Jean Talairach (1911-2007). An untold story of the pioneer of stereotactic and functional neurosurgery.

CONTEXT: The Department of neurosurgery of the Sainte-Anne Hospital hosted Jean Talairach who created and developed stereotactic neurosurgery in France. Despite numerous neurosurgical and neuroscientific achievements, little is known about the life of Jean Talairach. METHODS: Systematic screening of Sainte-Anne Hospital Museum, Henry Ey Library, and Bibliothèque Inter-Universitaire de Santé funds, and medical databases using the term "Jean Talairach". RESULTS: Jean Talairach started his medical career at the Sainte-Anne Hospital in 1942 as a psychiatrist and became a neurosurgeon due to his interest in stereotactic neurosurgery. During World War II, Jean Talairach joined the French Resistance in Paris, then the French First Army. Jean Talairach created an original and specific stereotactic methodology with appropriate stereotactic frame and tools and performed one of the first human stereotactic surgeries in 1948. He described the reference lines passing by the anterior and posterior commissures in 1952 and developed a tridimensional co-planar stereotactic atlas of the human brain. With the collaboration of Jean Bancaud, he created stereo-electroencephalography to investigate patients suffering from drug-resistant epilepsy. The "Sainte-Anne school" trained French and foreign stereotactic and functional neurosurgeons ensuring the spread of Jean Talairach's innovative ideas. Jean Talairach retired in 1980. CONCLUSION: Jean Talairach's achievements encapsulate the evolution of neurosurgery in France during the 20th century. He developed an original stereotactic methodology including a tridimensional stereotactic atlas of the human brain and a stereotactic frame. He created stereo-electroencephalography, which remains the gold-standard to investigate patients suffering from drug-resistant epilepsy.

Cryopreserved Stem Cells Incur Damages Due To Terrestrial Cosmic Rays Impairing Their Integrity Upon Long-Term Storage.

Stem cells have the capacity to ensure the renewal of tissues and organs. They could be used in the future for a wide range of therapeutic purposes and are preserved at liquid nitrogen temperature to prevent any chemical or biological activity up to several decades before their use. We show that the cryogenized cells accumulate damages coming from natural radiations, potentially inducing DNA double-strand breaks (DSBs). Such DNA damage in stem cells could lead to either mortality of the cells upon thawing or a mutation diminishing the therapeutic potential of the treatment. Many studies show how stem cells react to different levels of radiation; the effect of terrestrial cosmic rays being key, it is thus also important to investigate the effect of the natural radiation on the cryopreserved stem cell behavior over time. Our study showed that the cryostored stem cells totally shielded from cosmic rays had less DSBs upon long-term storage. This could have important implications on the long-term cryostorage strategy and quality control of different cell banks.

[Repurposing of chlorpromazine in COVID-19 treatment: the reCoVery study]. / Repositionnement de la chlorpromazine dans le traitement du COVID-19 : étude reCoVery.

