Glucose Hypometabolism Prompts RAN Translation and Exacerbates C9orf72-related ALS/FTD Phenotypes.

The most prevalent genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia is a (GGGGCC)n nucleotide repeat expansion (NRE) occurring in the first intron of the C9orf72 gene (C9). Brain glucose hypometabolism is consistently observed in C9-NRE carriers, even at pre-symptomatic stages, although its potential role in disease pathogenesis is unknown. Here, we identified alterations in glucose metabolic pathways and ATP levels in the brain of asymptomatic C9-BAC mice. We found that, through activation of the GCN2 kinase, glucose hypometabolism drives the production of dipeptide repeat proteins (DPRs), impairs the survival of C9 patient-derived neurons, and triggers motor dysfunction in C9-BAC mice. We also found that one of the arginine-rich DPRs (PR) can directly contribute to glucose metabolism and metabolic stress. These findings provide a mechanistic link between energy imbalances and C9-ALS/FTD pathogenesis and support a feedforward loop model that opens several opportunities for therapeutic intervention.

Light-induced charge generation in polymeric nanoparticles restores vision in advanced-stage retinitis pigmentosa rats.

Retinal dystrophies such as Retinitis pigmentosa are among the most prevalent causes of inherited legal blindness, for which treatments are in demand. Retinal prostheses have been developed to stimulate the inner retinal network that, initially spared by degeneration, deteriorates in the late stages of the disease. We recently reported that conjugated polymer nanoparticles persistently rescue visual activities after a single subretinal injection in the Royal College of Surgeons rat model of Retinitis pigmentosa. Here we demonstrate that conjugated polymer nanoparticles can reinstate physiological signals at the cortical level and visually driven activities when microinjected in 10-months-old Royal College of Surgeons rats bearing fully light-insensitive retinas. The extent of visual restoration positively correlates with the nanoparticle density and hybrid contacts with second-order retinal neurons. The results establish the functional role of organic photovoltaic nanoparticles in restoring visual activities in fully degenerate retinas with intense inner retina rewiring, a stage of the disease in which patients are subjected to prosthetic interventions.

The European Rare Disease Network for HHT Frameworks for management of hereditary haemorrhagic telangiectasia in general and speciality care.

Hereditary haemorrhagic telangiectasia (HHT) is a complex, multisystemic vascular dysplasia affecting approximately 85,000 European Citizens. In 2016, eight founding centres operating within 6 countries, set up a working group dedicated to HHT within what became the European Reference Network on Rare Multisystemic Vascular Diseases. By launch, combined experience exceeded 10,000 HHT patients, and Chairs representing 7 separate specialties provided a median of 24 years' experience in HHT. Integrated were expert patients who focused discussions on the patient experience. Following a 2016-2017 survey to capture priorities, and underpinned by more than 40 monthly meetings, and new data acquisitions, VASCERN HHT generated position statements that distinguish expert HHT care from non-expert HHT practice. Leadership was by specialists in the relevant sub-discipline(s), and 100% consensus was required amongst all clinicians before statements were published or disseminated. One major set of outputs targeted all healthcare professionals and their HHT patients, and include the new Orphanet definition; Do's and Don'ts for common situations; Outcome Measures suitable for all consultations; COVID-19; and anticoagulation. The second output set span aspects of vascular pathophysiology where greater understanding will assist organ-specific specialist clinicians to provide more informed care to HHT patients. These cover cerebral vascular malformations and screening; mucocutaneous telangiectasia and differential diagnosis; anti-angiogenic therapies; circulatory interplays between anaemia and arteriovenous malformations; and microbiological strategies to counteract loss of normal pulmonary capillary function. Overall, the integrated outputs, and documented current practices, provide frameworks for approaches that augment the health and safety of HHT patients in diverse health-care settings.

Magnetic force fields of isolated small nanoparticle clusters.

