Adherence to therapy among liver transplant patients as related to depression, anxiety, acceptance of the disease, and social support.

OBJECTIVE: This study aimed to assess the patients' adherence to therapeutic regimens after liver transplantation, taking into account the levels of depression and anxiety, acceptance of the disease, and social support. PATIENTS AND METHODS: The study group included N = 112 patients selected from 669 patients after liver transplantation. The Delphi method was used to develop a tool to assess the level of adherence to treatment regimens. The sources of data for this study were recommendations and the work of an expert panel. The next method used in the study was a diagnostic survey based on the following standardized research instruments: Inventory of Socially Supportive Behaviors (ISSB), Acceptance of Illness Scale (AIS), Beck Depression Inventory-II (BDI-II) and State-Trait Anxiety Inventory (STAI). RESULTS: The study group showed a medium level of adherence to therapeutic recommendations (6.8 ± 1.85). We observed a statistically significant positive correlation between acceptance of the disease and adherence to therapeutic recommendations (r = -0.20, t = -2.040, p = 0.044). Among the factors analyzed, six predictors were identified that significantly affect the level of adherence to therapeutic recommendations in a group of liver transplant patients. CONCLUSIONS: 1. Patients who accept their disease are a group of people who significantly worse adhere to therapeutic recommendations. 2. The main positive predictors of treatment adherence in the group of transplant patients are the search for various sources of information and declarative adherence to treatment recommendations. Negative predictors include the duration of the disease, side effects of the applied treatment, and comorbidities. 3. The patients who were informed that results depend on regular medication intake significantly more often followed therapeutic recommendations.

Comparison of the risk of cardiovascular diseases, stroke, and diabetes among the selected group of football referees and the group of general population men from Northern Poland - a pilot study.

OBJECTIVE: We aimed at comparing the total body fat and visceral adipose tissue content in football referees and in the control group of general population men. An assessment of compliance with health promoting behavior in both groups was carried out. PATIENTS AND METHODS: This study, conducted in Northern Poland, involved 112 men. The study group comprised 56 men, football referees. The control group consisted of randomly chosen general population men, not engaged in any sport activities. Assessment of compliance with health promoting behavior among football referees and general population men was based on ultrasound imaging using the BodyMetrix System device (IntelaMetrix, Poland). The study employed a survey questionnaire comprised of the original section and two standardized questionnaires: the Health Behavior Inventory (HBI) and the NEO-Five Factor Inventory (NEO-FFI): the Health Behavior Inventory (HBI) and the NEO-Five Factor Inventory (NEO-FFI). RESULTS: The visceral adipose tissue content in the study group (football referees) was found to be low, and the excess of body fat was 0-0.25 kg. In the control group, the trunk fat volume was found to be higher by more than 8% as compared with the study group. Also, the level of visceral adipose tissue was high, and the excess of body fat was 0-4 kg. CONCLUSIONS: Thanks to properly planned and systematically continued physical activity, despite non-compliance with certain pro-health principles (increased sweet supply and consumption of alcoholic beverages), football referees are characterized by the correct body fat volume and low level of visceral adipose tissue. The parameters were found to be markedly higher in the control group of randomly selected men from the general population. The risk of diabetes, stroke, and cardiovascular diseases among football referees was found to be very low.

Magnesium isotopes of the bulk solar wind from Genesis diamond-like carbon films.

NASA's Genesis Mission returned solar wind (SW) to the Earth for analysis to derive the composition of the solar photosphere from solar material. SW analyses control the precision of the derived solar compositions, but their ultimate accuracy is limited by the theoretical or empirical models of fractionation due to SW formation. Mg isotopes are "ground truth" for these models since, except for CAIs, planetary materials have a uniform Mg isotopic composition (within ≤1‰) so any significant isotopic fractionation of SW Mg is primarily that of SW formation and subsequent acceleration through the corona. This study analyzed Mg isotopes in a bulk SW diamond-like carbon (DLC) film on silicon collector returned by the Genesis Mission. A novel data reduction technique was required to account for variable ion yield and instrumental mass fractionation (IMF) in the DLC. The resulting SW Mg fractionation relative to the DSM-3 laboratory standard was (-14.4‰, -30.2‰) ± (4.1‰, 5.5‰), where the uncertainty is 2Æ¡ SE of the data combined with a 2.5‰ (total) error in the IMF determination. Two of the SW fractionation models considered generally agreed with our data. Their possible ramifications are discussed for O isotopes based on the CAI nebular composition of McKeegan et al. (2011).

