Immune response in peripheral axons delays disease progression in SOD1(G93A) mice.

BACKGROUND: Increasing evidence suggests that the immune system has a beneficial role in the progression of amyotrophic lateral sclerosis (ALS) although the mechanism remains unclear. Recently, we demonstrated that motor neurons (MNs) of C57SOD1(G93A) mice with slow disease progression activate molecules classically involved in the cross-talk with the immune system. This happens a lot less in 129SvSOD1(G93A) mice which, while expressing the same amount of transgene, had faster disease progression and earlier axonal damage. The present study investigated whether and how the immune response is involved in the preservation of motor axons in the mouse model of familial ALS with a more benign disease course. METHODS: First, the extent of axonal damage, Schwann cell proliferation, and neuromuscular junction (NMJ) denervation were compared between the two ALS mouse models at the disease onset. Then, we compared the expression levels of different immune molecules, the morphology of myelin sheaths, and the presence of blood-derived immune cell infiltrates in the sciatic nerve of the two SOD1G93A mouse strains using immunohistochemical, immunoblot, quantitative reverse transcription PCR, and rotating-polarization Coherent Anti-Stokes Raman Scattering techniques. RESULTS: Muscle denervation, axonal dysregulation, and myelin disruption together with reduced Schwann cell proliferation are prominent in 129SvSOD1(G93A) compared to C57SOD1(G93A) mice at the disease onset, and this correlates with a faster disease progression in the first strain. On the contrary, a striking increase of immune molecules such as CCL2, MHCI, and C3 was seen in sciatic nerves of slow progressor C57SOD1(G93A) mice and this was accompanied by heavy infiltration of CD8(+) T lymphocytes and macrophages. These phenomena were not detectable in the peripheral nervous system of fast-progressing mice. CONCLUSIONS: These data show for the first time that damaged MNs in SOD1-related ALS actively recruit immune cells in the peripheral nervous system to delay muscle denervation and prolong the lifespan. On the contrary, the lack of this response has a negative impact on the disease course

Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases

Microglial activation plays central roles in neuroinflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18 kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells depends on the transcription factor AP1 and is unique to a subset of rodent species within the Muroidea superfamily. Finally, we identify LCP2 and TFEC as potential markers of microglial activation in humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO-PET signals in humans reflect the density of inflammatory cells rather than activation state.Published versionThe authors thank the UK MS Society for financial support (grant number: C008-16.1). DRO was funded by an MRC Clinician Scientist Award (MR/N008219/1). P.M.M. acknowledges generous support from Edmond J Safra Foundation and Lily Safra, the NIHR Senior Investigator programme and the UK Dementia Research Institute which receives its funding from DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK. P.M.M. and D.R.O. thank the Imperial College Healthcare Trust-NIHR Biomedical Research Centre for infrastructure support and the Medical Research Council for support of TSPO studies (MR/N016343/1). E.A. was supported by the ALS Stichting (grant “The Dutch ALS Tissue Bank”). P.M. and B.B.T. are funded by the Swiss National Science Foundation (projects 320030_184713 and 310030_212322, respectively). S.T. was supported by an “Early Postdoc.Mobility” scholarship (P2GEP3_191446) from the Swiss National Science Foundation, a “Clinical Medicine Plus” scholarship from the Prof Dr. Max Cloëtta Foundation (Zurich, Switzerland), from the Jean et Madeleine Vachoux Foundation (Geneva, Switzerland) and from the University Hospitals of Geneva. This work was funded by NIH grants U01AG061356 (De Jager/Bennett), RF1AG057473 (De Jager/Bennett), and U01AG046152 (De Jager/Bennett) as part of the AMP-AD consortium, as well as NIH grants R01AG066831 (Menon) and U01AG072572 (De Jager/St George-Hyslop)

Serum levels of soluble CD30 improve international prognostic score in predicting the outcome of advanced Hodgkin's lymphoma