The usage of magnetic nanoparticles (NPs) in applications necessitates a precise mastering of their properties at the single nanoparticle level. There has been a lot of progress in the understanding of the magnetic properties of NPs, but incomparably less when interparticle interactions govern the overall magnetic response. Here, we present a quantitative investigation of magnetic fields generated by small clusters of NPs assembled on a dielectric non-magnetic surface. Structures ranging from individual NPs to fifth-fold particulate clusters are investigated in their magnetization saturation state by magnetic force microscopy and numerical calculations. It is found that the magnetic stray field does not increase proportionally with the number of NPs in the cluster. Both measured and calculated magnetic force fields underline the great importance of the exact spatial arrangement of NPs, shedding light on the magnetic force field distribution of particulate clusters, which is relevant for the quantitative evaluation of their magnetization and perceptibly for many applications.

Safety of direct oral anticoagulants in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular dysplasia resulting in visceral arteriovenous malformations and smaller mucocutaneous telangiectasia. Most patients experience recurrent nosebleeds and become anemic without iron supplementation. However, thousands may require anticoagulation for conditions such as venous thromboembolism and/or atrial fibrillation. Over decades, tolerance data has been published for almost 200 HHT-affected users of warfarin and heparins, but there are no published data for the newer direct oral anticoagulants (DOACs) in HHT. METHODS: To provide such data, a retrospective audit was conducted across the eight HHT centres of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), in Denmark, France, Germany, Italy, the Netherlands and the UK. RESULTS: Although HHT Centres had not specifically recommended the use of DOACs, 32 treatment episodes had been initiated by other clinicians in 28 patients reviewed at the Centres, at median age 65 years (range 30-84). Indications were for atrial fibrillation (16 treatment episodes) and venous thromboembolism (16 episodes). The 32 treatment episodes used Apixaban (n = 15), Rivaroxaban (n = 14), and Dabigatran (n = 3). HHT nosebleeds increased in severity in 24/32 treatment episodes (75%), leading to treatment discontinuation in 11 (34.4%). Treatment discontinuation was required for 4/15 (26.7%) Apixaban episodes and 7/14 (50%) Rivaroxaban episodes. By a 4 point scale of increasing severity, there was a trend for Rivaroxaban to be associated with a greater bleeding risk both including and excluding patients who had used more than one agent (age-adjusted coefficients 0.61 (95% confidence intervals 0.11, 1.20) and 0.74 (95% confidence intervals 0.12, 1.36) respectively. Associations were maintained after adjustment for gender and treatment indication. Extreme hemorrhagic responses, worse than anything experienced previously, with individual nosebleeds lasting hours requiring hospital admissions, blood transfusions and in all cases treatment discontinuation, occurred in 5/14 (35.7%) Rivaroxaban episodes compared to 3/15 (20%) Apixaban episodes and published rates of ~ 5% for warfarin and heparin. CONCLUSIONS: Currently, conventional heparin and warfarin remain first choice anticoagulants in HHT. If newer anticoagulants are considered, although study numbers are small, at this stage Apixaban appears to be associated with lesser bleeding risk than Rivaroxaban.

Pelvic floor rehabilitation for defecation disorders.

Pelvic floor rehabilitation is frequently recommended for defecation disorders, in both constipation and fecal incontinence. However, the lack of patient selection, together with the variety of rehabilitation methods and protocols, often jeopardize the results of this approach, causing difficulty in evaluating outcomes and addressing proper management, and above all, in obtaining scientific evidence for the efficacy of these methods for specific indications. The authors represent different gastroenterological and surgical scientific societies in Italy, and their aim was to identify the indications and agree on treatment protocols for pelvic floor rehabilitation of patients with defecation disorders. This was achieved by means of a modified Delphi method, utilizing a working team (10 members) which developed the statements and a consensus group (15 members, different from the previous ones) which voted twice also suggesting modifications of the statements.

In vitro and in vivo studies of the ALS-FTLD protein CHCHD10 reveal novel mitochondrial topology and protein interactions.