OBJECTIVES: The ongoing COVID-19 pandemic comprises a total of more than 2,350,000 cases and 160,000 deaths. The interest in anti-coronavirus drug development has been limited so far and effective methods to prevent or treat coronavirus infections in humans are still lacking. Urgent action is needed to fight this fatal coronavirus infection by reducing the number of infected people along with the infection contagiousness and severity. Since the beginning of the COVID-19 outbreak several weeks ago, we observe in GHU PARIS Psychiatrie & Neurosciences (Sainte-Anne hospital, Paris, France) a lower prevalence of symptomatic and severe forms of COVID-19 infections in psychiatric patients (∼4%) compared to health care professionals (∼14%). Similar observations have been noted in other psychiatric units in France and abroad. Our hypothesis is that psychiatric patients could be protected from severe forms of COVID-19 by their psychotropic treatments. Chlorpromazine (CPZ) is a phenothiazine derivative widely used in clinical routine in the treatment of acute and chronic psychoses. This first antipsychotic medication has been discovered in 1952 by Jean Delay and Pierre Deniker at Sainte-Anne hospital. In addition, to its antipsychotic effects, several in vitro studies have also demonstrated a CPZ antiviral activity via the inhibition of clathrin-mediated endocytosis. Recently, independent studies revealed that CPZ is an anti-MERS-CoV and an anti-SARS-CoV-1 drug. In comparison to other antiviral drugs, the main advantages of CPZ lie in its biodistribution: (i) preclinical and clinical studies have reported a high CPZ concentration in the lungs (20-200 times higher than in plasma), which is critical because of the respiratory tropism of SARS-CoV-2; (ii) CPZ is highly concentrated in saliva (30-100 times higher than in plasma) and could therefore reduce the contagiousness of COVID-19; (iii) CPZ can cross the blood-brain barrier and could therefore prevent the neurological forms of COVID-19. METHODS: Our hypothesis is that CPZ could decrease the unfavorable evolution of COVID-19 infection in oxygen-requiring patients without the need for intensive care, but also reduce the contagiousness of SARS-CoV-2. At this end, we designed a pilot, phase III, multicenter, single blind, randomized controlled clinical trial. Efficacy of CPZ will be assessed according to clinical, biological and radiological criteria. The main objective is to demonstrate a shorter time to response (TTR) to treatment in the CPZ+standard-of-care (CPZ+SOC) group, compared to the SOC group. Response to treatment is defined by a reduction of at least one level of severity on the WHO-Ordinal Scale for Clinical Improvement (WHO-OSCI). The secondary objectives are to demonstrate in the CPZ+SOC group, compared to the SOC group: (A) superior clinical improvement; (B) a greater decrease in the biological markers of viral attack by SARS-CoV-2 (PCR, viral load); (C) a greater decrease in inflammatory markers (e.g. CRP and lymphopenia); (D) a greater decrease in parenchymal involvement (chest CT) on the seventh day post-randomization; (E) to define the optimal dosage of CPZ and its tolerance; (F) to evaluate the biological parameters of response to treatment, in particular the involvement of inflammatory cytokines. Patient recruitment along with the main and secondary objectives are in line with WHO 2020 COVID-19 guidelines. CONCLUSION: This repositioning of CPZ as an anti-SARS-CoV-2 drug offers an alternative and rapid strategy to alleviate the virus propagation and the infection severity and lethality. This CPZ repositioning strategy also avoids numerous developmental and experimental steps and can save precious time to rapidly establish an anti-COVID-19 therapy with well-known, limited and easy to manage side effects. Indeed, CPZ is an FDA-approved drug with an excellent tolerance profile, prescribed for around 70 years in psychiatry but also in clinical routine in nausea and vomiting of pregnancy, in advanced cancer and also to treat headaches in various neurological conditions. The broad spectrum of CPZ treatment - including antipsychotic, anxiolytic, antiemetic, antiviral, immunomodulatory effects along with inhibition of clathrin-mediated endocytosis and modulation of blood-brain barrier - is in line with the historical French commercial name for CPZ, i.e. LARGACTIL, chosen as a reference to its "LARGe ACTion" properties. The discovery of those CPZ properties, as for many other molecules in psychiatry, is both the result of serendipity and careful clinical observations. Using this approach, the field of mental illness could provide innovative therapeutic approaches to fight SARS-CoV-2.

Symptomatic progestin-associated atypical grade II meningioma. A first case report.

BACKGROUND: Long-term use of high-dose progestin is known to promote the development of meningioma. Atypical meningioma in a patient under progestin has not previously been reported. CASE REPORT: A 53-year-old right-handed woman presented with focal onset seizures, without impaired consciousness. Medical history featured endometriosis, treated successively by cyproterone acetate 25mg/day for 2 months then 50mg/day for 101 months, and chlormadinone acetate 5mg/day for 68 months then 10mg/day for 83 months. Brain MRI revealed multiple extra-axial lesions suggestive of left central meningioma associated with anterior skull base meningiomatosis. Surgical resection of the left central meningioma was achieved and progestin was withdrawn. Neuropathology diagnosed grade II atypical meningioma. Close clinical and imaging monitoring was implemented without adjuvant oncological treatment. At 25 months, imaging follow-up showed no recurrence of the left central meningioma and a significant regression of all other lesions, except for the right frontal lesion. CONCLUSIONS: Neurosurgeons should be aware of the possible aggressiveness of meningioma in patients under progestin, and particularly those treated by different types of progestin over a long period of time without interruption. This may require systematic close monitoring, to adapt neurosurgical management.

Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy.

