Dominant CST3 variants cause adult onset leukodystrophy without amyloid angiopathy.

Leukodystrophies are rare genetic white matter disorders that have been regarded as mainly occurring in childhood. Recent years altered this perception, as a growing number of leukodystrophies was described to have an onset at adult ages. Still, many adult patients presenting with white matter changes remain without a specific molecular diagnosis. We describe a novel adult onset leukodystrophy in 16 patients from eight families carrying one of four different stop-gain or frameshift dominant variants in the CST3 gene. Clinical and radiological features differ markedly from the previously described Icelandic Cerebral Amyloid Angiopathy that was found in patients carrying p.Leu68Asn substitution in CST3. The clinical phenotype consists of recurrent episodes of hemiplegic migraine associated with transient unilateral focal deficits and slowly progressing motor symptoms and cognitive decline in mid-old adult ages. In addition, in some cases acute onset clinical deterioration led to a prolonged episode with reduced consciousness and even early death. Radiologically, pathognomonic changes are found at typical predilection sites involving the deep cerebral white matter sparing a periventricular and directly subcortical rim, the middle blade of corpus callosum, posterior limb of the internal capsule, middle cerebellar peduncles, cerebral peduncles, and specifically the globus pallidus. Histopathologic characterization in two autopsy cases did not reveal angiopathy, but instead micro- to macrocystic degeneration of the white matter. Astrocytes were activated at early stages and later on displayed severe degeneration and loss. In addition, despite loss of myelin, elevated numbers of partly apoptotic oligodendrocytes were observed. A structural comparison of the variants in CST3 suggests that specific truncations of Cystatin C result in an abnormal function, possibly by rendering the protein more prone to aggregation. Future studies are required to confirm the assumed effect on the protein and to determine pathophysiologic downstream events at the cellular level.

Observation of inverse Compton emission from a long γ-ray burst.

Long-duration γ-ray bursts (GRBs) originate from ultra-relativistic jets launched from the collapsing cores of dying massive stars. They are characterized by an initial phase of bright and highly variable radiation in the kiloelectronvolt-to-megaelectronvolt band, which is probably produced within the jet and lasts from milliseconds to minutes, known as the prompt emission1,2. Subsequently, the interaction of the jet with the surrounding medium generates shock waves that are responsible for the afterglow emission, which lasts from days to months and occurs over a broad energy range from the radio to the gigaelectronvolt bands1-6. The afterglow emission is generally well explained as synchrotron radiation emitted by electrons accelerated by the external shock7-9. Recently, intense long-lasting emission between 0.2 and 1 teraelectronvolts was observed from GRB 190114C10,11. Here we report multi-frequency observations of GRB 190114C, and study the evolution in time of the GRB emission across 17 orders of magnitude in energy, from 5 × 10-6 to 1012 electronvolts. We find that the broadband spectral energy distribution is double-peaked, with the teraelectronvolt emission constituting a distinct spectral component with power comparable to the synchrotron component. This component is associated with the afterglow and is satisfactorily explained by inverse Compton up-scattering of synchrotron photons by high-energy electrons. We find that the conditions required to account for the observed teraelectronvolt component are typical for GRBs, supporting the possibility that inverse Compton emission is commonly produced in GRBs.

Acceleration of electrons in the plasma wakefield of a proton bunch.

High-energy particle accelerators have been crucial in providing a deeper understanding of fundamental particles and the forces that govern their interactions. To increase the energy of the particles or to reduce the size of the accelerator, new acceleration schemes need to be developed. Plasma wakefield acceleration1-5, in which the electrons in a plasma are excited, leading to strong electric fields (so called 'wakefields'), is one such promising acceleration technique. Experiments have shown that an intense laser pulse6-9 or electron bunch10,11 traversing a plasma can drive electric fields of tens of gigavolts per metre and above-well beyond those achieved in conventional radio-frequency accelerators (about 0.1 gigavolt per metre). However, the low stored energy of laser pulses and electron bunches means that multiple acceleration stages are needed to reach very high particle energies5,12. The use of proton bunches is compelling because they have the potential to drive wakefields and to accelerate electrons to high energy in a single acceleration stage13. Long, thin proton bunches can be used because they undergo a process called self-modulation14-16, a particle-plasma interaction that splits the bunch longitudinally into a series of high-density microbunches, which then act resonantly to create large wakefields. The Advanced Wakefield (AWAKE) experiment at CERN17-19 uses high-intensity proton bunches-in which each proton has an energy of 400 gigaelectronvolts, resulting in a total bunch energy of 19 kilojoules-to drive a wakefield in a ten-metre-long plasma. Electron bunches are then injected into this wakefield. Here we present measurements of electrons accelerated up to two gigaelectronvolts at the AWAKE experiment, in a demonstration of proton-driven plasma wakefield acceleration. Measurements were conducted under various plasma conditions and the acceleration was found to be consistent and reliable. The potential for this scheme to produce very high-energy electron bunches in a single accelerating stage20 means that our results are an important step towards the development of future high-energy particle accelerators21,22.

