Faster disease progression in Parkinson's disease with type 2 diabetes is not associated with increased α-synuclein, tau, amyloid-β or vascular pathology

AIMS: Growing evidence suggests a shared pathogenesis between Parkinson's disease and diabetes although the underlying mechanisms remain unknown. The aim of this study is to evaluate the effect of type 2 diabetes on Parkinson's disease progression and to correlate neuropathological findings to elucidate pathogenic mechanisms. METHODS: In this cohort study, medical records were retrospectively reviewed of cases with pathologically-confirmed Parkinson's disease with and without pre-existing type 2 diabetes. Time to disability milestones (recurrent falls, wheelchair dependence, dementia, and care home placement) and survival were compared to assess disease progression and their risk estimated using Cox hazard regression models. Correlation with pathological data was performed, including quantification of α-synuclein in key brain regions and staging of vascular, Lewy and Alzheimer's pathologies. RESULTS: Patients with PD and diabetes (male 76%; age at death 78.6 ± 6.2 years) developed earlier falls (P < 0.001), wheelchair dependence (P = 0.004), dementia (P < 0.001), care home admission (P < 0.001) and had reduced survival (P < 0.001). Predating diabetes was independently associated with a two to three-fold increase in the risk of disability and death. Neuropathological assessment did not show any differences in global or regional vascular pathology, α-synuclein load in key brain areas, staging of Lewy pathology or Alzheimer's disease pathology. CONCLUSIONS: Pre-existing type 2 diabetes contributes to faster disease progression and reduced survival in Parkinson's disease which is not driven by increased vascular, Lewy or Alzheimer's pathologies. Additional non-specific neurodegeneration related to chronic brain insulin resistance may be involved

Porous medium equation with nonlocal pressure

We provide a rather complete description of the results obtained so far on the nonlinear diffusion equation $u_t=\nabla\cdot (u^{m-1}\nabla (-\Delta)^{-s}u)$, which describes a flow through a porous medium driven by a nonlocal pressure. We consider constant parameters $m>1$ and $0<s<1$, we assume that the solutions are non-negative, and the problem is posed in the whole space. We present a theory of existence of solutions, results on uniqueness, and relation to other models. As new results of this paper, we prove the existence of self-similar solutions in the range when $N=1$ and $m>2$, and the asymptotic behavior of solutions when $N=1$. The cases $m = 1$ and $m = 2$ were rather well known.Comment: 24 pages, 2 figure

Death, dying and informatics: misrepresenting religion on MedLine

BACKGROUND: The globalization of medical science carries for doctors worldwide a correlative duty to deepen their understanding of patients' cultural contexts and religious backgrounds, in order to satisfy each as a unique individual. To become better informed, practitioners may turn to MedLine, but it is unclear whether the information found there is an accurate representation of culture and religion. To test MedLine's representation of this field, we chose the topic of death and dying in the three major monotheistic religions. METHODS: We searched MedLine using PubMed in order to retrieve and thematically analyze full-length scholarly journal papers or case reports dealing with religious traditions and end-of-life care. Our search consisted of a string of words that included the most common denominations of the three religions, the standard heading terms used by the National Reference Center for Bioethics Literature (NRCBL), and the Medical Subject Headings (MeSH) used by the National Library of Medicine. Eligible articles were limited to English-language papers with an abstract. RESULTS: We found that while a bibliographic search in MedLine on this topic produced instant results and some valuable literature, the aggregate reflected a selection bias. American writers were over-represented given the global prevalence of these religious traditions. Denominationally affiliated authors predominated in representing the Christian traditions. The Islamic tradition was under-represented. CONCLUSION: MedLine's capability to identify the most current, reliable and accurate information about purely scientific topics should not be assumed to be the same case when considering the interface of religion, culture and end-of-life care

Association of autonomic symptoms with disease progression and survival in progressive supranuclear palsy

BACKGROUND: Development of autonomic failure is associated with more rapid disease course and shorter survival in patients with Parkinson's disease and multiple system atrophy. However, autonomic symptoms have not been specifically assessed as a prognostic factor in progressive supranuclear palsy (PSP). We evaluated whether development of autonomic symptoms is associated with disease progression and survival in PSP. METHODS: A retrospective review of clinical data from consecutive patients with autopsy-confirmed PSP from the Queen Square Brain Bank between January 2012 and November 2016 was performed. Time from disease onset to four autonomic symptoms (constipation, urinary symptoms, erectile dysfunction and orthostatic hypotension) were noted. Time from diagnosis to five disease milestones and survival were calculated to assess disease progression, and their risk was estimated through a Cox proportional hazards model. RESULTS: A total of 103 PSP patients were included. Urinary symptoms and constipation were present in 81% and 71% of cases, respectively. Early development of constipation and urinary symptoms were associated with higher risk of reaching the first disease milestone (respectively, HR: 0.88; 95% CI 0.83 to 0.92; p<0.001; and HR: 0.80; 95% CI 0.75 to 0.86; p<0.001) and with a shorter survival in these patients (respectively, HR: 0.73; 95% CI 0.64 to 0.84; p<0.001; and HR: 0.88; 95% CI 0.80 to 0.96; p=0.004). On multivariate analysis, Richardson syndrome phenotype was the other variable independently associated with shorter survival. CONCLUSIONS: Earlier urinary symptoms and constipation are associated with a more rapid disease progression and reduced survival in patients with PSP

An exact expression to calculate the derivatives of position-dependent observables in molecular simulations with flexible constraints

