Prolonged exercise testing in two children with a mild Multiple Acyl-CoA-Dehydrogenase deficiency

BACKGROUND: Multiple Acyl-CoA-Dehydrogenase deficiency (MADD) is an inherited metabolic disorder characterized by impaired oxidation of fatty acids and some amino acids. METHODS: We were interested whether children with MADD could tolerate a prolonged low-intensity exercise test and if this test could have any additional diagnostic value. Therefore, we performed a maximal exercise test and a low-intensity prolonged exercise test in 2 patients with MADD and in 5 control subjects. During a prolonged exercise test the subjects exercised on a cycle ergometer at a constant workload of 30% of their maximum for 90 minutes and heart rate, oxygen uptake, fuel utilization and changes in relevant blood and urinary parameters were monitored. RESULTS: The tests were tolerated well. During the prolonged exercise test the fatty acid oxidation (FAO) was quite low compared to 5 control subjects, while characteristic metabolites of MADD appeared in plasma and urine. CONCLUSION: We suggest that the prolonged exercise test could be of diagnostic importance and might replace the fasting test as a diagnostic procedure in some cases, particularly in patients with anamnestic signs of intolerance for prolonged exercise

Plant–soil feedback of native and range-expanding plant species is insensitive to temperature

Temperature change affects many aboveground and belowground ecosystem processes. Here we investigate the effect of a 5°C temperature increase on plant–soil feedback. We compare plant species from a temperate climate region with immigrant plants that originate from warmer regions and have recently shifted their range polewards. We tested whether the magnitude of plant–soil feedback is affected by ambient temperature and whether the effect of temperature differs between these groups of plant species. Six European/Eurasian plant species that recently colonized the Netherlands (non-natives), and six related species (natives) from the Netherlands were selected. Plant–soil feedback of these species was determined by comparing performance in conspecific and heterospecific soils. In order to test the effect of temperature on these plant–soil feedback interactions, the experiments were performed at two greenhouse temperatures of 20/15°C and 25/20°C, respectively. Inoculation with unconditioned soil had the same effect on natives and non-natives. However, the effect of conspecific conditioned soil was negative compared to heterospecific soil for natives, but was positive for non-natives. In both cases, plant–soil interactions were not affected by temperature. Therefore, we conclude that the temperature component of climate change does not affect the direction, or strength of plant–soil feedback, neither for native nor for non-native plant species. However, as the non-natives have a more positive soil feedback than natives, climate warming may introduce new plant species in temperate regions that have less soil-borne control of abundance

Monotonicity of Fitness Landscapes and Mutation Rate Control

A common view in evolutionary biology is that mutation rates are minimised. However, studies in combinatorial optimisation and search have shown a clear advantage of using variable mutation rates as a control parameter to optimise the performance of evolutionary algorithms. Much biological theory in this area is based on Ronald Fisher's work, who used Euclidean geometry to study the relation between mutation size and expected fitness of the offspring in infinite phenotypic spaces. Here we reconsider this theory based on the alternative geometry of discrete and finite spaces of DNA sequences. First, we consider the geometric case of fitness being isomorphic to distance from an optimum, and show how problems of optimal mutation rate control can be solved exactly or approximately depending on additional constraints of the problem. Then we consider the general case of fitness communicating only partial information about the distance. We define weak monotonicity of fitness landscapes and prove that this property holds in all landscapes that are continuous and open at the optimum. This theoretical result motivates our hypothesis that optimal mutation rate functions in such landscapes will increase when fitness decreases in some neighbourhood of an optimum, resembling the control functions derived in the geometric case. We test this hypothesis experimentally by analysing approximately optimal mutation rate control functions in 115 complete landscapes of binding scores between DNA sequences and transcription factors. Our findings support the hypothesis and find that the increase of mutation rate is more rapid in landscapes that are less monotonic (more rugged). We discuss the relevance of these findings to living organisms

Acute treatment of migraine. Breaking the paradigm of monotherapy

BACKGROUND: Migraine is a highly prevalent disorder. The disability provoked by its attacks results in suffering as well as considerable economic and social losses. The objective of migraine acute treatment is to restore the patient to normal function as quickly and consistently as possible. There are numerous drugs available for this purpose and despite recent advances in the understanding of the mechanisms and different biological systems involved in migraine attacks, with the development of specific 5-HT agonists known as triptans, current options for acute migraine still stand below the ideal. DISCUSSION: Monotherapeutic approaches are the rule but up to one third of all patients discontinue their medications due to lack of efficacy, headache recurrence, cost and/or side effects. In addition, a rationale has been suggested for the development of polytherapeutic approaches, simultaneously aiming at some of the biological systems involved. This paper reviews the fundamentals for this changing approach as well as the evidence of its better efficacy. CONCLUSION: As a conclusion, most of the patients with a past history of not responding (no pain-free at 2 hours and/or no sustained pain-free at 24 hours) in at least 5 previous attacks should undergo a combination therapy suiting to their individual profile, which must include analgesics or non-steroidal anti-inflammatory agents plus a triptan or a gastro kinetic drug. The three-drug regimen may also be considered. In addition, changing the right moment to take it and the choice for formulations other than oral has also to be determined individually and clearly posted to the patient