Sepsis, or systemic inflammatory response syndrome, is the major cause of critical illness resulting in admission to intensive care units. Sepsis is caused by severe infection and is associated with mortality in 60% of cases. Morbidity due to sepsis is complicated by neuromyopathy, and patients face long-term disability due to muscle weakness, energetic dysfunction, proteolysis and muscle wasting. These processes are triggered by pro-inflammatory cytokines and metabolic imbalances and are aggravated by malnutrition and drugs. Skeletal muscle regeneration depends on stem (satellite) cells. Herein we show that mitochondrial and metabolic alterations underlie the sepsis-induced long-term impairment of satellite cells and lead to inefficient muscle regeneration. Engrafting mesenchymal stem cells improves the septic status by decreasing cytokine levels, restoring mitochondrial and metabolic function in satellite cells, and improving muscle strength. These findings indicate that sepsis affects quiescent muscle stem cells and that mesenchymal stem cells might act as a preventive therapeutic approach for sepsis-related morbidity.

[American histoplasmosis: clinicopathological features in immunocompetent and immunocompromised patients. A report of two cases of infection by Histoplasma capsulatum on Reunion Island]. / Histoplasmose : aspects clinicopathologiques chez l'immunocompétent et l'immunodéprimé. À propos de deux cas d'infection à Histoplasma capsulatum sur l'Île de la Réunion.

INTRODUCTION: Histoplasmosis is a fungal infection caused by Histoplasma capsulatum var. capsulatum. It shows pulmonary or multivisceral involvement. Infective spores are inhaled from soils that contain bat or bird guano. The clinical picture depends on the intensity of the exposure and the immune status of the host. CASE REPORTS: We report two cases of histoplasmosis that reflect its variability in clinical and histopathological expression: a pseudo-tumoral nodular form or histoplasmoma in a pauci-symptomatic immunocompetent patient and a disseminated form with severe respiratory and mucocutaneous involvement in an immunocompromised patient. The histoplasmoma presented as a spiculated, hypermetabolic, solitary pulmonary nodule. Histopathological examination showed well-formed epithelioid granulomas with caseous central necrosis containing numerous histoplasma yeasts. In the patient with disseminated infection, the diagnosis was confirmed by seeing yeast forms in bronchoalveolar lavage fluid and skin biopsy. CONCLUSIONS: These patients are the second and third cases of histoplasmosis reported on Reunion Island. Both had traveled in endemic areas several years previously. The most likely pathophysiological mechanism is the reactivation of an old latent infection. There is, therefore, no argument at present in favor of the presence of contaminated soils on Reunion Island.

Bone mass and microarchitecture of irradiated and bone marrow-transplanted mice: influences of the donor strain.

UNLABELLED: Total body irradiation and bone marrow transplantation induced dramatic trabecular bone loss and cortical thickening in mice. Transplanted cells were engrafted in bone marrow, along trabeculae, and in periosteal and endosteal envelopes. None of the osteocytes were of donor origin. Bone microarchitecture of transplanted mice changed to tend toward the donor phenotype. INTRODUCTION: Osteopenia and osteoporosis are complications of bone marrow transplants (BMT) attributed to related chemotherapy. However, the specific influence of total body irradiation (TBI) is unknown. METHODS: We investigated the effects of TBI and BMT on bone mass and microarchitecture by micro-CT. Eighteen C57Bl/6 (B6) mice receiving lethal TBI had a BMT with marrow cells from green fluorescent protein--transgenic-C57Bl/6 (GFP) mice. Transplanted (T(GFP)B6), B6, and GFP mice were euthanized 1, 3, and 6 months after BMT or at a related age. RESULTS: T(GFP)B6 presented a dramatic bone loss compared with B6 and did not restore their trabecular bone mass over time, despite a cortical thickening 6 months after BMT. Serum testosterone levels were not significantly reduced after BMT. During aging, GFP mice have less trabeculae, thicker cortices, but a narrower femoral shaft than B6 mice. From 3 months after BMT, cortical characteristics of T(GFP)B6 mice differed statistically from B6 mice and were identical to those of GFP mice. GFP(+) cells were located along trabecular surfaces and in periosteal and endosteal envelopes, but none of the osteocytes expressed GFP. CONCLUSION: Our findings suggest that engrafted cells did not restore the irradiation-induced trabecular bone loss, but reconstituted a marrow microenvironment and bone remodeling similar to those of the donor. The effects of irradiation and graft on bone remodeling differed between cortical and trabecular bone.