Spectroscopic identification of r-process nucleosynthesis in a double neutron-star merger.

The merger of two neutron stars is predicted to give rise to three major detectable phenomena: a short burst of γ-rays, a gravitational-wave signal, and a transient optical-near-infrared source powered by the synthesis of large amounts of very heavy elements via rapid neutron capture (the r-process). Such transients, named 'macronovae' or 'kilonovae', are believed to be centres of production of rare elements such as gold and platinum. The most compelling evidence so far for a kilonova was a very faint near-infrared rebrightening in the afterglow of a short γ-ray burst at redshift z = 0.356, although findings indicating bluer events have been reported. Here we report the spectral identification and describe the physical properties of a bright kilonova associated with the gravitational-wave source GW170817 and γ-ray burst GRB 170817A associated with a galaxy at a distance of 40 megaparsecs from Earth. Using a series of spectra from ground-based observatories covering the wavelength range from the ultraviolet to the near-infrared, we find that the kilonova is characterized by rapidly expanding ejecta with spectral features similar to those predicted by current models. The ejecta is optically thick early on, with a velocity of about 0.2 times light speed, and reaches a radius of about 50 astronomical units in only 1.5 days. As the ejecta expands, broad absorption-like lines appear on the spectral continuum, indicating atomic species produced by nucleosynthesis that occurs in the post-merger fast-moving dynamical ejecta and in two slower (0.05 times light speed) wind regions. Comparison with spectral models suggests that the merger ejected 0.03 to 0.05 solar masses of material, including high-opacity lanthanides.

Experimental Observation of Proton Bunch Modulation in a Plasma at Varying Plasma Densities.

We give direct experimental evidence for the observation of the full transverse self-modulation of a long, relativistic proton bunch propagating through a dense plasma. The bunch exits the plasma with a periodic density modulation resulting from radial wakefield effects. We show that the modulation is seeded by a relativistic ionization front created using an intense laser pulse copropagating with the proton bunch. The modulation extends over the length of the proton bunch following the seed point. By varying the plasma density over one order of magnitude, we show that the modulation frequency scales with the expected dependence on the plasma density, i.e., it is equal to the plasma frequency, as expected from theory.

Experimental Observation of Plasma Wakefield Growth Driven by the Seeded Self-Modulation of a Proton Bunch.

We measure the effects of transverse wakefields driven by a relativistic proton bunch in plasma with densities of 2.1×10^{14} and 7.7×10^{14} electrons/cm^{3}. We show that these wakefields periodically defocus the proton bunch itself, consistently with the development of the seeded self-modulation process. We show that the defocusing increases both along the bunch and along the plasma by using time resolved and time-integrated measurements of the proton bunch transverse distribution. We evaluate the transverse wakefield amplitudes and show that they exceed their seed value (<15 MV/m) and reach over 300 MV/m. All these results confirm the development of the seeded self-modulation process, a necessary condition for external injection of low energy and acceleration of electrons to multi-GeV energy levels.

Intraoperative lymph node evaluation using 18F-FDG and a hand-held gamma probe in endometrial cancer surgery--a pilot study.

