Search for Dark Matter Annihilation Signals in the H.E.S.S. Inner Galaxy Survey.

The central region of the Milky Way is one of the foremost locations to look for dark matter (DM) signatures. We report the first results on a search for DM particle annihilation signals using new observations from an unprecedented γ-ray survey of the Galactic Center (GC) region, i.e., the Inner Galaxy Survey, at very high energies (≳100 GeV) performed with the H.E.S.S. array of five ground-based Cherenkov telescopes. No significant γ-ray excess is found in the search region of the 2014-2020 dataset and a profile likelihood ratio analysis is carried out to set exclusion limits on the annihilation cross section ⟨σv⟩. Assuming Einasto and Navarro-Frenk-White (NFW) DM density profiles at the GC, these constraints are the strongest obtained so far in the TeV DM mass range. For the Einasto profile, the constraints reach ⟨σv⟩ values of 3.7×10^{-26} cm^{3} s^{-1} for 1.5 TeV DM mass in the W^{+}W^{-} annihilation channel, and 1.2×10^{-26} cm^{3} s^{-1} for 0.7 TeV DM mass in the τ^{+}τ^{-} annihilation channel. With the H.E.S.S. Inner Galaxy Survey, ground-based γ-ray observations thus probe ⟨σv⟩ values expected from thermal-relic annihilating TeV DM particles.

Revealing x-ray and gamma ray temporal and spectral similarities in the GRB 190829A afterglow.

Gamma-ray bursts (GRBs), which are bright flashes of gamma rays from extragalactic sources followed by fading afterglow emission, are associated with stellar core collapse events. We report the detection of very-high-energy (VHE) gamma rays from the afterglow of GRB 190829A, between 4 and 56 hours after the trigger, using the High Energy Stereoscopic System (H.E.S.S.). The low luminosity and redshift of GRB 190829A reduce both internal and external absorption, allowing determination of its intrinsic energy spectrum. Between energies of 0.18 and 3.3 tera-electron volts, this spectrum is described by a power law with photon index of 2.07 ± 0.09, similar to the x-ray spectrum. The x-ray and VHE gamma-ray light curves also show similar decay profiles. These similar characteristics in the x-ray and gamma-ray bands challenge GRB afterglow emission scenarios.

A very-high-energy component deep in the γ-ray burst afterglow.

Gamma-ray bursts (GRBs) are brief flashes of γ-rays and are considered to be the most energetic explosive phenomena in the Universe1. The emission from GRBs comprises a short (typically tens of seconds) and bright prompt emission, followed by a much longer afterglow phase. During the afterglow phase, the shocked outflow-produced by the interaction between the ejected matter and the circumburst medium-slows down, and a gradual decrease in brightness is observed2. GRBs typically emit most of their energy via γ-rays with energies in the kiloelectronvolt-to-megaelectronvolt range, but a few photons with energies of tens of gigaelectronvolts have been detected by space-based instruments3. However, the origins of such high-energy (above one gigaelectronvolt) photons and the presence of very-high-energy (more than 100 gigaelectronvolts) emission have remained elusive4. Here we report observations of very-high-energy emission in the bright GRB 180720B deep in the GRB afterglow-ten hours after the end of the prompt emission phase, when the X-ray flux had already decayed by four orders of magnitude. Two possible explanations exist for the observed radiation: inverse Compton emission and synchrotron emission of ultrarelativistic electrons. Our observations show that the energy fluxes in the X-ray and γ-ray range and their photon indices remain comparable to each other throughout the afterglow. This discovery places distinct constraints on the GRB environment for both emission mechanisms, with the inverse Compton explanation alleviating the particle energy requirements for the emission observed at late times. The late timing of this detection has consequences for the future observations of GRBs at the highest energies.

Diagnosis associated with Tau higher than 1200 pg/mL: Insights from the clinical and laboratory practice.

