Non-linear dose-response of aluminium hydroxide adjuvant particles: Selective low dose neurotoxicity.

Aluminium (Al) oxyhydroxide (Alhydrogel), the main adjuvant licensed for human and animal vaccines, consists of primary nanoparticles that spontaneously agglomerate. Concerns about its safety emerged following recognition of its unexpectedly long-lasting biopersistence within immune cells in some individuals, and reports of chronic fatigue syndrome, cognitive dysfunction, myalgia, dysautonomia and autoimmune/inflammatory features temporally linked to multiple Al-containing vaccine administrations. Mouse experiments have documented its capture and slow transportation by monocyte-lineage cells from the injected muscle to lymphoid organs and eventually the brain.

The anti-hypertensive drug prazosin inhibits glioblastoma growth via the PKCδ-dependent inhibition of the AKT pathway.

A variety of drugs targeting monoamine receptors are routinely used in human pharmacology. We assessed the effect of these drugs on the viability of tumor-initiating cells isolated from patients with glioblastoma. Among the drugs targeting monoamine receptors, we identified prazosin, an α1- and α2B-adrenergic receptor antagonist, as the most potent inducer of patient-derived glioblastoma-initiating cell death.

Aluminum adjuvants of vaccines injected into the muscle: Normal fate, pathology and associated disease.

Aluminum oxyhydroxide (Alhydrogel(®)) is a nano-crystalline compound forming aggregates that has been introduced in vaccine for its immunologic adjuvant effect in 1926. It is the most commonly used adjuvant in human and veterinary vaccines but mechanisms by which it stimulates immune responses remain ill-defined. Although generally well tolerated on the short term, it has been suspected to occasionally cause delayed neurologic problems in susceptible individuals.

Fluorescent nanodiamonds as a relevant tag for the assessment of alum adjuvant particle biodisposition.

Background: Aluminum oxyhydroxide (alum) is a crystalline compound widely used as an immunologic adjuvant of vaccines. Concerns linked to alum particles have emerged following recognition of their causative role in the so-called macrophagic myofasciitis (MMF) lesion in patients with myalgic encephalomyelitis, revealing an unexpectedly long-lasting biopersistence of alum within immune cells and a fundamental misconception of its biodisposition. Evidence that aluminum-coated particles phagocytozed in the injected muscle and its draining lymph nodes can disseminate within phagocytes throughout the body and slowly accumulate in the brain further suggested that alum safety should be evaluated in the long term.

Biopersistence and brain translocation of aluminum adjuvants of vaccines.

Aluminum oxyhydroxide (alum) is a crystalline compound widely used as an immunological adjuvant of vaccines. Concerns linked to the use of alum particles emerged following recognition of their causative role in the so-called macrophagic myofasciitis (MMF) lesion detected in patients with myalgic encephalomyelitis/chronic fatigue/syndrome. MMF revealed an unexpectedly long-lasting biopersistence of alum within immune cells in presumably susceptible individuals, stressing the previous fundamental misconception of its biodisposition.

Clinical features in patients with long-lasting macrophagic myofasciitis.

Macrophagic myofasciitis (MMF) is an emerging condition characterized by specific muscle lesions assessing abnormal long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients usually are middle-aged adults, mainly presenting with diffuse arthromyalgias, chronic fatigue, and marked cognitive deficits, not related to pain, fatigue, or depression. Clinical features usually correspond to that observed in chronic fatigue syndrome/myalgic encephalomyelitis.

[Biopersistence and systemic distribution of intramuscularly injected particles: what impact on long-term tolerability of alum adjuvants?].

Aluminium oxyhydroxide (alum), a nanocrystalline compound that forms agglomerates, has been widely used as a vaccine adjuvant since 1927, but the mechanisms by which it stimulates immune responses remain poorly understood. Although generally well tolerated, alum may occasionally cause chronic health problems in presumably susceptible individuals. Some individuals may rarely develop delayed-onset diffuse myalgia, chronic exhaustion and cognitive dysfunction, associated with long-term persistence (up to 12 years) of alum-loaded macrophages at site of i.

Selective elevation of circulating CCL2/MCP1 levels in patients with longstanding post-vaccinal macrophagic myofasciitis and ASIA.

