Identification of prodromal presentations of Parkinson's disease among primary care outpatients in Germany

Background: This study aimed to identify clinical features that predate the diagnosis of PD in a primary care setting. Methods: This retrospective case-control study was based on data from the Disease Analyzer database (IQVIA) and included 17,702 patients with Parkinson's disease and 17,702 non-PD controls matched for age, sex, and index year. We analyzed the prevalence of 15 defined diagnoses and symptoms documented within 2 years, ≥2 to <5, and ≥5 to <10 years prior to the index date in patients with and without PD. Logistic regression analyses were conducted to assess the association between PD and the predefined diagnoses. Results: The prevalence of motor, neuropsychiatric and autonomic features was higher in those with a later diagnosis of Parkinson's disease than controls for all three periods except for rigidity in the ≥2 to <5 and ≥5 to <10-year periods and erectile dysfunction in the most recent period before diagnosis. The clinical presentation recorded in the greatest percentage of patients was depression, followed by dizziness, insomnia, and constipation, but these were also common in the control population. The odds ratios were highest for increase in tremor, followed by balance impairment and memory problems, particularly in the latest period before diagnosis, and by constipation particularly in the earliest period examined. Conclusion: The prodromal features of PD could be identified in this large primary care database in Germany with similar results to those found in previous database studies despite differences in methodologies and systems

Finite size corrections to random Boolean networks

Since their introduction, Boolean networks have been traditionally studied in view of their rich dynamical behavior under different update protocols and for their qualitative analogy with cell regulatory networks. More recently, tools borrowed from statistical physics of disordered systems and from computer science have provided a more complete characterization of their equilibrium behavior. However, the largest part of the results have been obtained in the thermodynamic limit, which is often far from being reached when dealing with realistic instances of the problem. The numerical analysis presented here aims at comparing - for a specific family of models - the outcomes given by the heuristic belief propagation algorithm with those given by exhaustive enumeration. In the second part of the paper some analytical considerations on the validity of the annealed approximation are discussed.Comment: Minor correction

Repositioning the Catalytic Triad Aspartic Acid of Haloalkane Dehalogenase: Effects on Stability, Kinetics, and Structure

Haloalkane dehalogenase (DhlA) catalyzes the hydrolysis of haloalkanes via an alkyl-enzyme intermediate. The covalent intermediate, which is formed by nucleophilic substitution with Asp124, is hydrolyzed by a water molecule that is activated by His289. The role of Asp260, which is the third member of the catalytic triad, was studied by site-directed mutagenesis. Mutation of Asp260 to asparagine resulted in a catalytically inactive D260N mutant, which demonstrates that the triad acid Asp260 is essential for dehalogenase activity. Furthermore, Asp260 has an important structural role, since the D260N enzyme accumulated mainly in inclusion bodies during expression, and neither substrate nor product could bind in the active-site cavity. Activity for brominated substrates was restored to D260N by replacing Asn148 with an aspartic or glutamic acid. Both double mutants D260N+N148D and D260N+N148E had a 10-fold reduced kcat and 40-fold higher Km values for 1,2-dibromoethane compared to the wild-type enzyme. Pre-steady-state kinetic analysis of the D260N+N148E double mutant showed that the decrease in kcat was mainly caused by a 220-fold reduction of the rate of carbon-bromine bond cleavage and a 10-fold decrease in the rate of hydrolysis of the alkyl-enzyme intermediate. On the other hand, bromide was released 12-fold faster and via a different pathway than in the wild-type enzyme. Molecular modeling of the mutant showed that Glu148 indeed could take over the interaction with His289 and that there was a change in charge distribution in the tunnel region that connects the active site with the solvent. On the basis of primary structure similarity between DhlA and other α/β-hydrolase fold dehalogenases, we propose that a conserved acidic residue at the equivalent position of Asn148 in DhlA is the third catalytic triad residue in the latter enzymes.

Assessing cognitive dysfunction in Parkinson's disease: An online tool to detect visuo-perceptual deficits.