Electron Microprobe/SIMS Determinations of Al in Olivine: Applications to Solar Wind, Pallasites and Trace Element Measurements.

Electron probe microanalyzer measurements of trace elements with high accuracy are challenging. Accurate Al measurements in olivine are required to calibrate SIMS implant reference materials for measurement of Al in the solar wind. We adopt a combined EPMA/SIMS approach that is useful for producing SIMS reference materials as well as for EPMA at the ~100 µg g-1 level. Even for mounts not polished with alumina photoelectron spectroscopy shows high levels of Al surface contamination. In order to minimize electron beam current density, a rastered 50 × 100 µm electron beam was adequate and minimized sensitivity to small Al-rich contaminants. Reproducible analyses of eleven SIMS-cleaned spots on San Carlos olivine agreed at 69.3 ± 1.0 µg g-1• The known Al mass fraction was used to calibrate an Al implant into San Carlos. Accurate measurements of Al were made for olivines in the pallasites: lmilac, Eagle Station and Springwater. Our focus was on Al in olivine, but our technique could be refined to give accurate electron probe measurements for other contamination-sensitive trace elements. For solar wind, it is projected that the Al/Mg abundance ratio can be determined to 6%, a factor of 2 more precise than the solar spectroscopic ratio.

The future of Genesis science.

Solar abundances are important to planetary science since the prevalent model assumes that the composition of the solar photosphere is that of the solar nebula from which planetary materials formed. Thus, solar abundances are a baseline for planetary science. Previously, solar abundances have only been available through spectroscopy or by proxy (CI). The Genesis spacecraft collected and returned samples of the solar wind for laboratory analyses. Elemental and isotopic abundances in solar wind from Genesis samples have been successfully measured despite the crash of the re-entry capsule. Here we present science rationales for a set of 12 important (and feasible postcrash) Science and Measurement Objectives as goals for the future (Table 1). We also review progress in Genesis sample analyses since the last major review (Burnett 2013). Considerable progress has been made toward understanding elemental fractionation during the extraction of the solar wind from the photosphere, a necessary step in determining true solar abundances from solar wind composition. The suitability of Genesis collectors for specific analyses is also assessed. Thus far, the prevalent model remains viable despite large isotopic variations in a number of volatile elements, but its validity and limitations can be further checked by several Objectives.

DETERMINING THE ELEMENTAL AND ISOTOPIC COMPOSITION OF THE PRESOLAR NEBULA FROM GENESIS DATA ANALYSIS: THE CASE OF OXYGEN.

We compare element and isotopic fractionations measured in solar wind samples collected by NASA's Genesis mission with those predicted from models incorporating both the ponderomotive force in the chromosphere and conservation of the first adiabatic invariant in the low corona. Generally good agreement is found, suggesting that these factors are consistent with the process of solar wind fractionation. Based on bulk wind measurements, we also consider in more detail the isotopic and elemental abundances of O. We find mild support for an O abundance in the range 8.75 - 8.83, with a value as low as 8.69 disfavored. A stronger conclusion must await solar wind regime specific measurements from the Genesis samples.

Catechol-oxide-methyltransferase (COMT rs4680:G>A) gene polymorphism does not affect analgesics' demand after elective hip replaceme.

