Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders

Background

Defects in genes involved in mitochondrial fatty-acid oxidation (mFAO) reduce the ability of patients to cope with metabolic challenges. mFAO enzymes accept multiple substrates of different chain length, leading to molecular competition among the substrates. Here, we combined computational modeling with quantitative mouse and patient data to investigate whether substrate competition affects pathway robustness in mFAO disorders.

Results

First, we used comprehensive biochemical analyses of wild-type mice and mice deficient for medium-chain acyl-CoA dehydrogenase (MCAD) to parameterize a detailed computational model of mFAO. Model simulations predicted that MCAD deficiency would have no effect on the pathway flux at low concentrations of the mFAO substrate palmitoyl-CoA. However, high concentrations of palmitoyl-CoA would induce a decline in flux and an accumulation of intermediate metabolites. We proved computationally that the predicted overload behavior was due to substrate competition in the pathway. Second, to study the clinical relevance of this mechanism, we used patients’ metabolite profiles and generated a humanized version of the computational model. While molecular competition did not affect the plasma metabolite profiles during MCAD deficiency, it was a key factor in explaining the characteristic acylcarnitine profiles of multiple acyl-CoA dehydrogenase deficient patients. The patient-specific computational models allowed us to predict the severity of the disease phenotype, providing a proof of principle for the systems medicine approach.

Conclusion

We conclude that substrate competition is at the basis of the physiology seen in patients with mFAO disorders, a finding that may explain why these patients run a risk of a life-threatening metabolic catastrophe.

     

Hypothermia during Carotid Endarterectomy: A Safety Study

BackgroundCEA is associated with peri-operative risk of brain ischemia, due both to emboli production caused by manipulation of the plaque and to potentially noxious reduction of cerebral blood flow by carotid clamping. Mild hypothermia (34–35°C) is probably the most effective approach to protect brain from ischemic insult. It is therefore a substantial hypothesis that hypothermia lowers the risk of ischemic brain damage potentially associated with CEA. Purpose of the study is to test whether systemic endovascular cooling to a target of 34.5–35°C, initiated before and maintained during CEA, is feasible and safe.MethodsThe study was carried out in 7 consecutive patients referred to the Vascular Surgery Unit and judged eligible for CEA. Cooling was initiated 60–90 min before CEA, by endovascular approach (Zoll system). The target temperature was maintained during CEA, followed by passive, controlled rewarming (0.4°C/h). The whole procedure was carried out under anesthesia.ResultsAll the patients enrolled had no adverse events. Two patients exhibited a transient bradycardia (heart rate 30 beats/min). There were no significant differences in the clinical status, laboratory and physiological data measured before and after CEA.ConclusionsSystemic cooling to 34.5–35.0°C, initiated before and maintained during carotid clamping, is feasible and safe.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02629653","term_id":"NCT02629653"}}NCT02629653     

Subcutaneous Progesterone Is Effective and Safe for Luteal Phase Support in IVF: An Individual Patient Data Meta-Analysis of the Phase III Trials

Objective

To summarize efficacy and safety data on a new progesterone compound which is available for subcutaneous administration as compared to vaginally administered progesterone for luteal phase support in patients undergoing IVF treatment.

Design

Data from two randomized phase III trials (07EU/Prg06 and 07USA/Prg05) performed according to GCP standards with a total sample size of 1435 per-protocol patients were meta-analyzed on an individual patient data level.

Setting

University affiliated reproductive medicine unit.

Patients

Subcutaneous progesterone was administered to a total of 714 subjects and vaginal progesterone was administered to a total of 721 subjects who underwent fresh embryo transfer after ovarian stimulation followed by IVF or ICSI. The subjects were between 18 and 42 years old and had a BMI <30kg/m².

Interventions

Subcutaneous progesterone 25 mg daily vs. either progesterone vaginal gel 90 mg daily (07EU/Prg06) or 100 mg intravaginal twice a day (07USA/Prg05) for luteal phase support in IVF patients.

Main outcome measures

Ongoing pregnancy rate beyond 10 gestational weeks, live birth rate and OHSS risk.

