UPTAKE, METABOLISM, AND METABOLIC EFFECTS OF THE ANTITUMOR TRICYCLIC NUCLEOSIDE, 3-AMINO-1, 5-DIHYDRO-5-METHYL-1-BETA-D-RIBOFURANOSYL-1, 4, 5, 6, 8 PENTAAZAACENAPHTHYLENE

The uptake, metabolism, and metabolic effects of the antitumor tricyclic nucleoside (TCN, NSC-154020) were studied in vitro. Uptake of TCN by human erythrocytes was concentrative, resulting mainly from the rapid intracellular phosphorylation of TCN. At high TCN doses, however, unchanged TCN was also concentrated within the erythrocytes. The initial linear rate of TCN uptake was saturable and obeyed Michaelis-Menten kinetics. TCN was metabolized chiefly to its 5'-monophosphate not only by human erythrocytes but also by wild-type Chinese hamster ovary (CHO) cells. In addition, three other metabolites were detected by means of high-performance liquid chromatography. The structures of these metabolites were elucidated by ultraviolet spectroscopy, infrared spectroscopy, mass spectrometry, and further confirmed by incubations with catabolic enzymes and intact wild-type or variant CHO cells. All were novel types of oxidative degradation products of TCN. Two are proposed to be (alpha) and (beta) anomers of a D-ribofuranosyl nucleoside with a pyrimido{4,5-c}pyridazine-4-one base structure. The third metabolite is most likely the 5'-monophosphate of the (beta) anomer. A CHO cell line deficient in adenosine kinase activity failed to phosphorylate either TCN or the (beta) anomer. No further phosphorylation of the 5'-monophosphates by normal cells occurred. Although the pathways leading to the formation of these TCN metabolites have not been proven, a mechanism is proposed to account for the above observations. The same adenosine kinase-deficient CHO cells were resistant to 500 (mu)M TCN, while wild-type cells could not clone in the presence of 20 (mu)M TCN. Simultaneous addition of purines, pyrimidines, and purine precursors failed to reverse this toxicity. TCN-treatment strongly inhibited formate or glycine incorporation into ATP and GTP of wild-type CHO cells. Hypoxanthine incorporation inhibited to a lesser degree, with the inhibition of incorporation into GTP being more pronounced. Although precursor incorporation into GTP was inhibited, GTP concentrations were elevated rather than reduced after 4-hr incubations with 20 (mu)M or 50 (mu)M TCN. These results suggested an impairment of GTP utilization. TCN (50 (mu)M) inhibited leucine and thymidine incorporation into HClO(,4)-insoluble material to 30-35% of control throughout 5-hr incubations. Incorporation of five other amino acids was inhibited to the same extent as leucine. Pulse-labeling assays (45 min) with uridine, leucine, and thymidine failed to reveal selective inhibition of DNA or protein synthesis by 0.05-50 (mu)M TCN; however, the patterns of inhibition were similar to those of known protein synthesis inhibitors. TCN 5'-monophosphate inhibited leucine incorporation by rabbit reticulocyte lysates; the inhibition was 2000 times less potent than that of cycloheximide. The 5'-monophosphate failed to inhibit a crude nuclear DNA-synthesizing system. Although TCN 5'-monophosphate apparently inhibits purine synthesis de novo, its cytotoxicity is not reversed by exogenous purines. Consequently, another mechanism such as direct inhibition of protein synthesis is probably a primary mechanism of toxicity. ^

Experimental Determination of Salinity, Temperature, Growth, and Metabolic Effects on Shell Isotope Chemistry of Mytilus edulis Collected from Maine and Greenland

To study the effects of temperature, salinity, and life processes (growth rates, size, metabolic effects, and physiological/ genetic effects) on newly precipitated bivalve carbonate, we quantified shell isotopic chemistry of adult and juvenile animals of the intertidal bivalve Mytilus edulis (Blue mussel) collected alive from western Greenland and the central Gulf of Maine and cultured them under controlled conditions. Data for juvenile and adult M. edulis bivalves cultured in this study, and previously by Wanamaker et al. (2006), yielded statistically identical paleotemperature relationships. On the basis of these experiments we have developed a species-specific paleotemperature equation for the bivalve M. edulis [T degrees C = 16.28 (+/- 0.10) -4.57 (+/- 0.15) {delta(18)O(c) VPBD - delta(18)O(w) VSMOW} + 0.06 (+/- 0.06) {delta(18)O(c) VPBD - delta(18)O(w) VSMOW}(2); r(2) = 0.99; N = 323; p < 0.0001]. Compared to the Kim and O'Neil (1997) inorganic calcite equation, M. edulis deposits its shell in isotope equilibrium (delta(18)O(calcite)) with ambient water. Carbon isotopes (delta(13)C(calcite)) from sampled shells were substantially more negative than predicted values, indicating an uptake of metabolic carbon into shell carbonate, and delta(13)C(calcite) disequilibrium increased with increasing salinity. Sampled shells of M. edulis showed no significant trends in delta(18)O(calcite) based on size, cultured growth rates, or geographic collection location, suggesting that vital effects do not affect delta(18)O(calcite) in M. edulis. The broad modern and paleogeographic distribution of this bivalve, its abundance during the Holocene, and the lack of an intraspecies physiologic isotope effect demonstrated here make it an ideal nearshore paleoceanographic proxy throughout much of the North Atlantic Ocean.