Pain in patients with hip osteoarthritis appears long before surgery, and requires effective management as it affects patient comfort and daily activities. Therefore, the search for factors influencing response rate to analgesics is mandatory. In recent years, increasing attention has been paid to genetic factors underlying pain threshold and treatment efficacy. Polymorphic gene of catechol-oxide-methyltransferase (COMT) is a candidate gene associated with pain pathology and treatment response. The aim of the study was to evaluate association between the COMT rs4680:G>A polymorphism and demand for analgesics in patients subjected to elective hip replacement. The study included 196 patients after hip replacement surgery. Opioid demand was recorded and analgesic efficacy was scored using a four-level verbal pain intensity scale. COMT rs4680:G>A polymorphism was analysed by PCR-RFLP method. The studied COMT genotypes did not influence opioid administration in the studied patients from the day of surgery till day 6 afterwards. The distribution of the COMT rs4680:G>A in the studied subjects was as follows: GA­52.04%, AA­23.98% and GG­23.98%. It can be concluded that the COMT rs4680:G>A polymorphism is not associated with opioid demand in patients after elective hip replacement.

The oxygen isotopic composition of the Sun inferred from captured solar wind.

All planetary materials sampled thus far vary in their relative abundance of the major isotope of oxygen, (16)O, such that it has not been possible to define a primordial solar system composition. We measured the oxygen isotopic composition of solar wind captured and returned to Earth by NASA's Genesis mission. Our results demonstrate that the Sun is highly enriched in (16)O relative to the Earth, Moon, Mars, and bulk meteorites. Because the solar photosphere preserves the average isotopic composition of the solar system for elements heavier than lithium, we conclude that essentially all rocky materials in the inner solar system were enriched in (17)O and (18)O, relative to (16)O, by ~7%, probably via non-mass-dependent chemistry before accretion of the first planetesimals.

A 15N-poor isotopic composition for the solar system as shown by Genesis solar wind samples.

The Genesis mission sampled solar wind ions to document the elemental and isotopic compositions of the Sun and, by inference, of the protosolar nebula. Nitrogen was a key target element because the extent and origin of its isotopic variations in solar system materials remain unknown. Isotopic analysis of a Genesis Solar Wind Concentrator target material shows that implanted solar wind nitrogen has a (15)N/(14)N ratio of 2.18 ± 0.02 × 10(-3) (that is, ≈40% poorer in (15)N relative to terrestrial atmosphere). The (15)N/(14)N ratio of the protosolar nebula was 2.27 ± 0.03 × 10(-3), which is the lowest (15)N/(14)N ratio known for solar system objects. This result demonstrates the extreme nitrogen isotopic heterogeneity of the nascent solar system and accounts for the (15)N-depleted components observed in solar system reservoirs.

Non-hepatic hyperammonaemia: an important, potentially reversible cause of encephalopathy.

The clinical syndrome of encephalopathy is most often encountered in the context of decompensated liver disease and the diagnosis is usually clear cut. Non-hepatic causes of encephalopathy are rarer and tend to present to a wide range of medical specialties with variable and episodic symptoms. Delay can result in the development of potentially life threatening complications, such as seizures and coma. Early recognition is vital. A history of similar episodes or clinical risk factors and early assessment of blood ammonia levels help establish the diagnosis. In addition to adequate supportive care, investigation of the underlying cause of the hyperammonaemia is essential and its reversal, where possible, will often result in complete recovery. Detection of an unborn error of metabolism should lead to the initiation of appropriate maintenance therapy and genetic counselling.

Identification of a selective nonpeptide antagonist of the anaphylatoxin C3a receptor that demonstrates antiinflammatory activity in animal models.

The anaphylatoxin C3a is a potent chemotactic peptide and inflammatory mediator released during complement activation which binds to and activates a G-protein-coupled receptor. Molecular cloning of the C3aR has facilitated studies to identify nonpeptide antagonists of the C3aR. A chemical lead that selectively inhibited the C3aR in a high throughput screen was identified and chemically optimized. The resulting antagonist, N(2)-[(2,2-diphenylethoxy)acetyl]-L-arginine (SB 290157), functioned as a competitive antagonist of (125)I-C3a radioligand binding to rat basophilic leukemia (RBL)-2H3 cells expressing the human C3aR (RBL-C3aR), with an IC(50) of 200 nM. SB 290157 was a functional antagonist, blocking C3a-induced C3aR internalization in a concentration-dependent manner and C3a-induced Ca(2+) mobilization in RBL-C3aR cells and human neutrophils with IC(50)s of 27.7 and 28 nM, respectively. SB 290157 was selective for the C3aR in that it did not antagonize the C5aR or six other chemotactic G protein-coupled receptors. Functional antagonism was not solely limited to the human C3aR; SB 290157 also inhibited C3a-induced Ca(2+) mobilization of RBL-2H3 cells expressing the mouse and guinea pig C3aRS: It potently inhibited C3a-mediated ATP release from guinea pig platelets and inhibited C3a-induced potentiation of the contractile response to field stimulation of perfused rat caudal artery. Furthermore, in animal models, SB 290157, inhibited neutrophil recruitment in a guinea pig LPS-induced airway neutrophilia model and decreased paw edema in a rat adjuvant-induced arthritis model. This selective antagonist may be useful to define the physiological and pathophysiological roles of the C3aR.