BackgroundPeople with Parkinson's disease (PD) who develop visuo-perceptual deficits are at higher risk of dementia, but we lack tests that detect subtle visuo-perceptual deficits and can be performed by untrained personnel. Hallucinations are associated with cognitive impairment and typically involve perception of complex objects. Changes in object perception may therefore be a sensitive marker of visuo-perceptual deficits in PD.ObjectiveWe developed an online platform to test visuo-perceptual function. We hypothesised that (1) visuo-perceptual deficits in PD could be detected using online tests, (2) object perception would be preferentially affected, and (3) these deficits would be caused by changes in perception rather than response bias.MethodsWe assessed 91 people with PD and 275 controls. Performance was compared using classical frequentist statistics. We then fitted a hierarchical Bayesian signal detection theory model to a subset of tasks.ResultsPeople with PD were worse than controls at object recognition, showing no deficits in other visuo-perceptual tests. Specifically, they were worse at identifying skewed images (P &lt; .0001); at detecting hidden objects (P = .0039); at identifying objects in peripheral vision (P &lt; .0001); and at detecting biological motion (P = .0065). In contrast, people with PD were not worse at mental rotation or subjective size perception. Using signal detection modelling, we found this effect was driven by change in perceptual sensitivity rather than response bias.ConclusionsOnline tests can detect visuo-perceptual deficits in people with PD, with object recognition particularly affected. Ultimately, visuo-perceptual tests may be developed to identify at-risk patients for clinical trials to slow PD dementia. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Advances in plant virus evolution: translating evolutionary insights into better disease management

[EN] Recent studies in plant virus evolution are revealing that genetic structure and behavior of virus and viroid populations can explain important pathogenic properties of these agents, such as host resistance breakdown, disease severity, and host shifting, among others. Genetic variation is essential for the survival of organisms. The exploration of how these subcellular parasites generate and maintain a certain frequency of mutations at the intra- and inter-host levels is revealing novel molecular virus plant interactions. They emphasize the role of host environment in the dynamic genetic composition of virus populations. Functional genomics has identified host factors that are transcriptionally altered after virus infections. The analyses of these data by means of systems biology approaches are uncovering critical plant genes specifically targeted by viruses during host adaptation. Also, a next-generation re-sequencing approach of a whole virus genome is opening new avenues to study virus recombination and the relationships between intra-host virus composition and pathogenesis. Altogether, the analyzed data indicate that systematic disruption of some specific parameters of evolving virus populations could lead to more efficient ways of disease prevention, eradication, or tolerable virus plant coexistence.Acosta-Leal, R.; Duffy, S.; Xiong, Z.; Hammond, R.; Elena Fito, SF. (2011). Advances in plant virus evolution: translating evolutionary insights into better disease management. Phytopathology. 101(10):1136-1148. doi:10.1094/ PHYTO-01-11-0017S113611481011

The functional neuroimaging correlates of psychogenic versus organic dystonia

The neurobiological basis of psychogenic movement disorders remains poorly understood and the management of these conditions difficult. Functional neuroimaging studies have provided some insight into the pathophysiology of disorders implicating particularly the prefrontal cortex, but there are no studies on psychogenic dystonia, and comparisons with findings in organic counterparts are rare. To understand the pathophysiology of these disorders better, we compared the similarities and differences in functional neuroimaging of patients with psychogenic dystonia and genetically determined dystonia, and tested hypotheses on the role of the prefrontal cortex in functional neurological disorders. Patients with psychogenic (n = 6) or organic (n = 5, DYT1 gene mutation positive) dystonia of the right leg, and matched healthy control subjects (n = 6) underwent positron emission tomography of regional cerebral blood flow. Participants were studied during rest, during fixed posturing of the right leg and during paced ankle movements. Continuous surface electromyography and footplate manometry monitored task performance. Averaging regional cerebral blood flow across all tasks, the organic dystonia group showed abnormal increases in the primary motor cortex and thalamus compared with controls, with decreases in the cerebellum. In contrast, the psychogenic dystonia group showed the opposite pattern, with abnormally increased blood flow in the cerebellum and basal ganglia, with decreases in the primary motor cortex. Comparing organic dystonia with psychogenic dystonia revealed significantly greater regional blood flow in the primary motor cortex, whereas psychogenic dystonia was associated with significantly greater blood flow in the cerebellum and basal ganglia (all P < 0.05, family-wise whole-brain corrected). Group × task interactions were also examined. During movement, compared with rest, there was abnormal activation in the right dorsolateral prefrontal cortex that was common to both organic and psychogenic dystonia groups (compared with control subjects, P < 0.05, family-wise small-volume correction). These data show a cortical-subcortical differentiation between organic and psychogenic dystonia in terms of regional blood flow, both at rest and during active motor tasks. The pathological prefrontal cortical activation was confirmed in, but was not specific to, psychogenic dystonia. This suggests that psychogenic and organic dystonia have different cortical and subcortical pathophysiology, while a derangement in mechanisms of motor attention may be a feature of both condition