[Intracranial ependymomas in adult patients. Diagnosis and histological prognostic factors]. / Ependymomes intracrâniens de l'adulte. Diagnostic histologique et facteurs histopronostiques.

BACKGROUND: Intracranial ependymomas are rare in adults and histopathological prognostic factors are poorly determined. PURPOSE: A retrospective multicentric study was conducted in France in order to assess the prognostic value of histology. MATERIAL: Between 1990 and 2004, 216 adult patients with newly diagnosed ependymomas were treated in 19 French centers. Eligibility required institutional histopathological confirmation of an ependymoma and available clinical history and MRI features (see comparison paper). METHODS: Histological preparations and one paraffin embedded block from each patient were sent to Pr D. Figarella-Branger in Marseille. Central review by four neuropathologists (D. Figarella-Branger, A. Maues de Paula, C. Fernandez and A. Jouvet) was performed. Specimens for which all pathologists agreed with the histological diagnosis of ependymomas were included, whereas cases for which all disagree were excluded and reclassified. In the event of doubt and/or discrepancies between pathologists immunostaining was performed in order to reach a consensus diagnosis. Diagnostic of ependymomas was confirmed in 121 cases (56%). In theses cases, ependymomas were classified according to the WHO system (subtype and grade). The potential prognostic value (overall survival OS and disease free survival DFS) of the following histological parameters was examined: perivascular pseudorosettes, ependymal rosettes, hyalinized vessels, mitotic index, microvascular proliferation, necrosis, area of increased cellularity, nuclear atypia, brain invasion and Mib-1 labelling index. RESULTS: Among the 121 ependymomas, 88 were grade II (47 classic, 17 cellular, 2 papillar, 6 clear cells and 16 tanicytic) and 33 grade III. WHO grading, occurrence of microvascular proliferation, necrosis, nuclear atypia and high proliferative index were correlated with both OS and DFS. Moreover, quantification of certain parameters enabled a reproducible grading system correlated with both OS and DFS.

Correlation of in vitro infiltration with glioma histological type in organotypic brain slices.

Diffuse invasion of the brain, an intrinsic property of gliomas, renders these tumours incurable, and is a principal determinant of their spatial and temporal growth. Knowledge of the invasive potential of gliomas is highly desired in order to understand their behaviour in vivo. Comprehensive ex vivo invasion studies including tumours of different histological types and grades are however lacking, mostly because reliable physiological invasion assays have been difficult to establish. Using an organotypic rodent brain slice assay, we evaluated the invasiveness of 42 grade II-IV glioma biopsy specimens, and correlated it with the histological phenotype, the absence or presence of deletions on chromosomes 1p and 19q assessed by fluorescent in situ hybridisation, and proliferation and apoptosis indices assessed by immunocytochemistry. Oligodendroglial tumours with 1p/19q loss were less invasive than astrocytic tumours of similar tumour grade. Correlation analysis of invasiveness cell proliferation and apoptosis further suggested that grade II-III oligodendroglial tumours with 1p/19q loss grow in situ as relatively circumscribed compact masses in contrast to the more infiltrative and more diffuse astrocytomas. Lower invasiveness may be an important characteristic of oligodendroglial tumours, adding to our understanding of their more indolent clinical evolution and responsiveness to therapy.

Expression of excitatory amino acid transporter-2 (EAAT-2) and glutamine synthetase (GS) in brain macrophages and microglia of SIVmac251-infected macaques.