Discovery of potent and selective phenylalanine derived CCR3 antagonists. Part 1.

The discovery of a series of phenylalanine derived CCR3 antagonists is reported. Parallel, solution-phase library synthesis has been utilized to delineate the structure-activity relationship leading to the synthesis of highly potent, CCR3-selective antagonists.

Identification of potent, selective non-peptide CC chemokine receptor-3 antagonist that inhibits eotaxin-, eotaxin-2-, and monocyte chemotactic protein-4-induced eosinophil migration.

Eosinophils have been implicated in the pathogenesis of asthma and other allergic diseases. Several CC chemokines including eotaxin (CCL-11), eotaxin-2 (CCL-24), RANTES (CCL-5), and monocyte chemotactic protein-3 (MCP-3, CCL-7) and 4 (MCP-4, CCL-13) are potent eosinophil chemotactic and activating peptides acting through CC chemokine receptor-3 (CCR3). Thus, antagonism of CCR3 could have a therapeutic role in asthma and other eosinophil-mediated diseases. A high throughput, cellular functional screen was configured using RBL-2H3 cells stably expressing CCR3 (RBL-2H3-CCR3) to identify non-peptide receptor antagonists. A small molecule CCR3 antagonist was identified, SK&F 45523, and chemical optimization led to the generation of a number of highly potent, selective CCR3 antagonists including SB-297006 and SB-328437. These compounds were further characterized in vitro and demonstrated high affinity, competitive inhibition of (125)I-eotaxin and (125)I-MCP-4 binding to human eosinophils. The compounds were potent inhibitors of eotaxin- and MCP-4-induced Ca(2+) mobilization in RBL-2H3-CCR3 cells and eosinophils. Additionally, SB-328437 inhibited eosinophil chemotaxis induced by three ligands that activate CCR3 with similar potencies. Selectivity was affirmed using a panel of 10 seven-transmembrane receptors. This is the first description of a non-peptide CCR3 antagonist, which should be useful in further elucidating the pathophysiological role of CCR3 in allergic inflammatory diseases.

Inositol stereoisomers stabilize an oligomeric aggregate of Alzheimer amyloid beta peptide and inhibit abeta -induced toxicity.

Inositol has 8 stereoisomers, four of which are physiologically active. myo-Inositol is the most abundant isomer in the brain and more recently shown that epi- and scyllo-inositol are also present. myo-Inositol complexes with Abeta42 in vitro to form a small stable micelle. The ability of inositol stereoisomers to interact with and stabilize small Abeta complexes was addressed. Circular dichroism spectroscopy demonstrated that epi- and scyllo- but not chiro-inositol were able to induce a structural transition from random to beta-structure in Abeta42. Alternatively, none of the stereoisomers were able to induce a structural transition in Abeta40. Electron microscopy demonstrated that inositol stabilizes small aggregates of Abeta42. We demonstrate that inositol-Abeta interactions result in a complex that is non-toxic to nerve growth factor-differentiated PC-12 cells and primary human neuronal cultures. The attenuation of toxicity is the result of Abeta-inositol interaction, as inositol uptake inhibitors had no effect on neuronal survival. The use of inositol stereoisomers allowed us to elucidate an important structure-activity relationship between Abeta and inositol. Inositol stereoisomers are naturally occurring molecules that readily cross the blood-brain barrier and may represent a viable treatment for AD through the complexation of Abeta and attenuation of Abeta neurotoxic effects.

