Changes in inflammatory activity,heart rate variability,and biochemical indices in young athletes during the annual training cycle

Inflammatory activity, heart rate variability (HRV), and biochemical and functional indices were assessed in young ski racers during the preparation, competition, and recovery periods of an annual training cycle. During the preparation period, autohemodilution (decreased red blood cell count (RBC) and hematocrit (Ht) levels) and a decrease in the systemic inflammatory activity (C-reactive protein) occurred, without significant differences in the HRV or serum protein and lipid profile. During the competition period, the systemic inflammatory activity increased by 50% (p = 0.047), eliminating differences from the control group, and the HRV indices (SDNN, HF, TP, and IT) decreased (p ≤ 0.013), indicating an increase in the sympathetic effects on the HRV. During the recovery period, hematological indices (Ht and RBC), inflammatory activity, and fibrinogen levels decreased, and the parasympathetic effects on the heart increased. These findings allowed us to conclude that mental and physical activation led to a moderate increase in the systemic inflammatory activity and a shift in the sympathovagal balance towards increased sympathetic activity, providing a nonspecific contribution to the physiological regulation of biochemical (lipoproteins and immunoglobulins) and hematological indices in the athletes. However, similar changes in many biochemical and hematological indices in both groups during the year indicated the important role of a common, probably seasonal, factor in the regulation.     

Prevention of cardiolipin oxidation and fatty acid cycling as two antioxidant mechanisms of cationic derivatives of plastoquinone (SkQs)

The present state of the art in studies on the mechanisms of antioxidant activities of mitochondria-targeted cationic plastoquinone derivatives (SkQs) is reviewed. Our experiments showed that these compounds can operate as antioxidants in two quite different ways, i.e. (i) by preventing peroxidation of cardiolipin [Antonenko et al., Biochemistry (Moscow) 73 (2008) 1273–1287] and (ii) by fatty acid cycling resulting in mild uncoupling that inhibits the formation of reactive oxygen species (ROS) in mitochondrial State 4 [Severin et al. Proc. Natl. Acad. Sci. USA 107 (2009), 663–668]. The quinol and cationic moieties of SkQ are involved in cases (i) and (ii), respectively. In case (i) SkQH₂ interrupts propagation of chain reactions involved in peroxidation of unsaturated fatty acid residues in cardiolipin, the formed SkQ^? being reduced back to SkQH₂ by heme b_H of complex III in an antimycin-sensitive way. Molecular dynamics simulation showed that there are two stable conformations of SkQ1 with the quinol residue localized near peroxyl radicals at C₉ or C₁₃ of the linoleate residue in cardiolipin. In mechanism (ii), fatty acid cycling mediated by the cationic SkQ moiety is involved. It consists of (a) transmembrane movement of the fatty acid anion/SkQ cation pair and (b) back flows of free SkQ cation and protonated fatty acid. The cycling results in a protonophorous effect that was demonstrated in planar phospholipid membranes and liposomes. In mitochondria, the cycling gives rise to mild uncoupling, thereby decreasing membrane potential and ROS generation coupled to reverse electron transport in the respiratory chain. In yeast cells, dodecyltriphenylphosphonium (С₁₂TPP), the cationic part of SkQ1, induces uncoupling that is mitochondria-targeted since С₁₂TPP is specifically accumulated in mitochondria and increases the H⁺ conductance of their inner membrane. The conductance of the outer cell membrane is not affected by С₁₂TPP.     

Knowledge,perception and practices of colorectal cancer screening in an ethnically diverse population