Na+-dependent transporters for glutamate (excitatory amino acid transporters, EAATs) clear extracellular glutamate in the brain and prevent excitotoxic neuronal damage. Glutamine synthetase (GS) provides metabolic support for neurones by producing the neurotrophic amino acid glutamine. EAAT and GS expression has recently been demonstrated in macrophages and microglial cells in vitro, and in two models of acute inflammation in vivo. This observation might modify our current understanding of brain inflammation, which considers activated microglia and brain macrophages as the main neurotoxic cells through their production of a variety of neurotoxins, including glutamate. EAAT and GS expression by these cells would entail neuroprotective and neurotrophic properties, counterbalancing the deleterious consequences of microglial activation. Macaque infection by the simian immunodeficiency virus (SIV) is considered the most relevant model for human acquired immunodeficiency syndrome (AIDS), including chronic inflammation of the brain at the early asymptomatic stage of the infection, followed by an AIDS-like disease where neuronal death occurs. We studied the expression of EAAT-2 and GS in the brains of three SIVmac251-infected and two noninfected cynomolgus macaques. We found that both microglia and brain macrophages expressed EAAT-2 and GS in infected primates, suggesting that these cells might, like astrocytes, clear extracellular glutamate and provide glutamine to neurones. Microglia and macrophages could thus have neuroprotective and neurotrophic properties in addition to their production of neurotoxins. This finding might explain the contrast between early intense microglial activation and the late occurrence of neuronal apoptotic cell death, which is mainly observed at the terminal stage of the disease.

Neuropathology and neurodegeneration in human immunodeficiency virus infection. Pathogenesis of HIV-induced lesions of the brain, correlations with HIV-associated disorders and modifications according to treatments.

A variety of HIV-induced lesions of the central nervous system (CNS) have been described, including HIV encephalitis, HIV leukoencephalopathy, axonal damage, and diffuse poliodystrophy with neuronal loss of variable severity resulting, at least partly, from an apoptotic process. However, no correlation could be established between these changes and HIV dementia (HIVD). From our study of HIV infected patients, it appeared that neuronal apoptosis is probably not related to a single cause. Microglial and glial activation, directly or indirectly related to HIV infection, plays a major role in neuronal apoptosis possibly through the mediation of oxidative stress. In our patients with full-blown AIDS, this mechanism predominated in the basal ganglia and correlated well with HIVD. Axonal damage, either secondary to microglial activation, or to systemic factors also contributes to neuronal apoptosis. Although massive neuronal loss may be responsible for HIVD in occasional cases, we conclude that neuronal apoptosis is a late event and does not represent the main pathological substrate of HIVD. The dementia more likely reflects a specific neuronal dysfunction resulting from the combined effects of several mechanisms, some of which may be reversible. Introduction of highly active antiretroviral therapy dramatically improved patient survival, however, its impact on the incidence and course of HIVD remains debatable. In our series, the incidence of HIVE has dramatically decreased since the introduction of multitherapies, but a number of cases remain whose cognitive disorders persist, despite HAART. The poor CNS penetration of many antiretroviral agents is a possible explanation, but irreversible "burnt out" HIV-induced CNS changes may also be responsible.

[Familial orthochromatic leukodystrophy: clinicopathological study of two cases]. / Leucodystrophies orthochromatiques familiales.

This paper reports the clinico-pathological data in a French family with orthochromatic leukodystrophy. The parents were first cousins and had seven children. Among those, two sisters and one brother presented with neurological signs, with onset around the 5(th) decade, including a dementing syndrome of frontal type, a tetrapyramidal syndrome, seizures, and, in one sibling, a cerebellar syndrome. CT scan or MRI showed diffuse involvement of the white matter. The neurological signs worsened progressively leading to death within 11 and 22 months. Neuropathological examination was performed in two cases. It revealed characteristic orthochromatic leukodystrophy. In one case, the presence of pigmented macrophages and astrocytes was suggestive of Van Bogaert and Nyssen disease. However there were some atypical features including the absence of pigmented cells in the second case whose clinical course was shorter, and the cavitary appearance of the white matter changes with a relative increase in the number of oligodendrocytes raising the issue of a possible link between this condition and cavitary orthochromatic leukodystrophies.

Design, synthesis and preliminary biological evaluation of a focused combinatorial library of stereodiverse carbohydrate-scaffold-based peptidomimetics.

A focused combinatorial library of 126 mimetics of the RGD sequence based on sugar scaffolds have been rationally constructed using molecular modeling, with a particular emphasis on the stereodiversity of the library. A liquid phase, mix and divide synthesis was used, active compounds being identified by using orthogonal libraries and recursive deconvolution strategies.

[Hereditary cerebral amyloid angiopathies]. / Les angiopathies amyloïdes cérébrales héréditaires.

