Soluble tumour necrosis factor receptors,tumour necrosis factor and interleukin-6 in serum in granulocytopenic patients with fever

Serum levels of TNF, IL-6 and soluble TNF receptors p55 and p75 (sTNFR-p55 and sTNFR-p75) were examined in 14 patients with acute myeloid leukaemia during 43 courses of chemotherapy. The patients experienced 30 episodes of fever which occurred during granulocytopenia (defined as granulocyte counts <0.2×10⁹/1) and six fever episodes when granulocyte counts were >1.0×10⁹/1. Febrile episodes were classified as microbiologically defined infection, clinically defined infection, and unexplained fever. Levels of bioactive IL-6 and immunoreactive TNF increased in response to fever during granulocytopenia, whereas bioactive TNF was not detected in any sample in this study. During granulocytopenia, both sTNFR rose significantly in microbiologically defined infection (P<0.01 for sTNFR-p55 and P<0.05 for sTNFR-p75), but not in the other two categories. The ratio of sTNFR-p55 to sTNFR-p75 was higher during febrile periods in granulocytopenia than in a non-granulocytopenic situation with granulocyte counts >1.0×10⁹/1 (P<0.01). We conclude that granulocytopenia affects release of the two sTNFR differently during febrile periods, and that release of sTNFR-p75 in response to fever is reduced during granulocytopenia, suggesting a role for the granulocytes in systemic release of sTNFR-p75.     

MgH2–CoO: a conversion-type composite electrode for LiBH4-based all-solid-state lithium ion batteries

Several studies have demonstrated that MgH₂ is a promising conversion-type anode toward Li. A major obstacle is the reversible capacity during cycling. Electrochemical co-existence of a mixed metal hydride-oxide conversion type anode is demonstrated for lithium ion batteries using a solid-state electrolyte. 75MgH₂·25CoO anodes are obtained from optimized mixing conditions avoiding reactions occurring during high-energy ball-milling. Electrochemical tests are carried out to investigate the cycling capability and reversibility of the on-going conversion reactions. The cycling led to formation of a single-plateau nanocomposite electrode with higher reversibility yield, lowered discharge–charge hysteresis and mitigated kinetic effect at high C-rate compared to MgH₂ anodes. It is believed that reduced diffusion pathways and less polarized electrodes are the origin of the improved properties. The designed composite-electrode shows good preservation and suitability with LiBH₄ solid electrolyte as revealed from electron microscopy analyses and X-ray photoelectron spectroscopy.

The findings point to a means of guided formation of MgH₂–CoO conversion-type nanocomposite electrode for all-solid-state Li-ion batteries.     

Pharmacological profile of astemizole-derived compounds at the histamine H1 and H4 receptor—H1/H4 receptor selectivity

Astemizole, a H₁R antagonist shows high affinity to the histamine H₁ receptor but only a moderate affinity to the histamine H₄ receptor. This study aims to modify the astemizole to keep high affinity to the histamine H₁ receptor and to increase affinity to the histamine H₄ receptor. Therefore, 13 astemizole-derived compounds and astemizole-JNJ7777120-derived hybrid compounds were synthesized and pharmacologically characterized at the histamine H₁ and H₄ receptors. The new compounds show affinity to the histamine H₁ receptor in the pK _i range from 5.3 to 8.8, whereas the affinity of these compounds to the histamine H₄ receptor was surprisingly rather low (pK _i from 4.4 to 5.6). Three representative compounds were docked into the histamine H₁ receptor and molecular dynamic studies were performed to explain the binding mode and the experimental results on a molecular level. Furthermore, taking into account the binding mode of compounds with high affinity to the histamine H₄ receptor, a H₁/H₄-pharmacophore hypothesis was developed.     

Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells

In this study, we explore the therapeutic potential of lapatinib a selective inhibitor of both the EGFR and HER2 tyrosine kinases for the treatment of endometrial cancer. The effect of lapatinib on tumour cell growth and receptor activation was studied in a panel of human endometrial cancer cell lines. Candidate molecular markers predicting sensitivity were assessed by baseline gene expression profiling, ELISA, and western blot analyses. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions between chemotherapeutic drugs and lapatinib. Concentration-dependent anti-proliferative effects of lapatinib were seen in all endometrial cancer cell lines tested, but varied significantly between individual cell lines (IC(50) range: 0.052-10.9 micromol). HER2 overexpression or increased expression of EGFR was significantly associated with in vitro sensitivity (P=0.024 or 0.011, respectively). Lapatinib exerts growth inhibition in a PTEN-independent manner. Sensitive cell lines also exhibited increased expression of EGFR ligands or HER3. In contrast, lapatinib-resistant cell lines exhibited high androgen receptor (AR) levels or epithelial-to-mesenchymal transition (post-EMT) features. In endometrial cancer cells, at a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for lapatinib plus carboplatin, paclitaxel, docetaxel, and doxorubicin. These observations provide a clear biologic rational to test lapatinib as a single agent or in combination with chemotherapy in endometrial cancer with HER2 overexpression. Expression of EGFR, its ligands, HER3, AR, and post-EMT markers warrant further evaluation to help define patients with HER2-nonoverexpressing endometrial cancer most likely to benefit from lapatinib.     

Affinity determinations of purified IgE and IgG antibodies against the major pollen allergens Phl p 5a and Bet v 1a: discrepancy between IgE and IgG binding strength

Allergen-specific IgE and IgG antibodies coexist in allergic individuals, but only IgE has anaphylactogenic capacity. This study aimed to determine the association, dissociation and equilibrium constants for the interaction of allergen-specific IgE and IgG with the major grass and birch pollen allergens Phl p 5a and Bet v 1a. We isolated specific IgE and IgG antibodies from pollen allergic patients' sera by a two-step affinity chromatography protocol and controlled the high purity in a recombinant allergen chip microarray. Surface plasmon resonance measurements of polyclonal IgE and IgG species revealed that their affinities diverge widely, being in the range of 10(-10) and 10(-11) M for IgE, but only 10(-6)-10(-7) M for IgG. Moreover, murine monoclonal IgG1 antibodies against the allergens showed affinities of 10(-7)-10(-8) M. Thus, we conclude from our data that even stringently affinity matured IgG cannot score the superior affinity of IgE antibodies to allergens.     

Stretch reflex variation in the relaxed and the pre-activated quadriceps muscle of normal humans

The stretch reflex to patellar tendon taps was quantified by force measurements at the ankle in 7 normal subjects. In each experiment the stretch reflex was elicited from 14 consecutive stretches by two types of hammers (an ordinary hand-held hammer and a motorized hammer) in the relaxed and the pre-activated quadriceps muscle. The coefficient of variation for the 14 stretch reflexes fell from 54% in the relaxed muscle to 39% in the contracting muscle (p less than 0.05). The stretch reflex varied less between the different levels of active contraction than between the relaxed state and the contracted level (p less than 0.05). The experiment was repeated in all subjects and at all contraction levels. The coefficient of variation of the mean for the two experiments fell non-significantly from a mean value of 27% in the relaxed muscle to 14% in the contracting muscle. The coefficients of variation for the two hammers were almost identical. It is concluded that quantification of the stretch reflex can be made more precisely in the contracting muscle.     

Quantitative-morphometric aspects of bergmann glial (Golgi epithelial) cell development in rats

Summary Bergmann glial (Golgi epithelial) cells in the cerebella of rats of various ages were stained by the rapid Golgi technique, and their radial stem processes were measured for length and diameter. Additionally, the average number of such processes per cell was counted, and the development of bushy lateral protrusions was quantified. The length of radial processes—depending on the thickness of the molecular layer—was found to increase up to the end of the 2nd year of life. This elongation was accompanied by a reduction of the mean process diameter which was, however, not sufficient to prevent an increase in the cytoplasmic volume of the elongating cells. A marked outgrowth of lateral protrusions was observed up to at least the 5th month of life. These data are compared with earlier findings on the development of rat brain stem fetal radial glia, and of rabbit retinal Müller cells. Common mechanisms of glial cell development are discussed.