Background: Colorectal cancer (CRC) screening improves survival and its success depends on the participation of the at-risk population. Few studies have adequately assessed screening knowledge, perception and participation according to birthplace. This study assesses the knowledge and perception of CRC in an ethnically diverse population, and evaluates the association with screening participation and intention. Identification of specific predictors of screening may aid the development of interventions to improve overall CRC screening. Methods: An interview-based survey, conducted on subjects aged 30–70 years, assessed knowledge and perception towards CRC and screening tests. Primary endpoints were screening participation and intent. Statistical methods used were Chi-square, Mann–Whitney U and logistic regression. Results: A total of 543 subjects (43% males, 53% Australian-born (AB), 63% aged 50 years and above) were recruited. Compared with AB, non-Australian-born (NAB) respondents had poorer knowledge, and NAB background predicted for poorer knowledge independent of sex, education, media and familiarity with CRC patient. Compared with AB respondents aged 50 years and above, NAB respondents had lower screening participation (17.4% vs. 31.8%; P = 0.01), lesser intention (75.8% vs. 90.5%; P < 0.001), and had received fewer doctors’ screening recommendations (16.5% vs. 27.1%; P = 0.04). In multivariate analysis, doctors’ recommendation, media and improved perception independently predicted screening participation; knowledge and media exposure predicted intent. Conclusions: The knowledge of CRC and screening is significantly poorer in the immigrant population. Knowledge predicts for greater screening intent. Therefore, implementing language- and culture-specific educational programs involving medical practitioners and media are necessary to improve CRC screening participation rates.     

Syntenin-1 is a new component of tetraspanin-enriched microdomains: mechanisms and consequences of the interaction of syntenin-1 with CD63

Tetraspanins are clustered in specific microdomains (named tetraspanin-enriched microdomains, or TERM) in the plasma membrane and regulate the functions of associated transmembrane receptors, including integrins and receptor tyrosine kinases. We have identified syntenin-1, a PDZ domain-containing protein, as a new component of TERM and show that syntenin-1 specifically interacts with the tetraspanin CD63. Detailed biochemical and heteronuclear magnetic resonance spectroscopy (NMR) studies have demonstrated that the interaction is mediated by the C-terminal cytoplasmic region of the tetraspanin and the PDZ domains of syntenin-1. Upon interaction, NMR chemical shift perturbations were predominantly localized to residues around the binding pocket of PDZ1, indicating a specific mode of recognition of the cytoplasmic tail of CD63. In addition, the C terminus of syntenin-1 has a stabilizing role in the CD63-syntenin-1 association, as deletion of the last 17 amino acids abolished the interaction. The CD63-syntenin-1 complex is abundant on the plasma membrane, and the elevated expression of the wild-type syntenin-1 slows down constitutive internalization of the tetraspanin. Furthermore, internalization of CD63 was completely blocked in cells expressing a syntenin-1 mutant lacking the first 100 amino acids. Previous results have shown that CD63 is internalized via AP-2-dependent mechanisms. Hence, our data indicate that syntenin-1 can counteract the AP-2-dependent internalization and identify this tandem PDZ protein as a new regulator of endocytosis.     

The β-glucuronidase catalyzed hydrolysis of a glucopyranosiduronamide and a glucopyranoside: Evidence for the oxocarbonium ion mechanism for bovine liver β-glucuronidase

Bovine β-glucuronidase (EC 3.2.1.31) catalyzes hydrolysis of ammonium 1-deoxy-1-(6-thiopurinyl)-β-D-glucopyranosiduronate (I), 1-deoxy-1-(6-thiopurinyl)-β-D-glucopyranosiduronamide (II), and 1-deoxy-1-(6-thiopurinyl)-β-D-glucopyranoside (III) to 6-mercaptopurine and the corresponding glucopyranose. Plots of log V_max and log V_max/Km $\text{vs.}\text{σ}{}_{\mathrm{I}}$, the comparative electronic substituent constant for -CO₂^?, -CONH₂, and -CH₂OH, gave slopes ?_I = ?5.1 (r=0.971) and ?_I = ?8.1 (r=0.998) respectively. These data, taken together with literature data, are interpreted to mean that the critical transition state has appreciable oxocarbonium ion character and that this transition state is primarily stabilized by the 6-carboxylate ion of the enzyme-bound substrate.     