Mutations in coiled-coil-helix-coiled-coil-helix-domain containing 10 (CHCHD10), a mitochondrial twin CX9C protein whose function is still unknown, cause myopathy, motor neuron disease, frontotemporal dementia, and Parkinson's disease. Here, we investigate CHCHD10 topology and its protein interactome, as well as the effects of CHCHD10 depletion or expression of disease-associated mutations in wild-type cells. We find that CHCHD10 associates with membranes in the mitochondrial intermembrane space, where it interacts with a closely related protein, CHCHD2. Furthermore, both CHCHD10 and CHCHD2 interact with p32/GC1QR, a protein with various intra and extra-mitochondrial functions. CHCHD10 and CHCHD2 have short half-lives, suggesting regulatory rather than structural functions. Cell lines with CHCHD10 knockdown do not display bioenergetic defects, but, unexpectedly, accumulate excessive intramitochondrial iron. In mice, CHCHD10 is expressed in many tissues, most abundantly in heart, skeletal muscle, liver, and in specific CNS regions, notably the dopaminergic neurons of the substantia nigra and spinal cord neurons, which is consistent with the pathology associated with CHCHD10 mutations. Homozygote CHCHD10 knockout mice are viable, have no gross phenotypes, no bioenergetic defects or ultrastructural mitochondrial abnormalities in brain, heart or skeletal muscle, indicating that functional redundancy or compensatory mechanisms for CHCHD10 loss occur in vivo. Instead, cells expressing S59L or R15L mutant versions of CHCHD10, but not WT, have impaired mitochondrial energy metabolism. Taken together, the evidence obtained from our in vitro and in vivo studies suggest that CHCHD10 mutants cause disease through a gain of toxic function mechanism, rather than a loss of function.

Lasing from dot-in-rod nanocrystals in planar polymer microcavities.

Colloidal nanocrystals attract considerable attention in the field of light emitting devices thanks to their high fluorescence quantum yield, low amplified spontaneous emission (ASE) threshold, and spectral tunability via electronic structure engineering and surface functionalization. Combining polymer microcavities with colloidal nanocrystals as gain material promises a solution-based fabrication route to plastic laser cavities as well as applications in the field of smart flexible large area light sources and sensors. Here we demonstrate lasing from polymer microcavities embedding solution processable dot-in-rod (DiR) CdSe/CdS nanocrystals. Two highly reflective polymer dielectric mirrors are prepared by spin-coating of alternated layers of polyacrylic acid and poly(N-vinyl carbazole), with their photonic band gap tailored to the emission of the DiRs. The DiRs are enclosed in the polymer microcavity by drop-cast deposition on one mirror, followed by pressing the mirrors onto each other. We obtain excellent overlap of the ASE band of the DiRs with the photonic band gap of the cavity and observe optically pumped lasing at 640 nm with a threshold of about 50 µJ cm-2.

Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis.

By causing mitochondrial DNA (mtDNA) mutations and oxidation of mitochondrial proteins, reactive oxygen species (ROS) leads to perturbations in mitochondrial proteostasis. Several studies have linked mtDNA mutations to metastasis of cancer cells but the nature of the mtDNA species involved remains unclear. Our data suggests that no common mtDNA mutation identifies metastatic cells; rather the metastatic potential of several ROS-generating mutations is largely determined by their mtDNA genomic landscapes, which can act either as an enhancer or repressor of metastasis. However, mtDNA landscapes of all metastatic cells are characterized by activation of the SIRT/FOXO/SOD2 axis of the mitochondrial unfolded protein response (UPRmt). The UPRmt promotes a complex transcription program ultimately increasing mitochondrial integrity and fitness in response to oxidative proteotoxic stress. Using SOD2 as a surrogate marker of the UPRmt, we found that in primary breast cancers, SOD2 is significantly increased in metastatic lesions. We propose that the ability of selected mtDNA species to activate the UPRmt is a process that is exploited by cancer cells to maintain mitochondrial fitness and facilitate metastasis.

Oxygen-iron interaction in liquid lead-bismuth eutectic alloy.