Renal uptake of different radiolabelled peptides is mediated by megalin: SPECT and biodistribution studies in megalin-deficient mice

Contains fulltext : 98302.pdf (publisher's version ) (Closed access)PURPOSE: Radiolabelled peptides used for peptide receptor radionuclide therapy are excreted mainly via the kidneys and are partly reabsorbed and retained in the proximal tubular cells. The resulting high renal radiation dose can cause nephrotoxicity, limiting the maximum activity dose and the effectiveness of peptide receptor radionuclide therapy. The mechanisms of kidney reabsorption of these peptides are incompletely understood, but the scavenger receptor megalin has been shown to play a role in the reabsorption of (111)In-octreotide. In this study, the role of megalin in the renal reabsorption of various relevant radiolabelled peptides was investigated. METHODS: Groups of kidney-specific megalin-deficient mice and wild-type mice were injected with (111)In-labelled somatostatin, exendin, neurotensin or minigastrin analogues. Single photon emission computed tomographic (SPECT) images of the kidneys were acquired and analysed quantitatively, or the animals were killed 3 h after injection and the activity concentration in the kidneys was measured. RESULTS: Megalin-deficient mice showed significantly lower uptake of all studied radiolabelled peptides in the kidneys, ranging from 22% ((111)In-octreotide) to 65% ((111)In-exendin) of uptake in wild-type kidneys. Quantitative analysis of renal uptake by SPECT and ex vivo measurements showed a very good correlation. CONCLUSION: Megalin is involved in the renal reabsorption of radiolabelled octreotide, octreotate, exendin, neurotensin and minigastrin. This knowledge may help in the design of strategies to reduce this reabsorption and the resulting nephrotoxicity in peptide receptor radionuclide therapy, enabling more effective therapy. Small-animal SPECT is an accurate tool, allowing in vivo quantification of renal uptake and serial measurements in individual mice

Immune cell constitution in bone marrow microenvironment predicts outcome in adult ALL

As novel immunological treatments are gaining a foothold in the treatment of acute lymphoblastic leukemia (ALL), it is elemental to examine ALL immunobiology in more detail. We used multiplexed immunohistochemistry (mIHC) to study the immune contexture in adult precursor B cell ALL bone marrow (BM). In addition, we developed a multivariate risk prediction model that stratified a poor survival group based on clinical parameters and mIHC data. We analyzed BM biopsy samples of ALL patients (n = 52) and healthy controls (n = 14) using mIHC with 30 different immunophenotype markers and computerized image analysis. In ALL BM, the proportions of M1-like macrophages, granzyme B+CD57+CD8+ T cells, and CD27+ T cells were decreased, whereas the proportions of myeloid-derived suppressor cells and M2-like macrophages were increased. Also, the expression of checkpoint molecules PD1 and CTLA4 was elevated. In the multivariate model, age, platelet count, and the proportion of PD1+TIM3+ double-positive CD4+ T cells differentiated a poor survival group. These results were validated by flow cytometry in a separate cohort (n = 31). In conclusion, the immune cell contexture in ALL BM differs from healthy controls. CD4+PD1+TIM3+ T cells were independent predictors of poor outcome in our multivariate risk model, suggesting that PD1 might serve as an attractive immuno-oncological target in B-ALL.Peer reviewe

Individual Variations in Maternal Care Early in Life Correlate with Later Life Decision-Making and c-Fos Expression in Prefrontal Subregions of Rats