CONTEXT: Cerebrospinal fluid (CSF) biomarkers are valuable tools for the diagnosis of neurological diseases. We aimed to investigate within a retrospective multicentric study the final diagnosis associated with very high CSF Tau levels and to identify patterns of biomarkers that would differentiate them in clinical practice, to help clinical biologists into physicians' counseling. PATIENTS AND METHODS: Within the national multicentric network ePLM, we included 1743 patients from January 1, 2008, to December 31, 2013, with CSF biomarkers assayed by the same Innotest assays (protein Tau, phospho-Tau [pTau], and Aß 1-42). We identified 205 patients with protein Tau concentration higher than 1200 pg/mL and final diagnosis. RESULTS: Among those patients, 105 (51.2%) were suffering from Alzheimer's disease, 37 (18%) from sporadic Creuztfeldt-Jakob disease, and 63 (30.7%) from other neurological diseases including paraneoplastic/ central nervous system tumor, frontotemporal dementia, other diagnoses, amyloid angiopathy, Lewy body dementia, and infections of the central nervous system. Phospho-Tau, Aß1-42 and Aß1-42/pTau values differed significantly between the three groups of patients (p < .001). An Aß1-42/pTau ratio between 4.7 and 9.7 was suggestive of other neurological diseases (threshold in AD: 8.3). CSF 14-3-3 was useful to discriminate Alzheimer's disease from Creuztfeldt-Jakob disease in case of Aß1-42 concentrations <550 pg/mL or pTau>60 pg/mL. CONCLUSION: This work emphasizes the interest of a well-thought-out interpretation of CSF biomarkers in neurological diseases, particularly in the case of high Tau protein concentrations in the CSF.

Modifications of the endosomal compartment in peripheral blood mononuclear cells and fibroblasts from Alzheimer's disease patients.

Identification of blood-based biomarkers of Alzheimer's disease (AD) remains a challenge. Neuropathological studies have identified enlarged endosomes in post-mortem brains as the earliest cellular change associated to AD. Here the presence of enlarged endosomes was investigated in peripheral blood mononuclear cells from 48 biologically defined AD patients (25 with mild cognitive impairment and 23 with dementia (AD-D)), and 23 age-matched healthy controls using immunocytochemistry and confocal microscopy. The volume and number of endosomes were not significantly different between AD and controls. However, the percentage of cells containing enlarged endosomes was significantly higher in the AD-D group as compared with controls. Furthermore, endosomal volumes significantly correlated to [C(11)]PiB cortical index measured by positron emission tomography in the AD group, independently of the APOE genotype, but not to the levels of amyloid-beta, tau and phosphorylated tau measured in the cerebrospinal fluid. Importantly, we confirmed the presence of enlarged endosomes in fibroblasts from six unrelated AD-D patients as compared with five cognitively normal controls. This study is the first, to our knowledge, to report morphological alterations of the endosomal compartment in peripheral cells from AD patients correlated to amyloid load that will now be evaluated as a possible biomarker.

Sensitivity analysis and optimization of sub-wavelength optical gratings using adjoints.

Numerical optimization of photonic devices is often limited by a large design space the finite-differences gradient method requires as many electric field computations as there are design parameters. Adjoint-based optimization can deliver the same gradients with only two electric field computations. Here, we derive the relevant adjoint formalism and illustrate its application for a waveguide slab, and for the design of optical sub-wavelength gratings.

[Biomarkers for early diagnosis of Alzheimer's disease: current update and future directions]. / Diagnostic biologique de la maladie d'Alzheimer: avancées, limites et perspectives.

