Computational analysis of the behavior of atmospheric pollution due to demographic, structural factors, vehicular flow and commerce activities

According to the latest assessments made by the world health organization (WHO2016), the atmospheric pollution (air), has become one of the main causes of morbidity and mortality in the world, with a steep growth of respiratory diseases, increase in lung cancer, ocular complications, and dermis diseases [1,2,3]. Currently, there are governments which still underestimate investments in environmental care, turning their countries into only consumers and predators of the ecosystem [1,2,3]. Worldwide, several cities have been implementing different regional strategies to decrease environmental pollution, however, these actions have not been effective enough and significant indices of contamination and emergency declarations persist [1,2,3]. Medellín is one of the cities most affected by polluting gases in Latin America due to the high growth of construction sector, high vehicular flow, increase in commerce, besides a little assertive planting trees system, among other reasons [1,2,3]. With the purpose of providing new researching elements which benefit the improvement of air quality in the cities of the world, it is pretended to mathematically model and computationally implement the behavior of the flow of air, e.g., in zones in the city of Medellín to determine the extent of pollution by tightness, impact of current architectural designs, vehicular transport, high commerce flow, and confinement in the public transport system. The simulations allowed to identify spotlights of particulate tightness caused by architectural designs of the city which do not benefit air flow. Also, recirculating gases were observed in different zones of the city. This research can offer greater knowledge around the incidence of pollution generated by structures and architecture. Likewise, these studies can contribute to a better urban, structural and ecological reordering in cities, the implementation of an assertive arborization system, and the possibility to orientate effective strategies over cleaning (purification) and contaminant extracting systems

Staging of Neurofibrillary Pathology in Alzheimer's Disease: A Study of the BrainNet Europe Consortium

It has been recognized that molecular classifications will form the basis for neuropathological diagnostic work in the future. Consequently, in order to reach a diagnosis of Alzheimer's disease (AD), the presence of hyperphosphorylated tau (HP-tau) and β-amyloid protein in brain tissue must be unequivocal. In addition, the stepwise progression of pathology needs to be assessed. This paper deals exclusively with the regional assessment of AD-related HP-tau pathology. The objective was to provide straightforward instructions to aid in the assessment of AD-related immunohistochemically (IHC) detected HP-tau pathology and to test the concordance of assessments made by 25 independent evaluators. The assessment of progression in 7-µm-thick sections was based on assessment of IHC labeled HP-tau immunoreactive neuropil threads (NTs). Our results indicate that good agreement can be reached when the lesions are substantial, i.e., the lesions have reached isocortical structures (stage V–VI absolute agreement 91%), whereas when only mild subtle lesions were present the agreement was poorer (I–II absolute agreement 50%). Thus, in a research setting when the extent of lesions is mild, it is strongly recommended that the assessment of lesions should be carried out by at least two independent observers

Changes of tau profiles in brains of the hamsters infected with scrapie strains 263 K or 139 A possibly associated with the alteration of phosphate kinases

<p>Abstract</p> <p>Background</p> <p>Phospho-tau deposition has been described in a rare genetic human prion disease, Gerstmann-Sträussler-Scheinker syndrome, but is not common neuropathological picture for other human and animal transmissible spongiform encephalopathies (TSEs). This study investigated the possible changes of tau and phosphorylated tau (p-tau, at Ser396, Ser404, and Ser202/Thr205) in scrapie experimental animals.</p> <p>Methods</p> <p>The profiles of tau and p-tau (p-tau, at Ser396, Ser404, and Ser202/Thr205) in the brain tissues of agents 263K- or 139A-infected hamsters were evaluated by Western blots and real-time PCR. Meanwhile, the transcriptional and expressive levels of GSK3β and CDK5 in the brains were tested.</p> <p>Results</p> <p>The contents of total tau and p-tau at Ser202/Thr205 increased, but p-tau at Ser396 and Ser404 decreased at the terminal stages, regardless of scrapie strains. Transcriptional levels of two tau isoforms were also increased. Additionally, it showed higher CDK5, but lower GSK3β transcriptional and expressive levels in the brains of scrapie-infected animals. Analysis of brain samples collected from different times after inoculated with agent 263 K revealed that the changes of tau profiles and phosphate kinases were time-relative events.</p> <p>Conclusion</p> <p>These data suggest that changes of profiles of p-tau at Ser396, Ser404 and Ser202/Thr205 are illness-correlative phenomena in TSEs, which may arise of the alteration of phosphate kinases. Alteration of tau, p-tau (Ser396, Ser404, and Ser202/Thr205), GSK3β and CDK5 were either intermediate or consequent events in TSE pathogenesis and proposed the potential linkage of these bioactive proteins with the pathogenesis of prion diseases.</p

Myoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions

Myoglobin, encoded by MB, is a small cytoplasmic globular hemoprotein highly expressed in cardiac myocytes and oxidative skeletal myofibers. Myoglobin binds O-2, facilitates its intracellular transport and serves as a controller of nitric oxide and reactive oxygen species. Here, we identify a recurrent c.292C>T ( p.His98Tyr) substitution in MB in fourteen members of six European families suffering from an autosomal dominant progressive myopathy with highly characteristic sarcoplasmic inclusions in skeletal and cardiac muscle. Myoglobinopathy manifests in adulthood with proximal and axial weakness that progresses to involve distal muscles and causes respiratory and cardiac failure. Biochemical characterization reveals that the mutant myoglobin has altered O-2 binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin. Preliminary studies show that mutant myoglobin may result in elevated superoxide levels at the cellular level. These data define a recognizable muscle disease associated with MB mutation.Peer reviewe

Assessment of β-amyloid deposits in human brain: a study of the BrainNet Europe Consortium

β-Amyloid (Aβ) related pathology shows a range of lesions which differ both qualitatively and quantitatively. Pathologists, to date, mainly focused on the assessment of both of these aspects but attempts to correlate the findings with clinical phenotypes are not convincing. It has been recently proposed in the same way as ι and α synuclein related lesions, also Aβ related pathology may follow a temporal evolution, i.e. distinct phases, characterized by a step-wise involvement of different brain-regions. Twenty-six independent observers reached an 81% absolute agreement while assessing the phase of Aβ, i.e. phase 1 = deposition of Aβ exclusively in neocortex, phase 2 = additionally in allocortex, phase 3 = additionally in diencephalon, phase 4 = additionally in brainstem, and phase 5 = additionally in cerebellum. These high agreement rates were reached when at least six brain regions were evaluated. Likewise, a high agreement (93%) was reached while assessing the absence/presence of cerebral amyloid angiopathy (CAA) and the type of CAA (74%) while examining the six brain regions. Of note, most of observers failed to detect capillary CAA when it was only mild and focal and thus instead of type 1, type 2 CAA was diagnosed. In conclusion, a reliable assessment of Aβ phase and presence/absence of CAA was achieved by a total of 26 observers who examined a standardized set of blocks taken from only six anatomical regions, applying commercially available reagents and by assessing them as instructed. Thus, one may consider rating of Aβ-phases as a diagnostic tool while analyzing subjects with suspected Alzheimer’s disease (AD). Because most of these blocks are currently routinely sampled by the majority of laboratories, assessment of the Aβ phase in AD is feasible even in large scale retrospective studies

Computational analysis of the behavior of atmospheric pollution due to demographic, structural factors, vehicular flow and commerce activities