Early life adversity affects hypothalamus-pituitary-adrenal axis activity, alters cognitive functioning and in humans is thought to increase the vulnerability to psychopathology–e.g. depression, anxiety and schizophrenia- later in life. Here we investigated whether subtle natural variations among individual rat pups in the amount of maternal care received, i.e. differences in the amount of licking and grooming (LG), correlate with anxiety and prefrontal cortex-dependent behavior in young adulthood. Therefore, we examined the correlation between LG received during the first postnatal week and later behavior in the elevated plus maze and in decision-making processes using a rodent version of the Iowa Gambling Task (rIGT). In our cohort of male and female animals a high degree of LG correlated with less anxiety in the elevated plus maze and more advantageous choices during the last 10 trials of the rIGT. In tissue collected 2 hrs after completion of the task, the correlation between LG and c-fos expression (a marker of neuronal activity) was established in structures important for IGT performance. Negative correlations existed between rIGT performance and c-fos expression in the lateral orbitofrontal cortex, prelimbic cortex, infralimbic cortex and insular cortex. The insular cortex correlations between c-fos expression and decision-making performance depended on LG background; this was also true for the lateral orbitofrontal cortex in female rats. Dendritic complexity of insular or infralimbic pyramidal neurons did not or weakly correlate with LG background. We conclude that natural variations in maternal care received by pups may significantly contribute to later-life decision-making and activity of underlying brain structures

Sexual knowledge, attitudes and activity of men conscripted into the military

<p>Abstract</p> <p>Background</p> <p>Military conscripts may experience a change in their attitude towards sex at times when sexual urges are at their peak during their physical growth. This study examines the experience, understanding, knowledge and attitudes regarding sexual activity of the military conscripts.</p> <p>Methods</p> <p>Data was obtained from a cross-sectional survey of 1127 young adult military conscripts, and were evaluated in Southern Taiwan from January to July 2009, their demographic data, sexual knowledge, attitudes and activities were assessed.</p> <p>Results</p> <p>Nearly 43% of the participants had performed penetrative vaginal intercourse at least once; 34% of the participants performed heterosexual oral sex at least once; almost 7% of participants had had homosexual intercourse, and 7.5% of participants had experienced homosexual oral sex in the past year. The mean sexual knowledge score based on 30 questions was 23.2 ± 4.0. The higher the educational level of the participants, the greater sexual knowledge they had obtained.</p> <p>Conclusion</p> <p>This study found that 43% of unmarried young recruits had experienced premarital sexual activity. However, their sexual knowledge was insufficient and should be strengthened by sex education from an earlier age. College aged and adult learners also have sex education needs, especially with regard to integrating sexuality and life, being able to relate responsibly as sexual beings to others, the use of contraception, and about sexually transmitted disease.</p> <p>Keywords</p> <p>Young recruits, Sexual behavior, Sexual knowledge, Sex education</p

Caregiver education in Parkinson’s disease: formative evaluation of a standardized program in seven European countries

The formative evaluation of a standardized psychosocial education program for patients with Parkinson's disease (PD) and their caregivers. The results of the participation of the caregivers are presented next to the data of the patients. Caregivers (n = 137) and patients with PD (n = 151) participated in the 8-week program in separate groups. Measurements were performed on psychosocial problems (BELA-P/A-k), health state (EQ-5D VAS), quality of life (PDQ-39) and depression (SDS) 1 week before and 1 week after the program. Participants rated their mood on a visual analogue scale before and after each session, and they filled in an evaluation questionnaire after the last session. Scores on the BELA-P/A-k improved significantly on the 'bothered by scale' as well as the 'need for help scale'. No improvements were found on EQ-5D VAS, PDQ-39 and SDS. Mood ratings improved significantly after each session. Most participants evaluated the program as positive. Feedback led to improvements in the program, which are incorporated in a final manual. The program was feasible to run in the different countries. This exploratory study led to improvements in the program and recommendations for further research. A study on the effectiveness of the program is the next step.Pathophysiology of paroxysmal and chronic degenerative progressive disorder of the central and periferal nervous syste

Phylogeography and Molecular Evolution of Potato virus Y

Potato virus Y (PVY) is an important plant pathogen, whose host range includes economically important crops such as potato, tobacco, tomato, and pepper. PVY presents three main strains (PVYO, PVYN and PVYC) and several recombinant forms. PVY has a worldwide distribution, yet the mechanisms that promote and maintain its population structure and genetic diversity are still unclear. In this study, we used a pool of 77 complete PVY genomes from isolates collected worldwide. After removing the effect of recombination in our data set, we used Bayesian techniques to study the influence of geography and host species in both PVY population structure and dynamics. We have also performed selection and covariation analyses to identify evolutionarily relevant amino acid residues. Our results show that both geographic and host-driven adaptations explain PVY diversification. Furthermore, purifying selection is the main force driving PVY evolution, although some indications of positive selection accounted for the diversification of the different strains. Interestingly, the analysis of P3N-PIPO, a recently described gene in potyviruses, seems to show a variable length among the isolates analyzed, and this variability is explained, in part, by host-driven adaptation