Results

The administration of subcutaneous progesterone versus intra-vaginal progesterone had no impact on ongoing pregnancy likelihood (OR = 0.865, 95% CI 0.694 to 1.077; P = n.s.), live birth likelihood (OR = 0.889, 95% CI 0.714 to 1.106; P = n.s.) or OHSS risk (OR = 0.995, 95% CI 0.565 to 1.754; P = n.s.) in regression analyses accounting for clustering of patients within trials, while adjusting for important confounders. Only female age and number of oocytes retrieved were significant predictors of live birth likelihood and OHSS risk.

Conclusion

No statistical significant or clinical significant differences exist between subcutaneous and vaginal progesterone for luteal phase support.     

Detecting Selection on Temporal and Spatial Scales: A Genomic Time-Series Assessment of Selective Responses to Devil Facial Tumor Disease

Detecting loci under selection is an important task in evolutionary biology. In conservation genetics detecting selection is key to investigating adaptation to the spread of infectious disease. Loci under selection can be detected on a spatial scale, accounting for differences in demographic history among populations, or on a temporal scale, tracing changes in allele frequencies over time. Here we use these two approaches to investigate selective responses to the spread of an infectious cancer—devil facial tumor disease (DFTD)—that since 1996 has ravaged the Tasmanian devil (Sarcophilus harrisii). Using time-series ‘restriction site associated DNA’ (RAD) markers from populations pre- and post DFTD arrival, and DFTD free populations, we infer loci under selection due to DFTD and investigate signatures of selection that are incongruent among methods, populations, and times. The lack of congruence among populations influenced by DFTD with respect to inferred loci under selection, and the direction of that selection, fail to implicate a consistent selective role for DFTD. Instead genetic drift is more likely driving the observed allele frequency changes over time. Our study illustrates the importance of applying methods with different performance optima e.g. accounting for population structure and background selection, and assessing congruence of the results.     

Assessing Stress in Zoo-Housed Western Lowland Gorillas (<Emphasis Type="Italic">Gorilla gorilla gorilla</Emphasis>) Using Allostatic Load

Stress contributes to the development of chronic degenerative diseases in primates. Allostatic load is an estimate of stress-induced physiological dysregulation based on an index of multiple biomarkers. It has been applied to humans to measure effects of stress and predict health outcomes. Assessing allostatic load in nonhuman primates may aid in understanding factors promoting compromised health and longevity in captive populations, as well as risk assessment among wild populations following human activities. We applied an allostatic load index to gorillas housed at the Columbus Zoo and Aquarium (N = 27, 1956–2014) using data from medical records and biomarkers from banked serum. We estimated allostatic load using seven biomarkers (albumin, cortisol, corticotropin-releasing hormone, dehydroepiandrosterone sulfate, glucose, interleukin-6, and tumor necrosis factor alpha) and then examined this index for associations with age, sex, number of stressful events, parturition, physiological health measures, and age at death. Stressful events were defined as agonistic interactions with wounding, translocations, and anesthetizations. Allostatic load positively associated with age and total number of lifetime stressful events. Allostatic load was significantly higher in females than in males. Allostatic load was not associated with number of pregnancies and was not different between nulliparous and parous females. Allostatic load associated positively with serum creatinine and triglyceride levels, showed a nonsignificant negative association with cholesterol, and did not associate significantly with age at death. These results demonstrate the potential utility of allostatic load for exploring long-term stress and health risks, as well as for evaluating environmental stressors for gorillas and other nonhuman primates in captivity and in the wild.     

Using behavioral observation for the longitudinal study of anger regulation in middle childhood

Assessing anger regulation via self-reports is fraught with problems, especially among children. Behavioral observation provides an ecologically valid alternative for measuring anger regulation. The present study uses data from two waves of a longitudinal study to present a behavioral observation approach for measuring anger regulation in middle childhood. At T1, 599 children from Germany (6–10 years old) were observed during an anger eliciting task, and the use of anger regulation strategies was coded. At T2, 3 years later, the observation was repeated with an age-appropriate version of the same task. Partial metric measurement invariance over time demonstrated the structural equivalence of the two versions. Maladaptive anger regulation between the two time points showed moderate stability. Validity was established by showing correlations with aggressive behavior, peer problems, and conduct problems (concurrent and predictive criterion validity). The study presents an ecologically valid and economic approach to assessing anger regulation strategies in situ.