In this work, we introduce an algorithm to compute the derivatives of physical observables along the constrained subspace when flexible constraints are imposed on the system (i.e., constraints in which the hard coordinates are fixed to configuration-dependent values). The presented scheme is exact, it does not contain any tunable parameter, and it only requires the calculation and inversion of a sub-block of the Hessian matrix of second derivatives of the function through which the constraints are defined. We also present a practical application to the case in which the sought observables are the Euclidean coordinates of complex molecular systems, and the function whose minimization defines the constraints is the potential energy. Finally, and in order to validate the method, which, as far as we are aware, is the first of its kind in the literature, we compare it to the natural and straightforward finite-differences approach in three molecules of biological relevance: methanol, N-methyl-acetamide and a tri-glycine peptideComment: 13 pages, 8 figures, published versio

Phosphorylated Dihydroceramides from Common Human Bacteria Are Recovered in Human Tissues

Novel phosphorylated dihydroceramide (PDHC) lipids produced by the periodontal pathogen Porphyromonas gingivalis include phosphoethanolamine (PE DHC) and phosphoglycerol dihydroceramides (PG DHC) lipids. These PDHC lipids mediate cellular effects through Toll-like receptor 2 (TLR2) including promotion of IL-6 secretion from dendritic cells and inhibition of osteoblast differentiation and function in vitro and in vivo. The PE DHC lipids also enhance (TLR2)-dependent murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. The unique non-mammalian structures of these lipids allows for their specific quantification in bacteria and human tissues using multiple reaction monitoring (MRM)-mass spectrometry (MS). Synthesis of these lipids by other common human bacteria and the presence of these lipids in human tissues have not yet been determined. We now report that synthesis of these lipids can be attributed to a small number of intestinal and oral organisms within the Bacteroides, Parabacteroides, Prevotella, Tannerella and Porphyromonas genera. Additionally, the PDHCs are not only present in gingival tissues, but are also present in human blood, vasculature tissues and brain. Finally, the distribution of these TLR2-activating lipids in human tissues varies with both the tissue site and disease status of the tissue suggesting a role for PDHCs in human disease

Identification of multiple system atrophy mimicking Parkinson's disease or progressive supranuclear palsy

WWe studied a subset of patients with autopsy-confirmed multiple system atrophy who presented a clinical picture that closely resembled either Parkinson’s disease or progressive supranuclear palsy. These mimics are not captured by the current diagnostic criteria for multiple system atrophy. Among 218 autopsy-proven multiple system atrophy cases reviewed, 177 (81.2%) were clinically diagnosed and pathologically confirmed as multiple system atrophy (i.e. typical cases), while the remaining 41 (18.8%) had received an alternative clinical diagnosis, including Parkinson’s disease (i.e. Parkinson’s disease mimics; n = 16) and progressive supranuclear palsy (i.e. progressive supranuclear palsy mimics; n = 17). We also reviewed the clinical records of another 105 patients with pathologically confirmed Parkinson’s disease or progressive supranuclear palsy, who had received a correct final clinical diagnosis (i.e. Parkinson’s disease, n = 35; progressive supranuclear palsy-Richardson syndrome, n = 35; and progressive supranuclear palsy-parkinsonism, n = 35). We investigated 12 red flag features that would support a diagnosis of multiple system atrophy according to the current diagnostic criteria. Compared with typical multiple system atrophy, Parkinson’s disease mimics more frequently had a good levodopa response and visual hallucinations. Vertical gaze palsy and apraxia of eyelid opening were more commonly observed in progressive supranuclear palsy mimics. Multiple logistic regression analysis revealed an increased likelihood of having multiple system atrophy [Parkinson’s disease mimic versus typical Parkinson’s disease, odds ratio (OR): 8.1; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 2.3] if a patient developed any one of seven selected red flag features in the first 10 years of disease. Severe autonomic dysfunction (orthostatic hypotension and/or urinary incontinence with the need for a urinary catheter) was more frequent in clinically atypical multiple system atrophy than other parkinsonian disorders (Parkinson’s disease mimic versus typical Parkinson’s disease, OR: 4.1; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 8.8). The atypical multiple system atrophy cases more frequently had autonomic dysfunction within 3 years of symptom onset than the pathologically confirmed patients with Parkinson’s disease or progressive supranuclear palsy (Parkinson’s disease mimic versus typical Parkinson’s disease, OR: 4.7; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 2.7). Using all included clinical features and 21 early clinical features within 3 years of symptom onset, we developed decision tree algorithms with combinations of clinical pointers to differentiate clinically atypical cases of multiple system atrophy from Parkinson’s disease or progressive supranuclear palsy

Measuring track vertical stiffness through dynamic monitoring

[EN] This paper proposes a methodology for the evaluation of the track condition by means of the measurement of the track stiffness. This magnitude is calculated from vertical acceleration data measured at the axle box of trains during their normal operation. From the corresponding vertical acceleration spectra, the dominant vibration frequencies for each track stretch are identified and the combined stiffness is then determined. Then the stiffness without the contribution of the rail is calculated. The results obtained for a High Speed ballasted track in several track stretches are within the range 120-130 kN/mm, a result consistent with direct stiffness measurements taken during previous studies. Therefore, the proposed methodology may be used to obtain a first insight to the track condition by means of a continuous measurement of the track combined stiffness. This offers an alternative to traditional stationary stiffness measuring devices and might be a useful complement to dedicated continuous monitoring vehicles.Cano, MJ.; Martínez Fernández, P.; Insa Franco, R. (2016). Measuring track vertical stiffness through dynamic monitoring. Proceedings of the Institution of Civil Engineers - Transport. 169(1). doi:10.1680/jtran.14.00081S169