OLOGRAM: Determining significance of total overlap length between genomic regions sets.

MOTIVATION: Various bioinformatics analyses provide sets of genomic coordinates of interest. Whether two such sets possess a functional relation is a frequent question. This is often determined by interpreting the statistical significance of their overlaps. However, only few existing methods consider the lengths of the overlap, and they do not provide a resolutive p-value. RESULTS: Here, we introduce OLOGRAM, which performs overlap statistics between sets of genomic regions described in BEDs or GTF. It uses Monte Carlo simulation, taking into account both the distributions of region and inter-region lengths, to fit a negative binomial model of the total overlap length. Exclusion of user-defined genomic areas during the shuffling is supported. AVAILABILITY: This tool is available through the command line interface of the pygtftk toolkit. It has been tested on Linux and OSX and is available on Bioconda and from https://github.com/dputhier/pygtftk under the GNU GPL license. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Multimodal MR imaging (diffusion, perfusion, and spectroscopy): is it possible to distinguish oligodendroglial tumor grade and 1p/19q codeletion in the pretherapeutic diagnosis?

BACKGROUND AND PURPOSE: Pretherapeutic determination of tumor grade and genotype in grade II and III oligodendroglial tumors is clinically important but is still challenging. Tumor grade and 1p/19q status are currently the 2 most important factors in therapeutic decision making for patients with these tumors. Histopathology and cMRI studies are still limited in some cases. In the present study, we were interested in determining whether the combination of PWI, DWI, and MR spectroscopy could help distinguish oligodendroglial tumors according to their histopathologic grade and genotype. MATERIALS AND METHODS: We retrospectively reviewed 50 adult patients with grade II and III oligodendrogliomas and oligoastrocytomas who had DWI, PWI, and MR spectroscopy at short and long TE data and known 1p/19q status. Univariate analyses and multivariate random forest models were performed to determine which criteria could differentiate between grades and genotypes. RESULTS: ADC, rCBV, rCBF, and rK2 were significantly different between grade II and III oligodendroglial tumors. DWI, PWI, and MR spectroscopy showed no significant difference between tumors with and without 1p/19q loss. Separation between tumor grades and genotypes with cMRI alone showed 31% and 48% misclassification rates, respectively. Multimodal MR imaging helps to determine tumor grade and 1p/19q genotype more accurately (misclassification rates of 17% and 40%, respectively). CONCLUSIONS: Although multimodal investigation of oligodendroglial tumors has a lower contribution to 1p/19q genotyping compared with cMRI alone, it greatly improves the accuracy of grading of these neoplasms. Use of multimodal MR imaging could thus provide valuable information that may assist clinicians in patient preoperative management and treatment decision making.

Comparative analysis of in vitro contracture tests with ryanodine and a combination of ryanodine with either halothane or caffeine: a comparative investigation in malignant hyperthermia.

BACKGROUND: The diagnosis of susceptibility to malignant hyperthermia (MH) is currently performed on muscle biopsies subjected to halothane-caffeine in vitro contracture tests (IVCTs). There is a consensus on our need to improve the diagnostic potential of IVCTs if we are to maximize the information available for research and diagnosis in MH. This study was designed as a pilot comparative study and we aimed at comparing the ryanodine test and new tests using a combination of ryanodine, halothane and caffeine. METHODS: One hundred and thirty-two subjects (52 MHS and 80 MHN) were included in this study and new IVCTs were performed in additional muscle biopsy specimens. The contracture time-course was compared considering the onset time of contracture (OT) and the time to reach a 10 mN contracture (10T). Cut-off values were determined using ROC analyses. RESULTS: For the ryanodine test, sensitivity and specificity calculated for OT were 84.6% and 90.4%, respectively, and were better than those obtained using 10T. Combined tests using either caffeine and ryanodine or halothane and ryanodine did provide higher sensitivities (from 85.3 to 93.9%). A better specificity was only observed for the IVC tests combining halothane (cumulated) and caffeine both with ryanodine (93.9% for both). The largest sensitivity was observed when halothane was used as a bolus and combined with ryanodine. The specificity was always larger with the combined tests as compared to the test using ryanodine alone (from 79.1 to 90.9%). This superiority was confirmed, at least in part, when comparing genetic investigations and the results of new tests in a subgroup of subjects. CONCLUSIONS: This pilot study showed a clear diagnostic potential for new IVC tests combining halothane, the triggering agent of MH, and ryanodine acting at the calcium release channel, and should be considered as a first step in the investigation of combined tests.

Intermittent sand filtration for wastewater treatment in rural areas of the Middle East--a pilot study.

This paper concentrates on Intermittent Sand Filtration (ISF) as a polishing stage for effluent from a facultative pond. During the three-year research program, the system operated with an influent flow-rate of 500-1,000 L/day and an average BOD concentration of 200-400 hydraulic and BOD loadings of 110-200 L/m2/day and 20-40 gBOD/m2/day, respectively. Flow to the ISF was applied intermittently with a different number of doses in each run. In addition, the effects of the frequency and the duration of rest periods (no feeding) were studied. Removal of 90-95% of BOD and 75-90% of COD and TSS was achieved consistently throughout the study period. Elevated levels of nitrification were observed with 95-100% removal of NH3. The ISF performed best when fed with 5-10 doses/day. Reducing the daily number of doses to 3/day at the same hydraulic loading rate resulted in a 20-30% reduction in removal efficiency. The 2-4 week rest period had no effect on the biological activity in the subsequent run. However, rest periods of more than 30 days were found to negatively affect removal efficiency.