Cerebral amyloid angiopathies are defined by the presence of amyloid substance in the walls of cerebral vessels. All amyloid substances have a particular physico-chemical structure, which imparts certain specific staining properties, but the biochemical composition of different amyloid types varies. Different forms of cerebral amyloid angiopathy have been identified, based on the biochemical nature of the protein deposited (e.g. beta-amyloid, cystatin C, transthyretin, gelsolin, amyloid protein Bri, prion protein). Some cerebral amyloid angiopathies are familial; these prompted genetic studies which in turn led to a better understanding of the genes coding for different amyloid proteins. As a group, cerebral amyloid angiopathies have certain neuropathological lesions in common. Infiltration by amyloid substance results in weakening of the small vessel walls and secondary complications responsible for changes such as microinfarcts and miliary haemorrhages in the cerebral cortex, lobar haemorrhages and/or leucoencephalopathy. These changes form the basis of the neurological complications: meningeal and cerebral haemorrhages, transient ischaemic episodes, vascular dementia. However each type of hereditary cerebral amyloid angiopathy has individual clinical and histopathological features reflecting the severity of arterial involvement, the extent of amyloid deposition within or outside the central nervous system, and the association with other neurodegenarative changes.

Progressive multifocal leukoencephalopathy and oligodendroglioma in a monkey co-infected by simian immunodeficiency virus and simian virus 40.

A rhesus monkey experimentally inoculated with simian immunodeficiency virus (SIV) mac251 was killed 42 months later because of poor general condition. CD4 lymphocyte count which was 3,430/mm3 before inoculation, had decreased to 638/mm3 2 months before death. Neuropathological examination revealed changes characteristic of progressive multifocal leukoencephalopathy (PML) in the white matter of the cerebral hemispheres and brain stem. In situ hybridization was negative for JC virus but markedly positive for simian virus 40 (SV40) in the nuclei of many oligodendrocytes. Many oligodendrocytes also expressed p53. Within an area involved by PML, there was a densely cellular tumor with honeycomb appearance and elongated vessels characteristic of oligodendrogliomas. Within the tumor in situ hybridization for SV40 and immunocytochemistry for p53 were negative. Opportunistic infection by SV40 has been occasionally reported in experimentally SIV-infected monkeys resulting in PML or malignant astrocytoma. Association of JC virus-induced PML and astrocytomas has been reported in three human cases without AIDS. In those cases, as in our monkey, polyomaviruses (SV40 or JC virus) were expressed in the areas with PML but not in the glial tumor. Association of PML and oligodendroglioma has not been reported previously to our knowledge. The relationship between oligodendrocyte proliferation and polyomavirus infection of oligodendrocytes is unclear. Our findings suggest that binding of the viral protein to p53 may result in inactivation of the pro-apoptotic protein favoring the proliferation of a randomly occurring tumoral clone of oligodendrocytes.

Neuropathy in diffuse infiltrative lymphocytosis syndrome: an HIV neuropathy, not a lymphoma.

OBJECTIVE: To determine whether CD8 lymphoid infiltrates in nerves of patients with HIV-associated diffuse infiltrative lymphocytosis syndrome (DILS) corresponds to a lymphomatous neoplastic process or to a proliferation of T cells reactional to HIV. BACKGROUND: DILS is characterized by persistent CD8 hyperlymphocytosis and multivisceral CD8 T-cell infiltration, which may affect peripheral nerves. METHODS: Presence of monoclonal T cells and HIV-1 proviral load were evaluated by polymerase chain reaction (PCR) techniques in frozen peripheral nerve samples from six patients with DILS neuropathy and 22 patients with other HIV-associated peripheral neuropathies, including mononeuritis multiplex (MM:6), inflammatory demyelinating polyneuropathies (IDP:6), distal sensory polyneuropathy (DSP:5), and toxic distal sensory polyneuropathy (TDSP:5). RESULTS: Five of six patients with DILS showed no detectable monoclonal T-cell clones in their nerves. Nerve proviral load in DILS (6.8 +/- 0.2 log/10(5) cells) was much higher than in MM (p < 0.008), IDP (p < 0.001), DSP (p < 0.001), and TDSP (p < 0.005). CONCLUSIONS: DILS neuropathy represents a separate entity among HIV-associated neuropathies. It is associated with massive HIV proviral load in nerve and must not be confused with a peripheral nerve T-cell lymphoma.