INTRODUCTION: The increased prevalence of the sporadic form of Alzheimer's disease (AD) has become a significant health issue in the elderly population. The need for early diagnosis is imperative because this, along with the development of novel therapeutic treatments, would permit the rapid and perhaps more efficient treatment of these debilitating disorders early on. BACKGROUND: Over the last decade, the potential use of certain biomarkers in the cerebrospinal fluid (CSF), and more recently, in the plasma has been investigated. Among the candidates studied includes the neurotoxic amyloid beta peptide and the Tau protein. However, although these two proteins have been clearly shown to be directly related to the pathophysiology of this disorder, it has proven difficult to establish a clear relationship between plasma or CSF levels of Abeta and Tau and the incidence and severity of AD in patients. This is due in part to differences in methodologies related to the detection sensitivity, as well as the variations in the biological data and consequent interpretation of the biochemical and biological data. Peripheral cells, in particular platelets and skin fibroblasts, could be an alternative solution as peripheral biological markers for the early diagnosis of AD. These cells are easily accessible from patients. Furthermore, they would provide a means not only to validate potential therapeutic strategies, but also to study the mechanisms involved in the development of AD, including APP processing. PERSPECTIVES: A combined strategy using both a fundamental mechanistic and an analytical approach of patient peripheral cells will allow the identification of new biological markers for AD, and hence permit immediate therapeutic strategies to be implemented.

Down-regulation of astroglial CYP2C, glucocorticoid receptor and constitutive androstane receptor genes in response to cocaine in human U373 MG astrocytoma cells.

Psychostimulant drugs abuse is associated with an increased risk of stroke. Cytochromes P450 (CYP), especially the astrocytic members of the CYP2C subfamily may play an important role in the modulation of cerebrovascular functions, by generating vasodilatator metabolites from arachidonic acid (AA). Our study examined the regulation of CYP2C genes in response to cocaine or amphetamine in the human astrocyte-like U373 MG cells, using reverse transcription-polymerase chain reaction (RT-PCR) and western-blot analysis. A treatment for 48h with increasing concentrations of cocaine caused a significant down-regulation of CYP2C8 and CYP2C9 genes and decreased the protein level. These effects were not observed with amphetamine. One mechanism of the CYP2C mRNA regulation implicates various specific receptors including glucocorticoid receptor (GR) and constitutive androstane receptor (CAR). Effects of cocaine on CYP2C were accompanied by a decrease in the GR and CAR gene expression suggesting that these nuclear receptors could be involved in the CYP2C repression by cocaine in the U373 MG cell line. These findings represent a possible molecular mechanism involved in the cerebrovascular risk associated with cocaine abuse.

[Astrocytic cytochromes p450: an enzyme subfamily critical for brain metabolism and neuroprotection]. / Les cytochromes P450 astrocytaires, une famille d'enzymes clés dans le métabolisme cérébral et la neuroprotection.

INTRODUCTION: Astrocytes are involved in multiple brain functions in physiological conditions. Cytochromes P450 are expressed in astrocytes and play a role in brain metabolism and in neuroprotection. BACKGROUND: Although the levels of various cytochromes P450 in brain regions are low, these enzymes were reported to be expressed at relatively high level in astroglial cells and may play a critical role in the biotransformation of endogenous or exogenous compounds. Astroglial cytochromes P450 expression suggests a putative capacity to metabolize psychoactive or lipophilic xenobiotics in situ, associated with pharmacological and/or toxicological consequences. Astrocytes appear to be the most active steroidogenic cells in the brain, expressing neurosteroïdogenic cytochromes P450 and producing various neurosteroids. Cytochrome P450 epoxygenase enzymes, which catalyze the formation of vasoactive compounds are also present in astrocytes, contributing to the regulation of the cerebral blood flow. PERSPECTIVES AND CONCLUSION: This review underlines the crucial roles of astroglial cytochromes P450 in brain functions. Identification of the molecular mechanisms involved in the regulation of these enzymes could open therapeutic perspectives and improve our understanding in neuroprotection.

Astroglial CYP1B1 up-regulation in inflammatory/oxidative toxic conditions: IL-1beta effect and protection by N-acetylcysteine.