Metabolic determinants of the onset of acidosis in exercising human muscle: a 31P-MRS study.

Onset of intracellular acidosis during muscular exercise has been generally attributed to activation or hyperactivation of nonoxidative ATP production but has not been analyzed quantitatively in terms of H(+) balance, i.e., production and removal mechanisms. To address this issue, we have analyzed the relation of intracellular acidosis to H(+) balance during exercise bouts in seven healthy subjects. Each subject performed a 6-min ramp rhythmic exercise (finger flexions) at low frequency (LF, 0.47 Hz), leading to slight acidosis, and at high frequency (HF, 0.85 Hz), inducing a larger acidosis. Metabolic changes were recorded using (31)P-magnetic resonance spectroscopy. Onset of intracellular acidosis was statistically identified after 3 and 4 min of exercise for HF and LF protocols, respectively. A detailed investigation of H(+) balance indicated that, for both protocols, nonoxidative ATP production preceded a change in pH. For HF and LF protocols, H(+) consumption through the creatine kinase equilibrium was constant in the face of increasing H(+) generation and efflux. For both protocols, changes in pH were not recorded as long as sources and sinks for H(+) approximately balanced. In contrast, a significant acidosis occurred after 4 min of LF exercise and 3 min of HF exercise, whereas the rise in H(+) generation exceeded the rise in H(+) efflux at a nearly constant H(+) uptake associated with phosphocreatine breakdown. We have clearly demonstrated that intracellular acidosis in exercising muscle does not occur exclusively as a result of nonoxidative ATP production but, rather, reflects changes in overall H(+) balance.

Citrulline/malate promotes aerobic energy production in human exercising muscle.

BACKGROUND: Previous studies have shown an antiasthenic effect of citrulline/malate (CM) but the mechanism of action at the muscular level remains unknown. OBJECTIVE: To investigate the effects of CM supplementation on muscle energetics. METHODS: Eighteen men complaining of fatigue but with no documented disease were included in the study. A rest-exercise (finger flexions)-recovery protocol was performed twice before (D-7 and D0), three times during (D3, D8, D15), and once after (D22) 15 days of oral supplementation with 6 g/day CM. Metabolism of the flexor digitorum superficialis was analysed by (31)P magnetic resonance spectroscopy at 4.7 T. RESULTS: Metabolic variables measured twice before CM ingestion showed no differences, indicating good reproducibility of measurements and no learning effect from repeating the exercise protocol. CM ingestion resulted in a significant reduction in the sensation of fatigue, a 34% increase in the rate of oxidative ATP production during exercise, and a 20% increase in the rate of phosphocreatine recovery after exercise, indicating a larger contribution of oxidative ATP synthesis to energy production. Considering subjects individually and variables characterising aerobic function, extrema were measured after either eight or 15 days of treatment, indicating chronological heterogeneity of treatment induced changes. One way analysis of variance confirmed improved aerobic function, which may be the result of an enhanced malate supply activating ATP production from the tricarboxylic acid cycle through anaplerotic reactions. CONCLUSION: The changes in muscle metabolism produced by CM treatment indicate that CM may promote aerobic energy production.

A noninvasive investigation of muscle energetics supports similarities between exertional heat stroke and malignant hyperthermia.

Exertional heat stroke (EHS) is usually triggered by strenuous exercise performed under hot and humid environmental conditions. Although the pathogenesis of an EHS episode differs from that of a clinical malignant hyperthermia (MH) crisis, both conditions share some similarities in symptoms, such as the abnormal increase in core temperature. By use of (31)P magnetic resonance spectroscopy, we analyzed the muscle energetics of 26 post-EHS subjects for whom in vitro halothane/caffeine contracture tests were abnormal and investigated possible similarities with subjects susceptible to MH. An early decrease of pH was noted during the first minute of exercise in EHS subjects as compared with controls. EHS subjects were divided into two subgroups according to the diagnostic score previously developed for MH subjects. The 19 subjects (73%) with a score higher than 2 displayed significantly larger caffeine-induced and earlier ryanodine-induced contractures on muscle biopsies as compared with the rest of the group (7 subjects). The results demonstrate that muscle energetics are abnormal in subjects who have experienced EHS and suggest a possible link between MH and EH, although all EHS cannot be considered as MH.

Forecasting physicochemical variables by a classification tree method. Application to the Berre Lagoon (south France).

The dynamics of the "Etang de Berre", a brackish lagoon situated close to the French Mediterranean sea coast, is strongly disturbed by freshwater inputs coming from an hydroelectric power station. The system dynamics has been described as a sequence of daily typical states from a set of physicochemical variables such as temperature, salinity and dissolved oxygen rates collected over three years by an automatic sampling station. Each daily pattern summarizes the evolution, hour by hour of the physicochemical variables. This article presents results of forecasts of the states of the system subjected to the simultaneous effects of meteorological conditions and freshwater releases. We recall the main step of the classification tree method used to build up the predictive model (Classification and Regression Trees, Breiman et al., 1984) and we propose a transfer procedure in order to test the stability of the model. Results obtained on the Etang de Berre data set allow us to describe and predict the effects of the environmental variables on the system dynamics with a margin of error. The transfer procedure applied after the tree building process gives a maximum gain in prediction accuracy of about 15%.