Henoch-Schönlein Purpura in children: Not only kidney but also lung

Background: Henoch-Sch\uf6nlein Purpura (HSP) is the most common vasculitis of childhood and affects the small blood vessels. Pulmonary involvement is a rare complication of HSP and diffuse alveolar hemorrhage (DAH) is the most frequent clinical presentation. Little is known about the real incidence of lung involvement during HSP in the pediatric age and about its diagnosis, management and outcome. Methods: In order to discuss the main clinical findings and the diagnosis and management of lung involvement in children with HSP, we performed a review of the literature of the last 40 years. Results: We identified 23 pediatric cases of HSP with lung involvement. DAH was the most frequent clinical presentation of the disease. Although it can be identified by chest x-ray (CXR), bronchoalveolar lavage (BAL) is the gold standard for diagnosis. Pulse methylprednisolone is the first-line of therapy in children with DAH. An immunosuppressive regimen consisting of cyclophosphamide or azathioprine plus corticosteroids is required when respiratory failure occurs. Four of the twenty-three patients died, while 18 children had a resolution of the pulmonary involvement. Conclusions: DAH is a life-threatening complication of HSP. Prompt diagnosis and adequate treatment are essential in order to achieve the best outcome

Focused ultrasound : tumour ablation and its potential to enhance immunological therapy to cancer

Various kinds of image-guided techniques have been successfully applied in the last years for the treatment of tumours, as alternative to surgical resection. High intensity focused ultrasound (HIFU) is a novel, totally non-invasive, image-guided technique that allows for achieving tissue destruction with the application of focused ultrasound at high intensity. This technique has been successfully applied for the treatment of a large variety of diseases, including oncological and non-oncological diseases. One of the most fascinating aspects of image-guided ablations, and particularly of HIFU, is the reported possibility of determining a sort of stimulation of the immune system, with an unexpected \u201csystemic\u201d response to treatments designed to be \u201clocal\u201d. In the present article the mechanisms of action of HIFU are described, and the main clinical applications of this technique are reported, with a particular focus on the immune-stimulation process that might originate from tumour ablations

Constraint methods for determining pathways and free energy of activated processes

Activated processes from chemical reactions up to conformational transitions of large biomolecules are hampered by barriers which are overcome only by the input of some free energy of activation. Hence, the characteristic and rate-determining barrier regions are not sufficiently sampled by usual simulation techniques. Constraints on a reaction coordinate r have turned out to be a suitable means to explore difficult pathways without changing potential function, energy or temperature. For a dense sequence of values of r, the corresponding sequence of simulations provides a pathway for the process. As only one coordinate among thousands is fixed during each simulation, the pathway essentially reflects the system's internal dynamics. From mean forces the free energy profile can be calculated to obtain reaction rates and insight in the reaction mechanism. In the last decade, theoretical tools and computing capacity have been developed to a degree where simulations give impressive qualitative insight in the processes at quantitative agreement with experiments. Here, we give an introduction to reaction pathways and coordinates, and develop the theory of free energy as the potential of mean force. We clarify the connection between mean force and constraint force which is the central quantity evaluated, and discuss the mass metric tensor correction. Well-behaved coordinates without tensor correction are considered. We discuss the theoretical background and practical implementation on the example of the reaction coordinate of targeted molecular dynamics simulation. Finally, we compare applications of constraint methods and other techniques developed for the same purpose, and discuss the limits of the approach

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)

Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the enhancing neuro Imaging genetics through meta analysis (ENIGMA) Consortium

BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Altered regional brain T2 relaxation times in individuals with chronic orofacial neuropathic pain