PURPOSE: The purpose of this pilot study was to assess feasibility, safety, and accuracy of detection of metastatic nodes intraoperatively with a hand-held gamma (PET) probe after administration of 18F-FDG in patients with high risk endometrial cancer (EC). MATERIALS AND METHODS: This is a prospective, cohort study. Twenty-two patients with clinical Stage I or II EC with high-risk histologic subtypes who were candidates for open surgical intervention were screened for the study. After screening, there were seven study patients (mean age: 64; range: 53-77) who were eligible for the study. In the entire cohort, there were 61 nodal stations that were assessed with a gamma counter intraoperatively, in vivo and again after removal of the node. All adverse events were recorded and operating room staff was monitored for radiation exposure. Resected nodes underwent histological assessment as per routine clinical practice. RESULTS: Range of maximal counts per second recorded in vivo and ex vivo were 0-86 and 0-17, respectively. Of all the nodes examined, one node was positive for metastatic disease; however, intraoperatively the lymph node readings were not higher than other lymph node basins assessed in same patient. No adverse events were recorded. The surgeons recorded the maximum average radiation exposure of all healthcare personnel with an average exposure of 0.08 mSV per case (range, 0.06-0.15). CONCLUSION: Use of hand-held gamma probe for intraoperative staging of patients with high risk EC is feasible, safe, and radiation exposure levels for all members of the healthcare team were within radiation safety guidelines. However, its use for detection of lymph node metastases needs further evaluation.

Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study.

BACKGROUND: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa. METHODS: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival. RESULTS: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94). CONCLUSIONS: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.

Persistent NRG1 Type III Overexpression in Spinal Motor Neurons Has No Therapeutic Effect on ALS-Related Pathology in SOD1G93A Mice.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting upper and lower motor neurons (MNs). Neuregulin-1 (NRG1) is a pleiotropic growth factor that has been shown to be potentially valuable for ALS when supplemented by means of viral-mediated gene therapy. However, these results are inconsistent with other reports. An alternative approach for investigating the therapeutic impact of NRG1 on ALS is the use of transgenic mouse lines with genetically defined NRG1 overexpression. Here, we took advantage of a mouse line with NRG1 type III overexpression in spinal cord α motor neurons (MN) to determine the impact of steadily enhanced NRG1 signalling on mutant superoxide dismutase 1 (SOD1)-induced disease. The phenotype of SOD1G93A-NRG1 double transgenic mice was analysed in detail, including neuropathology and extensive behavioural testing. At least 3 animals per condition and sex were histopathologically assessed, and a minimum of 10 mice per condition and sex were clinically evaluated. The accumulation of misfolded SOD1 (mfSOD1), MN degeneration, and a glia-mediated neuroinflammatory response are pathological hallmarks of ALS progression in SOD1G93A mice. None of these aspects was significantly improved when examined in double transgenic NRG1-SOD1G93A mice. In addition, behavioural testing revealed that NRG1 type III overexpression did not affect the survival of SOD1G93A mice but accelerated disease onset and worsened the motor phenotype.

Family relations and eating disorders. The effectiveness of an integrated approach in the treatment of anorexia and bulimia in teenagers: results of a case-control systemic research.

This article presents the results of a broader clinical research into the effectiveness of integrated treatments in teenage eating disorders, carried out at the Complex Operative Unit of Psychotherapy (Unità Operativa Complessa or U.O.C.) of the Department of Psychiatric Sciences and Psychological Medicine in collaboration with the Department of Neuropsychiatric Science for Child Development (Dipartimento di Scienze Neuropsichiatriche dell'Età Evolutiva), both at the "La Sapienza" University of Rome. The hypothesis of this research project is that in diagnosticable situations such as anorexia or bulimia, an integrated and multidisciplinary treatment, which combines medical-nutritional interventions and family psychotherapy, allows better results than a single kind of treatment, which is the usual medical- nutritional intervention supported by psychiatric counselling. Twenty-eight cases (16 of bulimia and 12 of anorexia) were selected and then subdivided, with a randomized distribution, into two (experimental and control) homogeneous groups of 14 patients. The grouping variables were the diagnosis, the disorder's seriousness and duration, BMI, gender, age, family composition and social status. The variables which have been examined in this article are the clinical parameters, which were valuated in accordance with the DSM IV-TR criteria, and relational parameters which were explored through the use of the W.F.T. Test (Wiltwyck Family Tasks). These parameters were tested at beginning as well as at the end of the therapies, in both the experimental group and the control group. Statistical analysis has shown that the experimental group, which was followed with the integrated treatment, experienced a significant improvement of the parameters as related to dysfunctional family interaction modalities, and that this improvement was correlated to the positive evolution of the clinical parameters. This improvement was not present or not of the same degree in the control group. The results, moreover, demonstrate the effectiveness of an integrated systemic treatment based on a complex approach compared to a reductionist approach.

Lymphadenectomy for high-grade endometrial cancer: Does it impact lymph node recurrence?