Experimental Determination of Salinity, Temperature, Growth, and Metabolic Effects on Shell Isotope Chemistry of Mytilus Edulis Collected from Maine and Greenland

To study the effects of temperature, salinity, and life processes (growth rates, size, metabolic effects, and physiological/ genetic effects) on newly precipitated bivalve carbonate, we quantified shell isotopic chemistry of adult and juvenile animals of the intertidal bivalve Mytilus edulis (Blue mussel) collected alive from western Greenland and the central Gulf of Maine and cultured them under controlled conditions. Data for juvenile and adult M. edulis bivalves cultured in this study, and previously by Wanamaker et al. (2006), yielded statistically identical paleotemperature relationships. On the basis of these experiments we have developed a species-specific paleotemperature equation for the bivalve M. edulis [T degrees C = 16.28 (+/- 0.10) -4.57 (+/- 0.15) {delta(18)O(c) VPBD - delta(18)O(w) VSMOW} + 0.06 (+/- 0.06) {delta(18)O(c) VPBD - delta(18)O(w) VSMOW}(2); r(2) = 0.99; N = 323; p < 0.0001]. Compared to the Kim and O'Neil (1997) inorganic calcite equation, M. edulis deposits its shell in isotope equilibrium (delta(18)O(calcite)) with ambient water. Carbon isotopes (delta(13)C(calcite)) from sampled shells were substantially more negative than predicted values, indicating an uptake of metabolic carbon into shell carbonate, and delta(13)C(calcite) disequilibrium increased with increasing salinity. Sampled shells of M. edulis showed no significant trends in delta(18)O(calcite) based on size, cultured growth rates, or geographic collection location, suggesting that vital effects do not affect delta(18)O(calcite) in M. edulis. The broad modern and paleogeographic distribution of this bivalve, its abundance during the Holocene, and the lack of an intraspecies physiologic isotope effect demonstrated here make it an ideal nearshore paleoceanographic proxy throughout much of the North Atlantic Ocean.

Vulnerability and Growth. Developmental dynamics and differential effects of the loss of an intimate partner in the second half of life. IP 12: Study outline and first results

This working report gives an overview of the Individual Project 12 “Vulnerability and growth. Developmental dynamics and differential effects of the loss of an intimate partner in the second half of life” of the Swiss National Centre of Competence in Research LIVES led by Pasqualina Perrig-Chiello, University of Bern. This longitudinal and interdisciplinary project aims at examining vulnerability and personal growth after a critical life event, namely the break-up of a long-term intimate relationship in the second half of life, be it due to divorce or due to bereavement. In this report we present details about the rationale, the main research questions, the hypotheses and the methods of the study. Special attention is given to the methodological approach. The authors give a first sample description and report on the validity of the data by comparing the sample with Swiss Labour Force Survey and Swiss Health Survey data.

Relaxing hydrotherapy WATSU (WaterShiatsu) and its effects in third trimester of pregnancy

Background WATSU (WaterShiatsu) is a bodywork-technique comprising buoyancy, passive stretches, massage, and acupressure that is administered in 35° C warm water. WATSU is believed to exert beneficial effects on pregnancy-related complaints. We conducted a pilot study to test the hypothesis that WATSU treatment during pregnancy can affect low back pain, everyday stress perception, quality of life, tonus of the uterus, amount of amniotic fluid, spontaneous course of breech presentations, and the success rate of external cephalic versions. Methods Healthy women with singleton pregnancies at gestational week 36 were included in our cohort control pilot trial. Participants in the treatment group (n = 8) received a standardized WATSU-treatment on their first and fourth day of study participation, while participants in the control group were in a waiting condition. Participants underwent ultrasound investigations and completed quantitative and qualitative questionnaires before and after intervention, as well as weekly until birth. Results In contrast to the control group, participants in the WATSU-treatment group reported significant relief of low back pain and stress. After WATSU treatment spontaneous version out of breech position occurred once in seven cases, and external cephalic version was successful in two out of three cases. As qualitative data indicate, WATSU was appreciated as a deep relaxing and enjoyable treatment method. No negative side-effects or adverse events were reported. Conclusion The findings from our pilot-study support the notion that WATSU might yield therapeutic benefits for pregnant women and warrant further research.