The International Prognostic Score (IPS) and circulating levels of the soluble form of CD30 molecule (sCD30) have both been associated with poor outcome in patients with advanced Hodgkin's lymphoma (HL). The aim of this study was to assess the prognostic power of the combined evaluation of sCD30 and IPS in these patients. PATIENTS AND METHODS: We included 101 patients with advanced HL, treated with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or MOPP (mechlorethamine, vincristine, procarbazine and prednisone)/ABVD chemotherapy with or without radiotherapy. All were tested for pre-treatment sCD30 levels. RESULTS: Six-year estimated overall survival (OS) and failure-free survival (FFS) was 89% +/- 3% and 75% +/- 4%, respectively. Thirty-three patients (33%) had IPS >2; their FFS was 60% compared with 82% in the remaining patients (P = 0.027). Serum sCD30 levels were > or =100 U/ml in 41 (41%) patients; their FFS at 6 years was 58%, compared with 87% in patients with sCD30 or =100 U/ml and IPS >2, FFS was significantly worse (44%) than in patients with low sCD30 and low IPS (89%) (P 2 and serum sCD30 levels > or =100 U/ml identifies a sizeable subgroup (18%) of advanced HL patients with very poor FFS, who might take advantage of intensified up-front treatment strategie

Serum levels of soluble CD30 improve International Prognostic Score in predicting the outcome of advanced Hodgkin's lymphoma

The International Prognostic Score (IPS) and circulating levels of the soluble form of CD30 molecule (sCD30) have both been associated with poor outcome in patients with advanced Hodgkin's lymphoma (HL). The aim of this study was to assess the prognostic power of the combined evaluation of sCD30 and IPS in these patients

New insights on the mechanisms of disease course variability in ALS from mutant SOD1 mouse models

Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous disease in terms of progression rate and survival. This is probably one of the reasons for the failure of many clinical trials and the lack of effective therapies. Similar variability is also seen in SOD1G93A mouse models based on their genetic background. For example, when the SOD1G93A transgene is expressed in C57BL6 background the phenotype is mild with slower disease progression than in the 129Sv mice expressing the same amount of transgene but showing faster progression and shorter lifespan. This review summarizes and discusses data obtained from the analysis of these two mouse models under different aspects such as the motor phenotype, neuropathological alterations in the central nervous system (CNS) and peripheral nervous system (PNS) and the motor neuron autonomous and non-cell autonomous mechanisms with the aim of finding elements to explain the different rates of disease progression. We also discuss the identification of promising prognostic biomarkers by comparative analysis of the two ALS mouse models. This analysis might possibly suggest new strategies for effective therapeutic intervention in ALS to slow significantly or even block the course of the disease

A bedform phase diagram for dense granular currents

Pyroclastic density currents (PDCs) are a life-threatening volcanic hazard. Our understanding and hazard assessments of these flows rely on interpretations of their deposits. The occurrence of stratified layers, cross-stratification, and bedforms in these deposits has been assumed as indicative of dilute, turbulent, supercritical flows causing traction-dominated deposition. Here we show, through analogue experiments, that a variety of bedforms can be produced by denser, aerated, granular currents, including backset bedforms that are formed in waning flows by an upstream-propagating granular bore. We are able to, for the first time, define phase fields for the formation of bedforms in PDC deposits. We examine how our findings impact the understanding of bedform features in outcrop, using the example of the Pozzolane Rosse ignimbrite of the Colli Albani volcano, Italy, and thus highlight that interpretations of the formative mechanisms of these features observed in the field must be reconsidered

Reply to Narkiewicz (2017) comment on "Thermal evolution of Paleozoic successions of the Holy Cross Mountains (Poland)"\u80\u9d

In this paper we reply to the criticisms advanced by Narkiewicz (2017) on the paper by Schito et al. (2017). We clarify the issues related to the stratigraphic and thermal maturity constraints used for reconstructing burial and thermal models of the two blocks of the Holy Cross Mountains. We also show how geological evidences brought by Narkiewicz (2017) as a proof of elevated Variscan heat flow are not conclusive or at least suggest the occurence of a localized thermal anomaly only along the area of the Holy Cross Fault. In the end, we performed new burial and thermal models in the Kielce region demonstrating that stratigraphic thickness variations between Schito et al. (2017) and Narkiewicz et al. (2010) produce only negligible differences in levels of thermal maturity of Paleozoic rocks. In addition, we outline that levels of thermal maturity for Silurian rocks can be matched only by using constant heat flow values through the Paleozoic and point to a decisive role for the absence of regional high Variscan heat flow in the area