INTRODUCTION: The diagnostic role of lymph node (LN) assessment is established in endometrial cancer. Our study assesses whether surgical removal of metastatic LNs has oncologic benefit in high-grade endometrial cancer. MATERIALS AND METHODS: High-grade endometrial cancer cases (2000-2010) were collected from two tertiary cancer centres. In patients with at least one positive LN, recurrence free survival (RFS) was compared by the number of LNs removed. Factors predicting nodal recurrence (NR) were explored. Univariate statistical analyses by log rank test and multivariable cox proportional hazards model were performed using SAS version 9.4. RESULTS: Of 570 patients identified, 334 patients underwent staging lymphadenectomy, 74 (22.2%) patients had at least one positive LN. The median RFS with at least one positive lymph node was 87.1 months (95% CI ≥ 14.3) when greater than 15 LNs were removed, compared to 16.9 months (95% CI, 13.6-35.6) and 17.3 months (95% CI, 8.5-39.8) when 5-15 and less than 5 LNs were removed, respectively (p = 0.02). In the cohort of 570 patients, there were 167 disease recurrences with location described on imaging, 98 (58.7%) had a NR and 69 (41.3%) recurred at other sites. Multivariable modeling identified that only positive LNs at surgical staging predicted NR (HR 3.8, 95% CI 1.4-10.2). CONCLUSION: In high-grade endometrial cancer, positive LNs predict NR, and RFS is longer with a more extensive LN dissection in women with positive LNs. Future prospective studies should evaluate the oncologic benefit of surgical removal of metastatic LNs in high-grade endometrial cancer.

Effective interactions between colloidal particles suspended in a bath of swimming cells.

The dynamics of passive colloidal tracers in a bath of self-propelled particles is receiving a lot of attention in the context of nonequilibrium statistical mechanics. Here we demonstrate that active baths are also capable of mediating effective interactions between suspended bodies. In particular we observe that a bath of swimming bacteria gives rise to a short range attraction similar to depletion forces in equilibrium colloidal suspensions. Using numerical simulations and experiments we show how the features of this interaction arise from the combination of nonequilibrium dynamics (peculiar of bacterial baths) and excluded volume effects.

Clinical, power Doppler sonography and histological assessment of the psoriatic plaque: short-term monitoring in patients treated with etanercept.

BACKGROUND: To date, the diagnosis of psoriasis is based on both clinical history and physical examination, and its severity is assessed by the Psoriasis Area and Severity Index (PASI). Continuous technological advances in the field of sonography have led to the development of equipment with high power Doppler frequency, which allows for very detailed morphological information regarding the dermal blood flow. OBJECTIVES: To compare power Doppler sonography (PDS) with clinical and histological findings before and after etanercept treatment in patients with psoriasis. METHODS: Twelve patients with a clinical diagnosis of psoriasis were enrolled in this study. The PASI, PDS and histological examinations were assessed in all patients on the same day at baseline, and after 12 weeks of biological treatment. PDS examination was performed by an experienced sonographer, using a sonographic system equipped with transducer ranging from 6 to 18 MHz and Doppler frequency ranging from 7 to 14 MHz. RESULTS: At follow up there was a significant decrease in PASI. A significant change was also detected for the PDS findings (P = 0·005). At baseline the median value for factor VIII staining was 1·5, and the median value for vascular endothelial growth factor (VEGF) staining was also 1·5. At follow up there was a significant decrease in both factor VIII and VEGF staining scores. Moreover, a positive correlation between reduction in PDS score and improvement in clinical and histological scores was found: Spearman's ρ = 0·639, P = 0·0022; Spearman's ρ = 0·619, P = 0·0013; Spearman's ρ = 0·765, P = 0·0002, respectively. CONCLUSIONS: Our results show a significant correlation between PDS findings and both PASI and histological degree of vascularization before and after etanercept treatment. These data provide evidence in favour of the validity of PDS in the assessment of dermal perfusional changes in patients with psoriatic plaques.

[Occupational medicine and communication: which role for print media?]. / Medicina del lavoro e comunicazione: l'uso dei media.

The diffusion of recent regulations on work safety has captured mass-media's interest on work accidents. The present work aims to highlight the role of print media in building a social representation of work safety, by performing a qualitative analysis of articles published between 2009 and 2010 in three of the main national newspapers. Results showed that print media are accurate in reporting news, but they do not serve as source of education in work safety's issues. Information is mainly focused around catastrophic events, with headlines inducing negative emotions. Very few articles contain a critical discussion of methods and operational proposals tested around the Country. A possible transformation of media's role in promoting work safety is discussed.