Several medical conditions sharing similar signs and symptoms may be related to immune adjuvants. These conditions described as ASIA (Autoimmune/inflammatory Syndrome Induced by Adjuvants), include a condition characterized by macrophagic myofasciitis (MMF) assessing long-term persistence of vaccine derived-alum adjuvants into macrophages at sites of previous immunization. Despite increasing data describing clinical manifestations of ASIA have been reported, biological markers are particularly lacking for their characterization and follow up.

Slow CCL2-dependent translocation of biopersistent particles from muscle to brain.

Background: Long-term biodistribution of nanomaterials used in medicine is largely unknown. This is the case for alum, the most widely used vaccine adjuvant, which is a nanocrystalline compound spontaneously forming micron/submicron-sized agglomerates. Although generally well tolerated, alum is occasionally detected within monocyte-lineage cells long after immunization in presumably susceptible individuals with systemic/neurologic manifestations or autoimmune (inflammatory) syndrome induced by adjuvants (ASIA).

Testicular biodistribution of 450 nm fluorescent latex particles after intramuscular injection in mice.

The significant expansion in the use of nanoparticles and submicron particles during the last 20 years has led to increasing concern about their potential toxicity to humans and particularly their impact on male fertility. Currently, an insufficient number of studies have focused on the testicular biodistribution of particles. The aim of our study was to assess the distribution of 450 nm fluorescent particles in mouse testes after intramuscular injection.

Clinical relevance of tumor cells with stem-like properties in pediatric brain tumors.

Background: Primitive brain tumors are the leading cause of cancer-related death in children. Tumor cells with stem-like properties (TSCs), thought to account for tumorigenesis and therapeutic resistance, have been isolated from high-grade gliomas in adults. Whether TSCs are a common component of pediatric brain tumors and are of clinical relevance remains to be determined.

CD133, CD15/SSEA-1, CD34 or side populations do not resume tumor-initiating properties of long-term cultured cancer stem cells from human malignant glio-neuronal tumors.

Background: Tumor initiating cells (TICs) provide a new paradigm for developing original therapeutic strategies.

Methods: We screened for TICs in 47 human adult brain malignant tumors. Cells forming floating spheres in culture, and endowed with all of the features expected from tumor cells with stem-like properties were obtained from glioblastomas, medulloblastoma but not oligodendrogliomas.

Astrocytes reverted to a neural progenitor-like state with transforming growth factor alpha are sensitized to cancerous transformation.

Gliomas, the most frequent primitive central nervous system tumors, have been suggested to originate from astrocytes or from neural progenitors/stem cells. However, the precise identity of the cells at the origin of gliomas remains a matter of debate because no pre-neoplastic state has been yet identified. Transforming growth factor (TGF)-alpha, an epidermal growth factor family member, is frequently overexpressed in the early stages of glioma progression.

Assessing cardiovascular risk factors after coronary artery bypass surgery: value of an aggressive strategy including systematic follow-up.

Introduction: Coronary revascularization surgery is a palliative treatment modality which should not preclude efforts to treat atherosclerosis.

Aim: To assess ongoing cardiovascular risk factors after coronary artery bypass surgery and develop a strategy to attenuate such factors.

Methods: 108 patients requiring a coronary artery bypass were included: 2 died soon after surgery and 6 were excluded for personal reasons.

Two temporal stages of oligodendroglial response to excitotoxic lesion in the gray matter of the adult rat brain.

Excitotoxic lesions in the gray matter induce profuse demyelination of passage and afferent fibers in areas of neuronal loss, independent of Wallerian degeneration. The time course of this phenomenon, which extends over weeks after the excitotoxin injection, suggests that demyelination is not related only to a direct effect of the toxin. In order to define mechanisms at work, a parallel study of myelin and oligodendrocytes was carried out following kainate injections into the adult rat thalamus.

Transforming growth factor alpha: a promoter of motoneuron survival of potential biological relevance.