Increased urinary zinc excretion in cancer patients is linked to immune activation and renal tubular cell dysfunction

Urinary zinc excretion is known to be increased in cancer patients, but the pathogenesis of this phenomenon remains uncertain. Both skeletal muscle catabolism and renal tubular cell dysfunction have been proposed to explain this observation. We have investigated urinary zinc and N-acetyl--d-glucosaminidase (NAG), an indicator of renal tubular cell dysfunction, as well as serum neopterin, an index of systemic immune activation, in 22 patients with cancer and seven controls. Both serum neopterin and urinary zinc were significantly elevated in cancer patients (15.8 ± 12.7 versus 7.3 ± 2.3 nmol l^–1 and 1.77 ± 0.80 versus 1.21 ± 0.41 mmol mol^–1 creatinine, P < 0 and P < 0.05, respectively), while NAG was similar in cancer patients and the controls (13.58 ± 13.80 versus 13.68 ± 12.19 kat mol^–1 creatinine). A significant correlation was observed between serum neopterin and urine zinc (rs = 0.5119, P < 0.02), serum neopterin and urine NAG (rs = 0.6761, P < 0.002), and urinary zinc and NAG (rs = 0.6348, P < 0.002). In conclusion, the present data indicate a link between urinary zinc excretion and immune activation as well as renal tubular cell dysfunction. In addition, renal tubular cell dysfunction appears to be linked to immune activation.     

Peripheral membrane molecules of leukocytes and NK cytotoxicity

Some leukocyte effector cell-surface molecules movement toward the adjoining target cells takes place during the reaction of NK cytotoxicity (NK R). The majority of the moving molecules are usually anchoredvia a divalent-ion-dependent interaction (PMM-M²⁺). The released PMM-M²⁺ can interact also with the secreted tumor necrosis factor alfa (TNF-α). In agreement with PMM-M²⁺ movement, the number of TNF-α binding sites on the target cell surface increases during NK R. In addition, antibodies against PMM-M²⁺, as well asd-mannose- or N-acetyl-d-glucosamine-terminated oligosaccharides of PMM-M²⁺ inhibit NK R. A more detailed analysis of PMM-M²⁺ with monoclonal antibodies used flow cytometry and cell-surface biotinylation. Only 3 of 31 tested CD antigens (CD2, LAK-1 and CD45) were passed through this first strongly restricted experimental screening. The EDTA-released LAK-1 antigen, but not CD2 and CD45, interact with TNF-α and cell surfacevia a mannose-inhibitable interaction dependent on the presence of Ca²⁺ ions. The mechanism of possible participation of PMM-M²⁺ in cytotoxic events is discussed in relation to Ca²⁺ influx and subsequent cytolysin secretion.     

Altered Transition Between Agonist-and Antagonist-Favoring States of μ-Opioid Receptor in Brain Membranes with Modified Microviscosity

Abstract: In unmodified synaptosomal brain membranes the presence of NaCl inhibited the binding to μ receptors of the tritiated opioid agonists etorphine, Tyr-D-Ala-Gly-(Me)Phe-Gly-ol, and sufentanil by 53, 43, and 37%, respectively, and increased that of the antagonist [³H]naltrexone by 54%. On the other hand, in membranes whose microviscosity was increased by incorporation of cholesteryl hemi-succinate (CHS) the effects of sodium on opioid agonist and antagonist binding were abolished and strongly reduced, respectively. Furthermore, in the modified membranes the ability of sodium to protect the opioid receptor from inactivation by the sulfhydryl-reactive agent N -ethyl-maleimide (NEM) was diminished. In CHS-treated membranes whose elevated microviscosity was reduced by the incorporation of oleic acid, the effectiveness of sodium in modulating opioid binding and attenuating receptor inactivation by NEM was restored. The results implicate membrane microviscosity in the mechanism by which sodium modulates the conversion between agonist-and antagonist-favoring states of μ opioid receptor.     

The influence of mechanical injury on the metabolic activity of transplanted cerebral cortex.

The authors studied the metabolic activity of rat embryonic cerebral cortex grafts (ED 15-16) implanted into rat brains immediately (TR0) and 14 days (TR14) after cavity formation. Over a period of two months, the ATP, lactate and glucose concentration in TR0 transplants remained at the same level as observed in the intact cortex, whereas in TR14 transplants the ATP and glucose concentration fell significantly and the lactate concentration rose. The DNA concentration rose in both types of transplants, but the increase was more pronounced in TR0 grafts. Choline acetyltransferase activity (a neuron marker) fell significantly in both cases, but the decrease was greater in TR14 transplants. The results indicate that grafts implanted into the brain immediately after cavities had been formed have better metabolic activity and are capable of longer survival than grafts implanted 14 days after cavitation.