Iron released by steel corrosion was found to be a key impurity in reactions with dissolved oxygen in liquid lead-bismuth eutectic alloys. The iron-oxygen-magnetite equilibrium was characterized, allowing the quantification of phenomena that are important for long-term operation of lead-alloy based installations such as corrosion rate control and management of precipitates.

Overcoming recurrent spontaneous abortions in women suffering from IgG subclass deficiency: high efficiency of low dose intravenous immunoglobulins treatment.

PROBLEM: It's well known that iv. immunoglobulins may be useful to overcome habitual abortions, but the mechanisms at the base of a successful outcome and the likelihoods are still unknown. METHOD OF STUDY: In one hundred and sixty women with habitual abortions and one hundred and sixty healthy mothers, we evaluated blood IgG subclasses; among the patients, sixteen merely showed IgG subclass deficiency, after leaving out any autoimmunity and/or coagulation disorders. All the patients (100%) showed IgG3, twelve (75%) IgG1, eight (50%) IgG4 and six (37,5%) IgG2 deficiency; healthy control people's IgG subclasses fell in normal range in 156 women, but just four women showed IgG2 and IgG4 deficiency with neither immune deficiency's clinical marks nor increased vulnerability to infections. All the patients were treated with whole immunoglobulins iv. infusion (200 mg/kg/monthly) all over the pregnancy. RESULTS: The successful pregnancy rate is very high (>90%): 100% out of women showing IgG1 (12/12), 87,5% of IgG3 (14/16), 75% of IgG4 (6/8) and 66% of IgG2 deficiency (4/6) had successful pregnancies. The Odd's Ratio between IgG subclass deficiency and recurrent abortions is 4,33 with confidence interval of 95%; chi square value is 7.68 (p<0.025). CONCLUSIONS: Low dose immunoglobulin infusion is the only effective way to reach successful pregnancy, despite previous habitual abortions in patients suffering from IgG subclass deficiency without autoimmunity and/or coagulation disorders, likely restoring idiotype-antiidiotype network; showing evidence of IgG subclasses deficiency (mostly IgG1 and IgG3) may help identify patients who can benefit from iv. immunoglobulin treatment.

Tranexamic acid for epistaxis in hereditary hemorrhagic telangiectasia patients: a European cross-over controlled trial in a rare disease.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder associated with abnormal angiogenesis and disabling epistaxis. Tranexamic acid (TA) has been widely used in the treatment of these severe bleeds but with no properly designed trial. OBJECTIVES: To demonstrate the efficacy of TA in epistaxis in HHT patients and to explore its safety of use. PATIENTS/METHODS: A randomized, placebo-controlled, double-blind, cross-over trial was conducted. Participants were randomized to receive TA (3 g a day) then placebo or the opposite sequence. The main analysis compared intra-individual mean duration of epistaxis under TA vs. placebo on a log scale. The primary outcome was the mean duration of epistaxis per month, assessed with specific grids to be completed by participants. The number of epistaxis episodes was recorded as a secondary outcome. RESULTS: A total of 118 randomized patients contributed to the statistical analysis. The mean duration of epistaxis per month was significantly shorter with TA than placebo (0.19 on the log scale; SD = 0.07; P = 0.005), corresponding to a decrease of 17.3% (15.7 min) in the duration of epistaxis per month (CI 95%, 5.5-27.6). The median number of epistaxis episodes per month was 22.1 episodes in the placebo arm vs. 23.3 episodes in the TA arm. No thrombophlebitis was observed. CONCLUSIONS: In the ATERO study, we demonstrated a significant decrease in the duration of epistaxis in HHT patients taking TA. No safety issues were recorded in our cohort of patients.

The structure of the corpus callosum in obsessive compulsive disorder.