Cognitive and emotional effects of carotid stenosis

PRINCIPLES Patients with carotid artery stenosis (CAS) are at risk of ipsilateral stroke and chronic compromise of cerebral blood flow. It is under debate whether the hypo-perfusion or embolism in CAS is directly related to cognitive impairment. Alternatively, CAS may be a marker for underlying risk factors, which themselves influence cognition. We aimed to determine cognitive performance level and the emotional state of patients with CAS. We hypothesised that patients with high grade stenosis, bilateral stenosis, symptomatic patients and/or those with relevant risk factors would suffer impairment of their cognitive performance and emotional state. METHODS A total of 68 patients with CAS of ≥70% were included in a prospective exploratory study design. All patients underwent structured assessment of executive functions, language, verbal and visual memory, motor speed, anxiety and depression. RESULTS Significantly more patients with CAS showed cognitive impairments (executive functions, word production, verbal and visual memory, motor speed) and anxiety than expected in a normative sample. Bilateral and symptomatic stenosis was associated with slower processing speed. Cognitive performance and anxiety level were not influenced by the side and the degree of stenosis or the presence of collaterals. Factors associated with less cognitive impairment included higher education level, female gender, ambidexterity and treated hypercholesterolemia. CONCLUSIONS Cognitive impairment and increased level of anxiety are frequent in patients with carotid stenosis. The lack of a correlation between cognitive functioning and degree of stenosis or the presence of collaterals, challenges the view that CAS per se leads to cognitive impairment.

Developmental changes in sleep biology and potential effects on adolescent behavior and caffeine use

Adolescent development includes changes in the biological regulatory processes for the timing of sleep. Circadian rhythm changes and changes to the sleep-pressure system (sleep homeostasis) during adolescence both favor later timing of sleep. These changes, combined with prevailing social pressures, are responsible for most teens sleeping too late and too little; those who sleep least report consuming more caffeine. Although direct research findings are scarce, the likelihood of use and abuse of caffeine-laden products grows across the adolescent years due, in part, to excessive sleepiness

Comparative Behavioral and Neural Effects of Tryptophan and Catecholamine Depletion in Remitted Depression

Background: Despite immense efforts into development of new antidepressant drugs, the increases of serotoninergic and catechominergic neurotransmission have remained the two major pharmacodynamic principles of current drug treatments for depression. Consequently, psychopathological or biological markers that predict response to drugs that selectively increase serotonin and/or catecholamine neurotransmission hold the potential to optimize the prescriber’s selection among currently available treatment options. The aim of this study was to elucidate the differential symptomatology and neurophysiology in response to reductions in serotonergic versus catecholaminergic neurotransmission in subjects at high risk of depression recurrence. Methods: Using identical neuroimaging procedures with [18F] fluorodeoxyglucose positron emission tomography after tryptophan depletion (TD) and catecholamine depletion (CD), subjects with remitted depression were compared to healthy controls in a double-blind, randomized, crossover design. Results: While TD induced significantly more depressed mood, sadness and hopelessness than CD, CD induced more inactivity, concentration difficulties, lassitude and somatic anxiety than TD. CD specifically increased glucose metabolism in the bilateral ventral striatum and decreased glucose metabolism in the bilateral orbitofrontal cortex, whereas TD specifically increased metabolism in the right prefrontal cortex and the posterior cingulate cortex (PCC). While we found direct associations between changes in brain metabolism and induced depressive symptoms following CD, the relationship between neural activity and symptoms was less clear after TD. Conclusions: In conclusion, this study showed that serotonin and catecholamines play common and differential roles in the pathophysiology of depression.

Oral prophylaxis and its effects on halitosis-associated and inflammatory parameters in patients with chronic periodontitis

OBJECTIVE A controlled clinical trial was conducted to evaluate the effects of oral prophylaxis on halitosis-associated, immunological and microbiological parameters. METHODS Thirty subjects were included in this controlled clinical trial (patients with generalized chronic periodontitis and controls without clinical attachment loss; each n = 15). Before oral prophylaxis and 14 days after (including tongue cleaning) volatile sulphur compounds (VSC), organoleptic scores and a tongue coating index were evaluated. The levels of IL-1β, IL-8, IL-10 and MMP-8 were measured in GCF, and also major periodontal pathogens were detected. Data were statistically analysed using anova and paired t-test. RESULTS Supragingival plaque and calculus removal with combined tongue cleaning was able to reduce significantly (P < 0.05) the VSC values in both groups (no significant differences between both groups). Two weeks after periodontal debridement, the VSC values were observed in the periodontitis group, but not in the control group, similar to the baseline values. The difference between the groups was statistically significant (P < 0.05). Only a repeated prophylaxis session in the periodontitis group was able to reduce VSC values significantly in comparison with baseline (P < 0.05). Organoleptic scores (10 and 30 cm) were significantly different (P < 0.05) between both groups before and after the treatment. Periodontal pathogens and host-derived markers were not significantly affected by a single prophylaxis session. CONCLUSIONS Oral prophylaxis may result in a significant decrease in VSC values. However, in periodontal diseases, a more complex treatment seems to be necessary.