The functional neuroimaging correlates of psychogenic versus organic dystonia

The neurobiological basis of psychogenic movement disorders remains poorly understood and the management of these conditions difficult. Functional neuroimaging studies have provided some insight into the pathophysiology of disorders implicating particularly the prefrontal cortex, but there are no studies on psychogenic dystonia, and comparisons with findings in organic counterparts are rare. To understand the pathophysiology of these disorders better, we compared the similarities and differences in functional neuroimaging of patients with psychogenic dystonia and genetically determined dystonia, and tested hypotheses on the role of the prefrontal cortex in functional neurological disorders. Patients with psychogenic (n = 6) or organic (n = 5, DYT1 gene mutation positive) dystonia of the right leg, and matched healthy control subjects (n = 6) underwent positron emission tomography of regional cerebral blood flow. Participants were studied during rest, during fixed posturing of the right leg and during paced ankle movements. Continuous surface electromyography and footplate manometry monitored task performance. Averaging regional cerebral blood flow across all tasks, the organic dystonia group showed abnormal increases in the primary motor cortex and thalamus compared with controls, with decreases in the cerebellum. In contrast, the psychogenic dystonia group showed the opposite pattern, with abnormally increased blood flow in the cerebellum and basal ganglia, with decreases in the primary motor cortex. Comparing organic dystonia with psychogenic dystonia revealed significantly greater regional blood flow in the primary motor cortex, whereas psychogenic dystonia was associated with significantly greater blood flow in the cerebellum and basal ganglia (all P &lt; 0.05, family-wise whole-brain corrected). Group × task interactions were also examined. During movement, compared with rest, there was abnormal activation in the right dorsolateral prefrontal cortex that was common to both organic and psychogenic dystonia groups (compared with control subjects, P &lt; 0.05, family-wise small-volume correction). These data show a cortical-subcortical differentiation between organic and psychogenic dystonia in terms of regional blood flow, both at rest and during active motor tasks. The pathological prefrontal cortical activation was confirmed in, but was not specific to, psychogenic dystonia. This suggests that psychogenic and organic dystonia have different cortical and subcortical pathophysiology, while a derangement in mechanisms of motor attention may be a feature of both conditions.</p

Uszkodzenie nadnerczy w następstwie tępych urazów: wskaźnik ciężkości doznanych obrażeń