Abnormal brain connectivity has recently been reported in obsessive compulsive disorder (OCD). However, structural differences in the corpus callosum (CC), the primary structure connecting the two hemispheres, have not been extensively studied. In this case-control study, we recruited 30 patients with OCD and 30 healthy control subjects carefully matched for age, sex and handedness. Combining surface-based mesh-modeling and voxel-based morphometry (VBM), we compared callosal thickness and white matter (WM) density in patients and controls. We investigated associations between callosal structure and cortical gray matter (GM) density, and we related CC measures to neuropsychological performance in OCD. OCD patients showed small anterior and posterior callosal regions compared to healthy control subjects. In the OCD group, anterior callosal thickness was positively correlated with GM density of the right mid-dorso-lateral prefrontal (BA 9/46) area, while posterior callosal thickness was positively correlated with GM density in the left supramarginal gyrus (BA 40). Moreover, posterior callosal WM density was positively correlated with verbal memory, visuo-spatial memory, verbal fluency, and visuo-spatial reasoning performances. Callosal attributes were related to GM density in cortical areas innervated by the CC, and were also related to performance in cognitive domains impaired in the disorder. The CC may therefore be integrally involved in OCD.

WITHDRAWN: The structure of the corpus callosum in obsessive compulsive disorder.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Folie à deux: double case-report of shared delusions with a fatal outcome.

BACKGROUND: Treatment of shared delusional disorder (folie à deux) often involves separation and use of antipsychotic medication, with uncertain outcomes and potential risks. METHODS: We report on two highly interdependent and chronically psychotic sisters with shared systematic delusion, followed by psychiatrists over several years. RESULTS: The dominant patient was diagnosed with schizoaffective disorder and her non-dominant sister with paranoid schizophrenia. Both received antipsychotics and supportive therapy as outpatients and allowed to continue conjoint therapy with individual psychiatrists-therapists. They returned for follow-up visits for 20 months, when the dominant decided to continue treatment alone, as her sister gradually improved symptomatically and functionally. After separation, the dominant became increasingly anxious. She impulsively ingested an overdose of the non-dominant sister's medicines and died of cardiac arrest, despite her sister's efforts to seek medical assistance. The surviving non-dominant sister developed anxiety and increasing agitation requiring psychiatric hospitalization and increased pharmacotherapy. She improved gradually, but continued to be dysfunctional and required placement in a psychiatric inpatient unit for several months, eventually doing better in a community-based rehabilitative program with regular psychiatric follow-up. CONCLUSIONS: Combined treatment of patients with folie à deux may encourage continuous pathological interactions, but separation may increase risk of adverse outcomes.

Mitochondrial DNA background modifies the bioenergetics of NARP/MILS ATP6 mutant cells.

Mutations in the mitochondrial DNA (mtDNA) encoded subunit 6 of ATPase (ATP6) are associated with variable disease expression, ranging from adult onset neuropathy, ataxia and retinitis pigmentosa (NARP) to fatal childhood maternally inherited Leigh's syndrome (MILS). Phenotypical variations have largely been attributed to mtDNA heteroplasmy. However, there is often a discrepancy between the levels of mutant mtDNA and disease severity. Therefore, the correlation among genetic defect, bioenergetic impairment and clinical outcome in NARP/MILS remains to be elucidated. We investigated the bioenergetics of cybrids from five patients carrying different ATP6 mutations: three harboring the T8993G, one with the T8993C and one with the T9176G mutation. The bioenergetic defects varied dramatically, not only among different ATP6 mutants, but also among lines carrying the same T8993G mutation. Mutants with the most severe ATP synthesis impairment showed defective respiration and disassembly of respiratory chain complexes. This indicates that respiratory chain defects modulate the bioenergetic impairment in NARP/MILS cells. Sequencing of the entire mtDNA from the different mutant cell lines identified variations in structural genes, resulting in amino acid changes that destabilize the respiratory chain. Taken together, these results indicate that the mtDNA background plays an important role in modulating the biochemical defects and clinical outcome in NARP/MILS.

[Predicting risk of suicide in bipolar and unipolar depression: correlation between temperament and personality]. / Prädiktion des Suizidrisikos bei bipolar und unipolar depressiven Patienten: Wechselwirkung von Temperament und Persönlichkeit.