Assessment of thermal evolution of Paleozoic successions of the Holy Cross Mountains (Poland)

Poland is considered the most prospective country for shale gas production in Europe. Hydrocarbon generation/expulsion scenarios, drawn in the latest intensive exploration phases, tend to overestimate maturation levels when compared with brand new data acquired after recent drillings. We tested an integrated workflow to correlate published and original thermal maturity datasets for the Paleozoic to Jurassic successions cropping out in the Holy Cross Mountains. These successions, when preserved in subsurface, host the major source rocks in the area. The application of the workflow allowed us to highlight the burial and thermal evolutionary scenarios of the two tectono-stratigraphic blocks of the Holy Cross Mountains (Łysogòry and Kielce blocks) and to propose this approach as a tool for reducing levels of uncertainty in thermal maturity assessment of Paleozoic successions worldwide. In particular, published datasets including colour alteration indexes of Paleozoic microfossils (conodont, acritarchs) and vitrinite and graptolite reflectance data, show differences in levels of thermal maturity for the Łysogòry (mid mature to overmature) and Kielce (immature to late mature) blocks. Original data, derived from optical analysis, pyrolysis, and Raman spectroscopy on kerogen, and X-Ray diffraction on fine-grained sediments, mostly confirm and integrate published data distribution. 1D thermal models, constrained by these data, show burial and exhumation events of different magnitude, during the Late Cretaceous, for the Łysogòry (maximum burial depths of 9 km) and Kielce (burial depths of 6 km) blocks that have been related to the Holy Cross Fault polyphase activity. In the end, Palynomorph Darkness Index and Raman spectroscopy on kerogen, for Llandoverian and Cambrian rocks, turned out to be promising tools for assessing thermal maturity of Paleozoic organic facies devoid of vitrinite macerals

Thermal interactions of the AD79 Vesuvius pyroclastic density currents and their deposits at Villa dei Papiri (Herculaneum archaeological site, Italy)

Pyroclastic density currents (PDCs) can have devastating impacts on urban settlements, due to their dynamic pressure and high temperatures. Our degree of understanding of the interplay between these hot currents and the affected infrastructures is thus fundamental not only to implement our strategies for risk reduction, but also to better understand PDC dynamics. We studied the temperature of emplacement of PDC deposits that destroyed and buried the Villa dei Papiri, an aristocratic Roman edifice located just outside the Herculaneum city, during the AD79 plinian eruption of Mt Vesuvius (Italy) by using the thermal remanent magnetization of embedded lithic clasts. The PDC deposits around and inside the Villa show substantial internal thermal disequilibrium. In areas affected by convective mixing with surface water or with collapsed walls, temperatures average at around 270 °C (min 190 °C, max 300 °C). Where the deposits show no evidence of mixing with external material, the temperature is much higher, averaging at 350 °C (min 300 °C; max 440 °C). Numerical simulations and comparison with temperatures retrieved at the very same sites from the reflectance of charcoal fragments indicate that such thermal disequilibrium can be maintained inside the PDC deposit for time-scales well over 24 hours, i.e. the acquisition time of deposit temperatures for common proxies. We reconstructed in detail the history of the progressive destruction and burial of Villa dei Papiri and infer that the rather homogeneous highest deposit temperatures (average 350 °C) were carried by the ash-sized fraction in thermal equilibrium with the fluid phase of the incoming PDCs. These temperatures can be lowered on short time- (less than hours) and length-scales (meters to tens of meters) only where convective mixing with external materials or fluids occurs. By contrast, where the Villa walls remained standing the thermal exchange was only conductive and very slow, i.e. negligible at 50 cm distance from contact after 24 hours. We then argue that the state of conservation of materials buried by PDC deposits largely depends on the style of the thermal interactions. Here we also suggest that PDC deposit temperatures are excellent proxies for the temperatures of basal parts of PDCs close to their depositional boundary layer. This general conclusion stresses the importance of mapping of deposit temperatures for the understanding of thermal processes associated with PDC flow dynamics and during their interaction with the affected environment