Intradural extramedullary granular cell tumour in a cat.

A 7-year-old domestic shorthair cat was evaluated for progressive paraparesis, inability to jump, a paralysed tail and inability to void the bladder. Neurologic examination was consistent with a L4-S3 localisation. Survey radiographs of the lumbar vertebral column revealed L4-L7 vertebral body remodelling. A pre-contrast T1-weighted hyperintense, diffusely enhancing intradural lesion extending from L4 to S1 vertebral bodies was detected by MRI. Large, mesenchymal, round-to-polygonal cells arranged in nests or sheets were found on histologic examination at post mortem. These cells were characterised by abundant intracytoplasmic PAS-positive, diastase-resistant granules and positive immunoexpression of vimentin, S-100, neuron-specific enolase and desmin. This is the first report of a spinal granular cell tumour in a cat.

MLH1 expression sensitises ovarian cancer cells to cell death mediated by XIAP inhibition.

BACKGROUND: The X-linked inhibitor of apoptosis protein (XIAP), an endogenous apoptosis suppressor, can determine the level of caspase accumulation and the resultant response to apoptosis-inducing agents such as cisplatin in epithelial ovarian cancer (EOC). In addition, the mismatch repair protein, hMLH1, has been linked to DNA damage-induced apoptosis by cisplatin by both p53-dependent and -independent mechanisms. METHODS: In this study, hMLH1 expression was correlated with clinical response to platinum drugs and survival in advanced stage (III-IV) EOC patients. We then investigated whether MLH1 loss was a determinant in anti-apoptosis response to cisplatin mediated by XIAP in isogenic and established EOC cell lines with differential p53 status. RESULTS: The percentage of cells undergoing cisplatin-induced cell killing was higher in MLH1-proficient cells than in MLH1-defective cells. In addition, the presence of wild-type hMLH1 or hMLH1 re-expression significantly increased sensitivity to 6-thioguanine, a MMR-dependent agent. Cell-death response to 6-thioguanine and cisplatin was associated with significant proteolysis of MLH1, with XIAP destabilisation and increased caspase-3 activity. The siRNA-mediated inhibition of XIAP increased MLH1 proteolysis and cell death in MLH1-proficient cells but not in MLH1-defective cells. CONCLUSION: These data suggest that XIAP inhibitors may prove to be an effective means of sensitising EOC to MLH1-dependent apoptosis.

ABCB1 c.-6-180T>G polymorphism and clinical risk factors in a multi-breed cohort of dogs with refractory idiopathic epilepsy.

Epilepsy is the most common chronic neurological disorder in dogs. Approximately 20-30% of dogs do not achieve satisfactory seizure control with two or more anti-epileptic drugs at appropriate dosages. This condition, defined as refractory epilepsy, is a multifactorial condition involving both acquired and genetic factors. The P glycoprotein might play and important role in the pathophysiological mechanism and it is encoded by the ABCB1 gene. An association between a single nucleotide variation of the ABCB1 gene (c.-6-180T>G) and phenobarbital resistance has previously been reported in a Border collie population with idiopathic epilepsy. To date, the presence and relevance of this polymorphism has not been assessed in other breeds. A multicentre retrospective, case-control study was conducted to investigate associations between ABCB1 c.-6-180T>G, clinical variables, and refractoriness in a multi-breed population of dogs with refractory idiopathic epilepsy. A secondary aim was to evaluate the possible involvement of the ABCB1 c.-6-180T>G single nucleotide variation this population. Fifty-two refractory and 50 responsive dogs with idiopathic epilepsy were enrolled. Of these, 45 refractory and 50 responsive (control) dogs were genotyped. The G allele was found in several breeds, but there was no evidence of association with refractoriness (P=0.69). The uncertain role of the c.-6-180T>G variation was further suggested by an association between the T/T genotype with both refractoriness and responsiveness in different breeds. Furthermore, high seizure density (cluster seizure) was the main clinical risk factor for refractory idiopathic epilepsy (P=0.003).

Publisher Correction: NRG1 type I dependent autoparacrine stimulation of Schwann cells in onion bulbs of peripheral neuropathies.

Michael W. Sereda was incorrectly associated with the Department of Cellular Neurophysiology, Hanover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany. The correct affiliations for Michael W. Sereda are Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany and Department of Clinical Neurophysiology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.