OBJECTIVE: The aim of this study was to evaluate the roles of personality and affective temperament traits in the prediction of suicide risk in mood disorders. METHODS: The participants were 147 psychiatric inpatients with bipolar disorders I and II and major depressive disorder. Patients undertook the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego self-rating questionnaire, the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), and the Beck Hopelessness Scale. RESULTS: Sixty-four subjects were diagnosed with increased suicidal risk based on the Mini International Neuropsychiatric Interview (MINI). Logistic regression analysis resulted in two models predictive of MINI-based suicidal risk: irritable temperament and the MMPI-2 scale. Multiple regression analysis further indicated that higher hyperthymic values are protective against hopelessness, while MINI-based suicidal intent is a predictor of hopelessness. CONCLUSIONS: Personality and affective temperament traits may have a role in the prediction of suicide.

Contrast echocardiography for pulmonary arteriovenous malformations screening: does any bubble matter?

AIMS: To evaluate diagnostic accuracy of contrast echocardiography (CE) as compared with CT, for the screening of pulmonary arteriovenous malformations (PAVMs) in hereditary haemorrhagic telangiectasia (HHT); to evaluate the clinical significance of semi-quantitative analysis of a shunt on CE. METHODS AND RESULTS: A blinded prospective study was conducted in 190 consecutive subjects at risk of HHT who underwent screening for PAVMs, including clinical evaluation, pulse oximetry, standard and CE, and chest multirow CT without contrast medium. A semi-quantitative analysis of the shunt size was performed according to the contrast echo opacification of the left-sided chambers: Grade 0, no bubbles; 1, occasional filling with <20 bubbles; 2, moderate filling; 3, complete opacification. The first 100 patients were compared with 100 controls. A total of 119 (63%) patients had positive CE (32.2% Grade 1, 13.1% Grade 2, 11% Grade 3, 6.3% with patent foramen ovale). The overall diagnostic performance of CE was sensitivity 1.00, specificity 0.49, positive predictive value (PPV) 0.32, negative predictive value (NPV) 1.00. The PPV for the different grades was 0.00 for Grade 1, 0.56 for Grade 2, 1.00 for Grade 3; the NPV of Grade 0 was 1.00. A significant correlation was found between the CE grading and the number of PAVM, and complications (P < 0.0001). CONCLUSION: CE is an extremely sensitive procedure for the detection of PAVMs with substantial clinical impact.

Phase-space structures in quantum-plasma wave turbulence.

The quasilinear theory of the Wigner-Poisson system in one spatial dimension is examined. Conservation laws and properties of the stationary solutions are determined. Quantum effects are shown to manifest themselves in transient periodic oscillations of the averaged Wigner function in velocity space. The quantum quasilinear theory is checked against numerical simulations of the bump-on-tail and two-stream instabilities. The predicted wavelength of the oscillations in velocity space agrees well with the numerical results.

Ethical questions in human clinical psychopharmacology: should the focus be on placebo administration?

Of all ethical issues in clinical trial designs, only placebo use is dealt with acrimony and unwarranted, rhetoric emphasis. Many misconceptions are biased and may hamper research in the mechanisms of healing and recovery if placebo is banned from clinical trials, as some influential ethicists propose. Current treatments in psychiatry are by no means optimal and may vary in their effect across studies, rendering difficult to find the best available therapeutic method with which to compare new drugs. Because drugs possess specific mechanisms, it is not possible to compare drugs with different mechanisms as to their relevance in the pathophysiology of a given disorder. Placebo acts through non-specific mechanisms and is the ideal control for any disorder whose pathophysiology is relatively unknown and its treatment is still suboptimal. Sticking to short-term patient benefit in a trial reflects an individualistically oriented thinking in contemporary ethics and is likely to limit further research and efforts to better understand the mechanisms of disease and drug action, but also those related to general body reactance and self-healing, which are enhanced by placebo administration. Because in history ethics are swinging between two opposed views, it is possible that in the near future, the balance will move towards communitarianism, which is more likely to better serve long-term patient needs. Ethicists should also consider some other aspects of human experimentation, such as the consistency of research lines and the trend to substitute older drugs with their metabolites or enantiomers.