According to the latest assessments made by the world health organization (WHO2016), the atmospheric pollution (air), has become one of the main causes of morbidity and mortality in the world, with a steep growth of respiratory diseases, increase in lung cancer, ocular complications, and dermis diseases [1,2,3]. Currently, there are governments which still underestimate investments in environmental care, turning their countries into only consumers and predators of the ecosystem [1,2,3]. Worldwide, several cities have been implementing different regional strategies to decrease environmental pollution, however, these actions have not been effective enough and significant indices of contamination and emergency declarations persist [1,2,3]. Medellín is one of the cities most affected by polluting gases in Latin America due to the high growth of construction sector, high vehicular flow, increase in commerce, besides a little assertive planting trees system, among other reasons [1,2,3]. With the purpose of providing new researching elements which benefit the improvement of air quality in the cities of the world, it is pretended to mathematically model and computationally implement the behavior of the flow of air, e.g., in zones in the city of Medellín to determine the extent of pollution by tightness, impact of current architectural designs, vehicular transport, high commerce flow, and confinement in the public transport system. The simulations allowed to identify spotlights of particulate tightness caused by architectural designs of the city which do not benefit air flow. Also, recirculating gases were observed in different zones of the city. This research can offer greater knowledge around the incidence of pollution generated by structures and architecture. Likewise, these studies can contribute to a better urban, structural and ecological reordering in cities, the implementation of an assertive arborization system, and the possibility to orientate effective strategies over cleaning (purification) and contaminant extracting systems

A post-mortem study to compare the 5-HT1A receptor binding of a PET agonist and a PET antagonist in Alzheimer's disease

Présentation oraleInternational audienceAim. The 5-HT1A serotonin receptors located in hippocampus are known to be linked to memory processes. PET clinical imaging studies with [18F]MPPF have documented the decrease of 5-HT1A receptor expression in Alzheimer's disease patients, interpreted as neuronal loss. Interestingly, other [18F]MPPF PET studies have reported a specific increase in hippocampal 5-HT1A receptor binding during a pre-dementia stage of Alzheimer's disease (mild cognitive impairment). If this increase in [18F]MPPF binding may be explained by compensatory mechanisms, the pharmacological properties of this PET radiotracer limit its biological interpretation. It is known indeed that [18F]MPPF, which is an antagonist like a majority of available PET receptor radioligands, binds non-specifically to the high-affinity state of 5-HT1A receptors (functional) and to the low-affinity state of these receptors (decoupled from G proteins and non-functional). On the contrary, an agonist binds selectively to the high-affinity state of the receptor which are functional. The Aim of this study is demonstrate that the binding of a 5-HT1A PET agonist provides complementary information to the binding of a 5-HT1A PET antagonist, to improve understanding of the functional impairment of 5-HT1A receptors during Alzheimer's disease. Materials and MJethods. We compared in postmortem human brain sections the specific binding of [18F]F15599, a 5-HT1A PET agonist we developed previously, with the specific binding of [18F]MPPF, a 5-HT1A PET antagonist. Thirty-µm coronal sections were cut across hippocampi of 18 patients at different Braak's stages (from 0 to VI). The days of radiotracers synthesis, the brain slides were incubated in a saline buffer containing 37 kBq/mL of [18F]MPPF or [18F]F15599. Hippocampal subregions were drawn according to a brain atlas and binding quantification was performed with extemporaneous fluorine-18 scales. The specific binding of both radiotracers was determined by addition of 100 nM of serotonin and the agonist binding of [18F]F15599 was revealed by addition of 10 μM of Gpp(NH)p. Results and Conclusion. The autoradiography distribution of both 5-HT1A PET radiotracers varied across hippocampus regions. The highest binding density was found in the pyramidal layer of CA1, followed by the molecular layer of the dentate gyrus. The incubation with 10 μM of Gpp(NH)p, a non-hydrolysable analogue of GTP, reduced significantly [18F]F15599 binding, confirming its specific binding to G-coupled 5-HT1A receptors. [18F]F15599 binding compared to [18F]MPPF binding revealed specific modifications of the density of functional 5-HT1A correlated to the Braak's stages. These results justify an extension of this concept of functional PET imaging in clinical studies