Introduction: Adrenal gland injuries (AGI) are seen increasingly frequently owing to advances in modern imaging techniques. This study describes a series of patients with blunt AGI, with the emphasis on AGI as a marker of injury severity, CT-radiographic classification of AGI and associated injury patterns. Material and methods: A retrospective review of blunt trauma patients with AGI was performed. Variables examined included demographics, mechanism of injury, length of hospital and ICU stay, clinical status on admission, AGI characteristics, associated injuries, complications, procedures, mortality and discharge disposition. Results: There were 29 AGI patients with a mean injury severity score of 25. The most common injury mechanisms were motor-vehicular collisions (15/29) and falls (5/29). Right-sided AGI (16/29) outnumbered left-sided (12/29) injuries. The most common CT-radiographic types of AGI were adrenal gland contusions and lacerations with limited "blush". While patterns of injuries differed between right and left-sided AGI, the mean number of injuries did not. The most common associated injuries included extremity (21/29), rib (20/29) and spinal fractures (18/29). Common procedures included orthopaedic fixation (10/29), vena cava filter (8/29) and tracheostomy (5/29). A median of two complications per patient was reported, including adrenal insufficiency in two patients. Mortality was 17%. The median hospital and ICU length of stay were 15 and 12 days, respectively. Conclusions: Adrenal gland injury is associated with significant morbidity and mortality. With modern imaging modalities capable of reliably detecting adrenal injury, the presence of AGI should be considered a marker of overall injury severity. The authors provide a CT-radiographic classification of adrenal injuries.Wstęp: W związku z postępem w zakresie nowoczesnych metod obrazowania coraz częściej stwierdza się uszkodzenia nadnerczy (AGI, adrenal gland injuries). W tym badaniu opisano grupę chorych, którzy doznali uszkodzenia nadnerczy w wyniku tępego urazu. Zwrócono szczególną uwagę na AGI jako wskaźnik ciężkości odniesionych obrażeń, klasyfikację AGI na podstawie tomografii komputerowej i charakter współistniejących obrażeń. Materiał i metody: Przeprowadzono retrospektywną analizę danych pacjentów, którzy doznali AGI w wyniku tępego urazu. W badaniu uwzględniono dane demograficzne, mechanizm powstania urazu, czas hospitalizacji oraz pobytu na oddziale intensywnej opieki medycznej, stan kliniczny w chwili przyjęcia do szpitala, cechy AGI, doznane obrażenia, powikłania, zastosowane procedury medyczne, odsetek zgonów i dalsze postępowanie. Wyniki: Do badania włączono 29 osób z AGI, u których średnia ocena ciężkości obrażeń wynosiła 25. Najczęstszymi przyczynami urazu były wypadki motocyklowe (15/29) i upadki (5/29). Liczba prawostronnych AGI (16/29) była wyższa niż liczba uszkodzeń lewostronnych (12/29). Najczęściej stwierdzanym rodzajem uszkodzeń AGI w badaniu tomograficznym było stłuczenie i rozdarcie narządu z niewielkim krwawieniem. Chociaż charakter uszkodzeń różnił się w zależności od prawo- lub lewostronnej lokalizacji AGI, średnia liczba uszkodzeń była taka sama. Najczęstszymi współwystępującymi obrażeniami były złamania kończyn (21/29), żeber (20/29) i kręgów (18/29). Do najczęściej wykonywanych procedur należały: unieruchomienie ortopedyczne (10/29), wszczepienie filtra do żyły głównej (8/29) i tracheostomia (5/29). Mediana liczby powikłań u poszczególnych chorych wynosiła 2 (włączając niewydolność nadnerczy u 2 osób). Odsetek zgonów wynosił 17%. Mediana okresu hospitalizacji i pobytu na oddziale intensywnej opieki medycznej wynosiła odpowiednio 15 i 12 dni. Wnioski: Uszkodzenie nadnerczy wiąże się ze znaczną chorobowością i śmiertelnością. Dostępne obecnie nowoczesne metody obrazowania umożliwiają wykrycie uszkodzeń nadnerczy. Należałoby rozważyć przyjęcie obecności AGI jako markera ciężkości doznanych obrażeń. Autorzy przedstawili klasyfikację uszkodzeń nadnerczy na podstawie badań tomograficznych

Climate Engineering Responses to Climate Emergencies

Despite efforts to stabilize CO_2 concentrations, it is possible that the climate system could respond abruptly with catastrophic consequences. Intentional intervention in the climate system to avoid or ameliorate such consequences has been proposed as one possible response, should such a scenario arise. In a one-week study, the authors of this report conducted a technical review and evaluation of proposed climate engineering concepts that might serve as a rapid palliative response to such climate emergency scenarios. Because of their potential to induce a prompt (less than one year) global cooling, this study concentrated on Shortwave Climate Engineering (SWCE) methods for moderately reducing the amount of shortwave solar radiation reaching the Earth. The study's main objective was to outline a decade-long agenda of technical research that would maximally reduce the uncertainty surrounding the benefits and risks associated with SWCE. For rigor of technical analysis, the study focused the research agenda on one particular SWCE concept--stratospheric aerosol injection--and in doing so developed several conceptual frameworks and methods valuable for assessing any SWCE proposal.Comment: 66 pp., 5 figs., published by Novim, Santa Barbara, Cal., revised referenc