Shedding of TNF receptors in multiple sclerosis patients.

OBJECTIVE: To evaluate the rate of shedding of tumor necrosis factor (TNF) receptors (TNFRs) in MS patients. BACKGROUND: It was previously suggested that TNF might play a significant role in the immunopathologic mechanism of MS. TNF mediates its biologic effects by interacting with two distinct receptors: TNFR-p55 and TNFR-p75. Both of these receptors exist in soluble and membrane-bound forms. Soluble receptors have been shown to influence TNF activity in vitro and in vivo and maintain balance between active, free TNF and inactive form of this cytokine bound to its soluble receptors. METHODS: In the current study, the authors measured shedding of TNFRs from cell surface of peripheral blood mononuclear cells, peripheral blood lymphocytes, and monocytes in three groups of MS patients: relapsing-remitting in relapse, relapsing-remitting in remission, and chronic progressive. RESULTS: The authors observed a significant distortion in generation of both soluble TNF receptors. Whereas the TNFR-p55 was shed at lower rate compared with healthy volunteers, the shedding of TNFR-p75 was significantly higher in MS patients. CONCLUSION: Disturbance in TNFR shedding might contribute to the distortion of a fine balance between circulating TNF and its natural inhibitors in MS.

Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits interleukin-8-induced neutrophil migration.

Interleukin-8 (IL-8) and closely related Glu-Leu-Arg (ELR) containing CXC chemokines, including growth-related oncogene (GRO)alpha, GRObeta, GROgamma, and epithelial cell-derived neutrophil-activating peptide-78 (ENA-78), are potent neutrophil chemotactic and activating peptides, which are proposed to be major mediators of inflammation. IL-8 activates neutrophils by binding to two distinct seven-transmembrane (7-TMR) G-protein coupled receptors CXCR1 (IL-8RA) and CXCR2 (IL-8RB), while GROalpha, GRObeta, GROgamma, and ENA-78 bind to and activate only CXCR2. A chemical lead, which selectively inhibited CXCR2 was discovered by high throughput screening and chemically optimized. SB 225002 (N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea) is the first reported potent and selective non-peptide inhibitor of a chemokine receptor. It is an antagonist of 125I-IL-8 binding to CXCR2 with an IC50 = 22 nM. SB 225002 showed >150-fold selectivity over CXCR1 and four other 7-TMRs tested. In vitro, SB 225002 potently inhibited human and rabbit neutrophil chemotaxis induced by both IL-8 and GROalpha. In vivo, SB 225002 selectively blocked IL-8-induced neutrophil margination in rabbits. The present findings suggest that CXCR2 is responsible for neutrophil chemotaxis and margination induced by IL-8. This selective antagonist will be a useful tool compound to define the role of CXCR2 in inflammatory diseases where neutrophils play a major role.

MHC class I-restricted lysis of human oligodendrocytes by myelin basic protein peptide-specific CD8 T lymphocytes.

Multiple sclerosis (MS) is considered to be an autoimmune disease that is directed either at myelin or at its cell of origin, the oligodendrocytes (OL). The inflammatory lesions in the central nervous system contain multiple myelin Ag-restricted and nonrestricted cell populations with the potential to mediate tissue injury. Previous studies indicate that it is possible to generate MHC class I-restricted myelin peptide-specific cytotoxic CD8 T cells, and that human adult OLs express MHC class I molecules in vitro. The purpose of this study was to demonstrate that myelin basic protein peptide-specific CD8 T cells could induce OL injury. We generated CD8 T cell lines from six healthy donors and five MS patients, and all cell lines were HLA-A2 positive. The obtained CD8 cell lines induced lysis of HLA-A2- but not HLA-A3-transfected HMy2.C1R cells in the presence of myelin basic protein peptide 110-118. In the absence of exogenous peptide, the CD8 T cell lines were cytotoxic to HLA-A2 but not to non-HLA-A2 OLs. Cytotoxicity was blocked with anti-MHC class I-blocking Ab. These results support the postulate that autoreactive CD8 cytotoxic T cells can contribute to the tissue injury in MS.