Expression of transforming growth factor alpha (TGFalpha), a member of the epidermal growth factor (EGF) family, is a general response of adult murine motoneurons to genetic and experimental lesions, TGFalpha appearing as an inducer of astrogliosis in these situations. Here we address the possibility that TGFalpha expression is not specific to pathological situations but may participate to the embryonic development of motoneurons. mRNA of TGFalpha and its receptor, the EGF receptor (EGFR), were detected by ribonuclease protection assay in the ventral part of the cervical spinal cord from embryonic day 12 (E12) until adult ages.

Glial and endothelial cell response to a fetal transplant of purified neurons.

Astrocytes, microglia and endothelial cells display very specific phenotypic characteristics in the intact adult CNS, which appear quite versatile when grown in culture without neurons. Indirect evidence from in vitro co-culture studies and analysis of the effects of specific neuronal removal in vivo, does accordingly favour a role of neurons for the phenotypic repression of these cells in the intact brain. In order to provide more direct evidence for such neuronal influence, we attempted to induce, in the rat brain, a reversal of the post-lesional activation of astrocytes, microglia and endothelial cells by transplantation of fetal neurons purified by immunopanning.

Long-term histological follow-up of genetically modified myoblasts grafted into the brain.

Although primary muscle cells have been used as intracerebral vehicles for transgene expression in the past, data concerning their long-term survival after grafting into the brain, and the reaction of the host tissue to their implantation are lacking. In order to study these aspects, we have implanted, into the brain, primary muscle cells infected ex vivo with recombinant retroviruses carrying the E. coli LacZ gene.

Morphological maturation of thalamic neurons as studied in fetal neural transplants.

This study attempts to determine whether fetal thalamic neuroblasts from rat embryos (embryonic age 15 days) labeled with horseradish peroxidase (HRP) can differentiate into their normal dendritic phenotype when transplanted as a cell suspension into a lesioned site in the adult somatosensory thalamus. The HRP labeling provided a Golgi-like staining of numerous neurons up to 12-14 days after transplantation. There were three main results.

Transforming growth factor alpha (TGF alpha) expression in degenerating motoneurons of the murine mutant wobbler: a neuronal signal for astrogliosis?

The enhanced expression of the trophic factor transforming growth factor alpha (TGF alpha) in reactive astrocytes following CNS injury suggests that TGF alpha has a role in the development of astrogliosis. We explored this hypothesis in the murine mutant wobbler, which presents a progressive motoneuronal degeneration associated with an astrogliosis. Evolution of astrogliosis, and expression of TGF alpha precursor (pro-TGF alpha) and of its receptor were examined over the course of the disease, using genetically diagnosed animals and immunocytochemical techniques.

In vivo transfer of a marker gene to study motoneuronal development.

Adenovirus vectors containing a marker gene (lacZ from Escherichia coli) are potent for transferring the gene to neurones after intraparenchymal injections. Expression of the marker gene may lead to the synthesis of an enormous amount of beta-galactosidase which diffuses throughout the entire neurone, providing a 'Golgi-like' staining. This suggested that the technique may be used to study the morphology of specific neuronal populations.

Maturation and integration of purified foetal neurons transplanted into the adult brain.

Fetal neural transplants presently developed as a therapeutic strategy for neurodegenerative diseases include both the neurons of interest and their cellular environment. These glial and vascular cells may be detrimental by, for instance, expressing foreign MHC antigens. This study was undertaken to determine whether purified neurons would survive transplantation into an adult host brain.

[Connections of the posterior region of the thalamus in rats].

Using retrograde and anterograde tracing methods we have studied in the posterior region of the thalamus of the rat the distribution of: (1) the terminal fields of the main afferents arising from somatosensory centers (dorsal column nuclei, interpolar trigeminal subnucleus, somatosensory cortex), motor centers (red nucleus, motor cortex) and multimodal structures (deep layers of the superior colliculus, zona incerta, cingular cortex) and of (2) the neurons giving rise to the main efferents towards the sensorimotor cortex, the red nucleus, the deep layers of the superior colliculus and the zone incerta. The overlap of the retrograde and anterograde labeling reveals a relatively homogeneous region. Considering however the cortical connections, three different subdivisions can be distinguished: a caudal pole completely devoid of cortical connections, a medial subdivision receiving cortical afferents from the sensorimotor and cingulate cortices and a rostral pole reciprocally connected with the sensorimotor cortex.