Multiple verification in computational modeling of bone pathologies

We introduce a model checking approach to diagnose the emerging of bone pathologies. The implementation of a new model of bone remodeling in PRISM has led to an interesting characterization of osteoporosis as a defective bone remodeling dynamics with respect to other bone pathologies. Our approach allows to derive three types of model checking-based diagnostic estimators. The first diagnostic measure focuses on the level of bone mineral density, which is currently used in medical practice. In addition, we have introduced a novel diagnostic estimator which uses the full patient clinical record, here simulated using the modeling framework. This estimator detects rapid (months) negative changes in bone mineral density. Independently of the actual bone mineral density, when the decrease occurs rapidly it is important to alarm the patient and monitor him/her more closely to detect insurgence of other bone co-morbidities. A third estimator takes into account the variance of the bone density, which could address the investigation of metabolic syndromes, diabetes and cancer. Our implementation could make use of different logical combinations of these statistical estimators and could incorporate other biomarkers for other systemic co-morbidities (for example diabetes and thalassemia). We are delighted to report that the combination of stochastic modeling with formal methods motivate new diagnostic framework for complex pathologies. In particular our approach takes into consideration important properties of biosystems such as multiscale and self-adaptiveness. The multi-diagnosis could be further expanded, inching towards the complexity of human diseases. Finally, we briefly introduce self-adaptiveness in formal methods which is a key property in the regulative mechanisms of biological systems and well known in other mathematical and engineering areas.Comment: In Proceedings CompMod 2011, arXiv:1109.104

Supplementation with n-3 long-chain polyunsaturated fatty acids or olive oil in men and women with renal disease induces differential changes in the DNA methylation of FADS2 and ELOVL5 in peripheral blood mononuclear cells

BACKGROUND: Studies in animal models and in cultured cells have shown that fatty acids can induce alterations in the DNA methylation of specific genes. There have been no studies of the effects of fatty acid supplementation on the epigenetic regulation of genes in adult humans.METHODS AND RESULTS: We investigated the effect of supplementing renal patients with 4 g daily of either n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) or olive oil (OO) for 8 weeks on the methylation status of individual CpG loci in the 5' regulatory region of genes involved in PUFA biosynthesis in peripheral blood mononuclear cells from men and women (aged 53 to 63 years). OO and n-3 LCPUFA each altered (>10% difference in methylation) 2/22 fatty acid desaturase (FADS)-2 CpGs, while n-3 LCPUFA, but not OO, altered (>10%) 1/12 ELOVL5 CpGs in men. OO altered (>6%) 8/22 FADS2 CpGs and (>3%) 3/12 elongase (ELOVL)-5 CpGs, while n-3 LCPUFA altered (>5%) 3/22 FADS2 CpGs and 2/12 (>3%) ELOVL5 CpGs in women. FADS1 or ELOVL2 methylation was unchanged. The n-3 PUFA supplementation findings were replicated in blood DNA from healthy adults (aged 23 to 30 years). The methylation status of the altered CpGs in FADS2 and ELOVL5 was associated negatively with the level of their transcripts.CONCLUSIONS: These findings show that modest fatty acid supplementation can induce altered methylation of specific CpG loci in adult humans, contingent on the nature of the supplement and on sex. This has implications for understanding the effect of fatty acids on PUFA metabolism and cell function

What is the impact of n-3 PUFAs on inflammation markers in Type 2 diabetic mellitus populations?: a systematic review and meta-analysis of randomized controlled trials

ObjectivesTo explore the possible role of n-3 polyunsaturated fatty acids (PUFAs) in lowering inflammation markers in individuals with type 2 diabetes mellitus.MethodsPubMed, CNKI and Cochrane databases were searched until December 30, 2015; references from papers or reviews were also retrieved and screened. Screening was performed by two independent researchers, and randomized controlled trials reporting the specific n-3 PUFA type, dose, frequency, and duration of treatment, as well as the baseline and follow-up concentrations of inflammation markers, including interleukin 2 (IL-2), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-?) and C-reactive protein (CRP), were selected for final analysis. Data analysis was performed using RevMan 5.2 software.ResultsEight studies involving 955 participants were included; all reported CRP. Only one included study reported IL-2 or IL-6 while two studies reported TNF-?. N-3 PUFAs significantly reduced CRP concentration compared with control [SMD 95 % CI, 1.90 (0.64, 3.16), Z?=?2.96, P?=?0.003, random effect model].ConclusionsN-3 PUFAs decrease CRP concentration in type-2 diabetes mellitus. However, larger and rigorously designed RCTs are required to confirm this finding and extend it into other inflammatory biomarkers

The Equivalence between Biology and Computation

Abstract. A major challenge in computational systems biology is the articulation of a biological process in a form which can be understood by the biologist yet is amenable to computational execution. Process calculi have proved to especially powerful computational tools for mod-elling and reasoning about biological processes and we have previously described, and implemented, a Narrative approach to describing biolog-ical models which is a biologically intuitive high level language that can be translated into executable process calculus programs. Here we discuss an extension to the narrative approach which attempts to directly link biological data with Narrative primitives by suggesting an equivalence relationship between a string (the amino acid sequence) and a process. We outline future challenges in applying this approach more generally.

What is a natural cause of death? A survey of how coroners in England and Wales approach borderline cases

Aim—Many deaths fall in the "grey" area between those that are clearly natural and those that are unnatural. There are no guidelines to help doctors in dealing with such cases and death certification is often arbitrary and inconsistent. In an attempt to initiate debate on these difficult areas, and with the ultimate aim of achieving national consensus, the views of coroners in England and Wales were sought. Methods—Sixteen clinical scenarios, with causes of death, were circulated to all coroners in England and Wales. For each case they were asked to provide a verdict, with explanation. The deaths fell into three groups: (1) postoperative, (2) a combination of trauma and natural disease, and (3) infectious disease. Results—Sixty four questionnaires were returned. There was near consensus (> 80% concordance) in only two of the 16 cases. In five, there was no significant agreement between coroners in the verdicts returned ("natural causes" versus "misadventure/accidental"). These included all three cases in which death resulted from a combination of trauma and natural disease (a fall after a grand mal fit; falls resulting in fractures of bones affected by metastatic carcinoma and osteoporosis), bronchopneumonia after hip replacement for osteoarthritis, and new variant Creutzfeldt-Jakob disease. The comments made for each case indicate that the variation between coroners in whether or not to hold an inquest, and the verdict arrived at, reflect the lack of a definition for natural causes, together with differences in the personal attitudes of each coroner. Conclusions—There is considerable variation in the way in which coroners approach these borderline cases, many of which are common in clinical practice. This study indicates a need for discussion, working towards a national consensus on such issues. It highlights the importance of good communication between coroners and medical staff at a local level. Key Words: coroner • necropsy • death certificatio