden attitude; care and support attitude; and social isolation attitude. Conclusions: The results of this study support the importance of including the SO of people with MD in the rehabilitation process.     

In-silico cell surface modeling reveals mechanism for initial steps of B-cell receptor signal transduction

Ligand binding to B-cell receptors (BcRs) on the B-cell surface induces crosslinking and phosphorylation of BCRs by the Src family kinases, followed by initiation of signaling. Although the nature of the earliest events following receptor engagement is currently under intensive investigation, the precise connection between crosslinking and the signaling cascade triggering has thus far remained unclear.Using a novel multiscale, agent-based simulation of B-cell surface dynamics, we present a coherent quantitative analysis of the initial stages of B-cell activation following ligand presentation. The simulation reproduces experimental results of H³ uptake, immunoglobulin secretion, immunoelectron photomicrography and FRET. While merging multiple experimental techniques, the simulation captures all essential events in the first twenty seconds following ligand presentation, and is used to make predictions on subsequent molecular events. We show that B-cell activation is mediated through a positive feedback loop between Lyn and ITAM phosphorylation, but that specificity is achieved through a combination of BcR spatial segregation and BcR selective partitioning within lipid rafts following clustering.     

A randomized prospective study on the effect of short and long Buserelin treatment in women with repeated unsuccessful in vitro fertilization (IVF) cycles due to inadequate ovarian response

Fifty four women with repeated unsuccessful in vitro fertilization (IVF) cycles due to inadequate ovarian response to stimulation with human menopausal gonadotropins (hMG) participated in this study. They were randomized to receive either gonadotropin releasing hormone agonist (GNRHa), Buserelin, prior to and during induction of ovulation by hMG (Group I—long protocol), or GnRHa starting on the first day of the cycle together with induction of ovulation by hMG (Group II—short protocol). Mean follicular phase serum luteinizing hormone (LH) and progesterone (P) levels were significantly lower in Group I than in Group II (P<0.01). Cancellation rate was significantly lower in Group I than in Group II (P<0.01). The long GNRHa protocol resulted in statistically significant lower cancellation rates, more oocytes per pickup (OPU), more embryos trans-ferred per patient, and a higher pregnancy rate. Significantly more hMG ampoules and more treatments days were required in the long GNRHa protocol. Our data demonstrate that the use of GNRHa prior to and during ovarian stimulation with hMG offers a very good alternative for patients with repetitive unsuccessful IVF cycles due to inadequate response.     

Cytotoxic and antitumor activity of a recombinant immunotoxin composed of disulfide-stabilized anti-TAC Fv fragment and truncated pseudomonas exotoxin

Disulfide-stabilized Fv (dsFv)-immunotoxins are recombinant immunotoxins in which the inherently unstable Fv moiety, composed of the V_H-V_L heterodimer, is stabilized by a disulfide bond engineered between structurally conserved framework positions of V_H and V_L. Anti-Tac(dsFv)-PE38KDEL is composed of such a dsFv, directed to the α subunit of the IL2 receptor (IL2R), and containing a truncated form of Pseudomonas exotoxin (PE38KDEL). We have found this new type of immunotoxin to be indistinguishable in its in vitro activity and specificity from its single-chain immunotoxin counterpart, anti-Tac(Fv)-PE38KDEL. We have now examined the therapeutically relevant factors, including stability, pharmacokinetics, and antitumor activity of this new disulfide-stabilized Fv-immunotoxin. We found that anti-Tac(dsFv)-PE38KDEL was specifically cytotoxic to human activated T-lymphocytes in addition to IL2R bearing cell lines. Anti-Tac(dsFv)-PE38KDEL was considerably more stable at 37° C in human serum and in buffered saline than the single-chain immunotoxin, anti-Tac(Fv)-PE38KDEL. The half-life in blood was similar for both immunotoxins (approx. 20 min). The therapeutic potential of the disu Hide-stabilized immunotoxin was evaluated using an animal model of immunodeficient mice bearing subcutaneous tumor xenografts of human IL2R-bearing cells. Anti-Tac(dsFv)-PE38KDEL caused complete regression of tumors with no toxic effects in mice. Because dsFv-immunotoxins are more stable and can be produced with significantly improved yields compared to scFv-immunotoxins, dsFv-immunotoxin may be more useful for therapeutic applications. © 1994 Wiley-Liss, Inc.