© 2018 The Authors The neural mechanisms underlying the development and maintenance of chronic pain following nerve injury remain unclear. There is growing evidence that chronic neuropathic pain is associated with altered thalamic firing patterns, thalamocortical dysrhythmia and altered infra-slow oscillations in ascending pain pathways. Preclinical and post-mortem human studies have revealed that neuropathic pain is associated with prolonged astrocyte activation in the dorsal horn and we have suggested that this may result in altered gliotransmission, which results in altered resting neural rhythm in the ascending pain pathway. Evidence of astrocyte activation above the level of the dorsal horn in living humans is lacking and direct measurement of astrocyte activation in living humans is not possible, however, there is evidence that regional alterations in T2 relaxation times are indicative of astrogliosis. The aim of this study was to use T2 relaxometry to explore regional brain anatomy of the ascending pain pathway in individuals with chronic orofacial neuropathic pain. We found that in individuals with trigeminal neuropathic pain, decreases in T2 relaxation times occurred in the region of the spinal trigeminal nucleus and primary somatosensory cortex, as well as in higher order processing regions such as the dorsolateral prefrontal, cingulate and hippocampal/parahippocampal cortices. We speculate that these regional changes in T2 relaxation times reflect prolonged astrocyte activation, which results in altered brain rhythm and ultimately the constant perception of pain. Blocking prolonged astrocyte activation may be effective in preventing and even reversing the development of chronic pain following neural injury

Brainstem pain-control circuitry connectivity in chronic neuropathic pain

© 2018 the authors. Preclinical investigations have suggested that altered functioning of brainstem pain-modulation circuits may be crucial for the maintenance of some chronic pain conditions. While some human psychophysical studies show that patients with chronic pain display altered pain-modulation efficacy, it remains unknown whether brainstem pain-modulation circuits are altered in individuals with chronic pain. The aim of the present investigation was to determine whether, in humans, chronic pain following nerve injury is associated with altered ongoing functioning of the brainstem descending modulation systems. Using resting-state functional magnetic resonance imaging, we found that male and female patients with chronic neuropathic orofacial pain show increased functional connectivity between the rostral ventromedial medulla (RVM) and other brainstem pain-modulatory regions, including the ventrolateral periaqueductal gray (vlPAG) and locus ceruleus (LC). We also identified an increase in RVM functional connectivity with the region that receives orofacial nociceptor afferents, the spinal trigeminal nucleus. In addition, the vlPAG and LC displayed increased functional connectivity strengths with higher brain regions, including the hippocampus, nucleus accumbens, and anterior cingulate cortex, in individuals with chronic pain. These data reveal that chronic pain is associated with altered ongoing functioning within the endogenous pain-modulation network. These changes may underlie enhanced descending facilitation of processing at the primary synapse, resulting in increased nociceptive transmission to higher brain centers. Further, our findings show that higher brain regions interact with the brainstem modulation system differently in chronic pain, possibly reflecting top–down engagement of the circuitry alongside altered reward processing in pain conditions

Phenazines and biosurfactants interact in the biological control of soil-borne diseases caused by Pythium spp.

In this study, the putative role of phenazines and rhamnolipid-biosurfactants, antagonistic metabolites produced by Pseudomonas aeruginosa PNA1, was tested in the biological control of Pythium splendens on bean (Phaseolus vulgaris L) and Pythium myriotylum on cocoyam (Xanthosoma sagittifolium L Schott). A rhamnolipid-deficient and a phenazine-deficient mutant of PNA1 were used either separately or jointly in plant experiments. When the mutants were applied separately, no disease-suppressive effect was observed, although both mutants still produced one of the antagonistic compounds (phenazines or rhamnolipids). When the mutants were concurrently introduced in the soil, the biocontrol activity was restored to wild-type levels. Bean seeds developed significantly less pre-emergence damping-off caused by P. splendens when treated with a mixture of purified phenazine-1-carboxamide and rhamnolipids than with any of the chemicals alone. When phenazines and rhamnolipids were combined at concentrations that had no observable effects when the metabolites were applied separately, mycelial growth of P. myriotylum was significantly reduced. In addition, microscopic analysis revealed substantial vacuolization and disintegration of Pythium hyphae after incubation in liquid medium amended with both metabolites. Results of this study indicate that phenazines and biosurfactants are acting synergistically in the control of Pythium spp