The present work aims to determine the relevance of an astrocytoma cell line U373 MG, for assessing the role of some astroglial cytochrome P450 in neurotoxicity and neuroprotection. CYP1B1, CYP2C8, CYP2C9, CYP2D6, CYP2J2, CYP2E1 and CYP4A11 mRNA were detected by reverse transcriptase-polymerase chain reaction in control U373 MG cell cultures. Among them we focused on CYP1B1 expression. After 48 h treatment with a range of concentrations of interleukin-1beta (1, 5, 10 ng/ml) used to simulate stress conditions, CYP1B1 mRNA expression was enhanced in a dose-dependent way. This increased expression was followed 24 h later by an increase in protein level, determined by Western-blot. N-acetylcysteine (NAC) partially inhibited this effect both on the mRNA and protein levels. As CYP1B1 activates procarcinogenic compounds to reactive metabolites, an increase in this P450 isoform will participate to toxic consequences of an inflammatory/oxidative stress. NAC will prevent this deleterious effect.

Comparison between patient-controlled analgesia and subcutaneous morphine in elderly patients after total hip replacement.

BACKGROUND: The goal of this study was to evaluate the effectiveness on postoperative pain, and cognitive impact, of patient-controlled analgesia (PCA) compared with subcutaneous (s.c.) injections of morphine in elderly patients undergoing total hip replacement (THR). METHODS: Forty patients older than 70 yr were randomly assigned to two different postoperative analgesic techniques for 48 h: i.v. PCA morphine (dose, 1 mg; lockout interval, 8 min; PCA group) or regular s.c. morphine injections (SC group). Postoperative pain was assessed at rest and when moving, using a visual analogue scale (VAS) every 4 h. A Mini Mental Status (MMS) examination was used to assess cognitive functions before surgery, at 2 h, 24 h and 48 h after surgery, and at hospital discharge. Side-effects were also recorded systematically during the first 48 h after surgery. RESULTS: The PCA group showed significantly lower pain scores than the SC group both at rest and during mobilization. However, the clinical significance of pain scores was weak. There was no intergroup difference in postoperative MMS scores. The incidence of side-effects was similar in both groups. CONCLUSIONS: We conclude that in healthy elderly subjects undergoing THR, the flexibility of the analgesic regimen is more important than the route of administration with regard to efficacy, adverse effects and recovery of cognitive function.

[Retrospective comparative study of extended nephrectomies by surgery and by retroperitoneal laparoscopy]. / Etude comparative rétrospective des néphrectomies élargies par voie chirurgicale et par laparoscopie rétropéritonéale.

OBJECTIVE: To evaluate the results of radical retroperitoneal laparoscopic nephrectomy in terms of tolerance, morbidity and oncologic control. MATERIAL AND METHODS: 22 radical nephrectomies have been carried out by retroperitoneal laparoscopy. One surgical conversion has been necessary. This series has been retrospectively compared to 16 radical nephrectomies by open surgery. RESULTS: Both series were comparable. Operative time was not significantly different in the two groups. Blood loss was less with laparoscopic surgery (p < 10-3). We did not see any difference in antalgic consumption during the first post-operative day and in intensive care and hospital stay. Post-operative complications were less in the laparoscopy group (p = 0.04). We observed no death or reccurrence with a mean follow-up of 8.7 months for the laparoscopy group vs 32.2 for the open group. CONCLUSIONS: Radical retroperitoneal laparoscopic nephrectomy is a recent surgical technique which has the same oncologic standards as open surgery. Blood loss and post-operative complications are significantly reduced. Survival needs to be evaluated on long term follow-up.

U373-MG response to interleukin-1beta-induced oxidative stress.

Oxidative stress has been involved in various neurological disorders and, in the central nervous system, astrocytes represent the cell type that contributes to neuroprotection via glutathione (GSH) metabolism, GSH-metabolizing enzymes like gamma-glutamyltransferase (GGT), and apoE secretion. In this study, using IL-1beta, a proinflammatory and prooxidant cytokine that is increased in numerous pathological situations, cells of astrocytoma cell line U373-MG were exposed to an oxidative stress, leading to c-Jun and c-Fos activation. IL-1beta decreased both GGT activity and intracellular GSH content and increased apoE secretion, initiating astroglial response to injury. We observed that antioxidants inhibit IL-1beta effects on c-Jun and c-Fos proteins, GGT activity and the GSH pool but not on apoE secretion. Our results allow us to conclude that neurological disorders associated with an IL-1beta-induced oxidative stress could be, at least experimentally, reversible in the presence of one antioxidant, N-acetylcysteine.