Diffusion-weighted imaging in brain aspergillosis

articleBrain aspergillosis is a rare pathology, occurring mainly in immunocompromised patients, responsible for multiple cerebral septic infarctions. Some researchers have described magnetic resonance (MR) findings in cerebral invasive aspergillosis, but diffusion-weighted imaging (DWI) has rarely been reported, especially in typical non-enhancing lesions, while it may be helpful for early differential diagnosis and may allow earlier antifungal treatment. We describe three cases of patients presenting brain aspergillosis, with MR imaging including diffusion-weighted sequences and apparent diffusion coefficient (ADC) cartography. The three patients described in this study presented a total of 23 circular lesions, and one patient presented an infarction area in the territory of the right middle cerebral artery. Lesions were ring-enhancing for one patient, and presented no enhancement for the other two. Eleven lesions were very bright on DWI, with reduced ADC values. Twelve lesions, either enhancing or not enhancing, presented a 'target-like' aspect with central and peripheral hypointense areas on DWI, corresponding to higher ADC value areas, and intermediate marked hypersignal on DWI. This typical aspect of aspergillosis lesions on DWI may allow early diagnosis and treatment of cerebral aspergillosis, and is helpful for differentiating aspergillosis lesions from other infectious or malignant lesions affecting immunocompromised patients

Motor neuron involvement in anti-Ma2-associated paraneoplastic neurological syndrome

Objective: To present clinical, radiological, and pathological features of a cohort of patients with motor neuron involvement in association with anti-Ma2 antibodies (Ma2-Ab). Methods: Retrospective case-series of patients with definite paraneoplastic neurological syndrome (PNS) and Ma2-Ab, and cases identified from a review of the literature. Results: Among 33 Ma2-Ab patients referred between 2002 and 2016, we retrospectively identified three patients (9.1%) with a motor neuron syndrome (MNS). Seven additional cases were retrieved among the 75 Ma2-patients reported in the literature (9.3%). A total of ten patients are, therefore, described herein. MNS was evident as combined upper and lower MNS in four patients, isolated upper MNS in two, and isolated lower MNS in one; three patients were diagnosed with myeloradiculopathy. The most common MNS signs/symptoms were: hyperreflexia (80%), proximal weakness (60%), proximal upper-limb fasciculations (50%), head drop (40%), and dysarthria/dysphagia (30%). Brain MRI abnormalities included bilateral pyramidal tract T2-weighted/FLAIR hyperintensities (three patients). Spine MRI found bilateral, symmetric, T2-weighted signal abnormalities in the anterior horn in two patients. CSF examination was abnormal in nine patients. Cancer was found in seven patients (four testicular, two lung, and one mesothelioma). Eight patients underwent first-line immunotherapy. Second-line immunotherapy was adopted in all our patients and in none of those identified in the literature. Motor improvement was observed in 33% of our patients, and 20% in the literature series. Conclusions: Motor neuron involvement could complicate Ma2-Ab-associated PNS in almost 10% of patients and must be carefully studied to adapt treatment. This disorder differs from amyotrophic lateral sclerosis

Histone deacetylase 6 is a FoxO transcription factor-dependent effector in skeletal muscle atrophy.

Skeletal muscle atrophy is a severe condition of muscle mass loss. Muscle atrophy is caused by a down-regulation of protein synthesis and by an increase of protein breakdown due to the ubiquitin-proteasome system and autophagy activation. Up-regulation of specific genes, such as the muscle-specific E3 ubiquitin ligase MAFbx, by FoxO transcription factors is essential to initiate muscle protein ubiquitination and degradation during atrophy. HDAC6 is a particular HDAC, which is functionally related to the ubiquitin proteasome system via its ubiquitin binding domain. We show that HDAC6 is up-regulated during muscle atrophy. HDAC6 activation is dependent on the transcription factor FoxO3a, and the inactivation of HDAC6 in mice protects against muscle wasting. HDAC6 is able to interact with MAFbx, a key ubiquitin ligase involved in muscle atrophy. Our findings demonstrate the implication of HDAC6 in skeletal muscle wasting and identify HDAC6 as a new downstream target of FoxO3a in stress response. This work provides new insights in skeletal muscle atrophy development and opens interesting perspectives on HDAC6 as a valuable marker of muscle atrophy and a potential target for pharmacological treatments