[Concurrent chemotherapy and hyperfractionated radiotherapy for non-operable carcinoma of the bladder]. / Chimiothérapie et radiothérapie hyperfractionnée concomitantes pour carcinomes de vessie non opérables.

Two sequences of concomitant chemotherapy with 5-FU + cisplatin and hyperfractionated radiotherapy (67.2 Gy/56 fractions/38 days, two fractions of 1.2 Gy per day spaced to 6 hours) in the bladder volume were administered to 17 patients with infiltrative carcinoma of the bladder (1 pT1, 6 pT2, 8 pT3a, 2 pT3b or pT4, 8/17 N0-2). They were separated by an interval of 21 days with an intermediate bladder tumor evaluation. A complete histological response was observed in 69% (11 of 16 evaluable patients). With a mean follow-up of 21 months, the bladder preservation was stated in 8/11 (73%) of patients treated, of whom 6 with a complete tumor response, and 2 with a pTa recurrence; these results are similar to other series reported with conventional radiation therapy. No deficit in the bladder was observed in these eight patients.

[Anatomical and clinical effects of neoadjuvant hormonal treatment before radical prostatectomy]. / Effets anatomo-cliniques du traitement hormonal néo-adjuvant avant prostatectomie radicale.

Neoadjuvant endocrine treatment before radical prostatectomy is designed to reduce the positive margin rate and therefore the risk of recurrence. It usually consists of complete androgen blockade for 3 months, but no consensus has been reached concerning the type of blockade and the optimal duration. The main histological changes consist of glandular atrophy with pycnosis and vacuolization of tumour cells. These changes could reflect increased apoptosis. The residual tumour is usually small. PIN become rare, raising the problem of possible chemoprevention. The overall result is a markedly increased frequency of intracapsular tumours and a reduction of at least 50% of positive margins. However, some authors consider that this is simply due to a more detailed histological examination. The frequency of seminal vesicle and lymph node involvement does not appear to be modified. Endocrine therapy could act on the apoptosis-proliferation balance and also decrease the number of circulating cells. However, the intermediate results of randomized studies are contradictory. As improvement in overall survival remains the main objective, only a longer follow-up will be able to clearly determine the value or uselessness of neoadjuvant endocrine treatment before radical prostatectomy.

[Is surgery useful in kidney cancer with lymph node invasion?]. / La chirurgie est-elle utile dans le cancer du rein avec envahissement ganglionnaire?

SUMMARY: lymph node involvement in renal cell carcinoma is factor of very poor prognosis. In a series of 55 node-positive patients, 33 (60%) had simultaneous renal vein or vena cava invasion and 32 (58.2%) had metastases. Gross lymph node involvement was found in 39 patients (70.9%). Patients without venous invasion or metastasis may have a prolonged survival. In this group, those with microscopic nodal involvement can be cured, as the 10 and 15-year the actuarial survival rate is 54.5% Formal lymphadenectomy might have played a role in these results. Surgery can be performed when vein invasion is present without metastasis, but the prognosis is generally poor. Survival does not seem to be influenced by surgery when metastasis is present, regardless of the vein status.

Esplenectomias. Revision de 103 casos. / Splenectomies. Review of 103 cases

Los autores revisan las indicaciones medicas y quirurgicas de las esplenectomias, aportando una casuistica de 103 pacientes operados en las Clinicas Quirurgicas 1 de la Facultad de Medicina - Hospital Pasteur. Llaman la atencion sobre las eventuales complicaciones de esta cirugia y mencionan un aspecto bastante nuevo y de poca difusion en nuestro medio como es el tratamiento incruento de los traumatismos de bazo