An atypical presentation of diffuse midline pontine glioma in a middle age patient: Case report.

INTRODUCTION: Diffuse midline glioma is a newly WHO defined entity (grade IV) (Louis et al., 2016) which includes diffuse intrinsic pontine glioma (DIPG) reported in pediatric population and, occasionally, in young adults. Here, we present a detailed description of an atypical case of diffuse midline glioma in a 53 years old woman. CASE REPORT: A caucasian woman aged 53 from Ukraine, was referred to another neurological department complaining of 3 months history of progressive postural instability and gait impairment with frequent falling. Magnetic resonance demonstrated two brainstem lesions, hyperintense in FLAIR with "patchy" peripheral enhancement, leptomeningeal and cranial nerves enhancement. CSF was normal. Due to positive antinuclear antibodies test (ANA 1:360), intravenous steroid treatment was administered and reported to initially improve the patient condition. However, the following weeks the lady worsened. Imaging features were unchanged. Because quantiferon test resulted positive, MRI-Spectroscopy showed an inflammatory pattern and MRI perfusion study and brain FDG-PET, were normal, tubercolar granulomatous hypothesis was initially favored. Antitubercular therapy with isoniazid, pyrazinamide, ethambutol and rifampicin was started without any clinical improvement. Hence, the biopsy was proposed. The procedure revealed a diffuse midline pontine glioma. Considering the advanced stage of the disease, radiotherapy was not indicated. Patient died after eight months from the onset of neurological disturbances. CONCLUSION: Our case shows that diffuse midline glioma is a CNS tumor not limited to young population but occurring also in middle aged patients with an insidious pattern. We therefore recommend to perform biopsy at very early stages in patients with atypical brainstem lesions.

Sumoylation in Lens Differentiation and Pathogenesis.

Sumoylation, a post-translational modification discovered over a decade ago, turns out to be a very important regulatory mechanism mediating multiple cellular processes. Recent studies from our laboratory and others also revealed that it plays a crucial role in regulating both differentiation and pathogenesis of the ocular lens. This review will summarize these progresses.

Magnetic resonance imaging characteristics of ischemic stroke in an Afro-Caribbean population: A 1-year prospective MRI study on 534 consecutive patients.

PURPOSES: Few population-based MRI studies on stroke, particularly in African-descent populations, are available. Based on a 1-year Afro-Caribbean population-based study MRI, ischemic stroke characteristics were extensively analyzed. METHODS: All strokes occurring in Martinique (390,371 inhabitants) were prospectively included. Ascertainment was based, whenever possible, on MRI. All patients were categorized as single- (subclassified as cortical, cortical-subcortical, subcortical, lacunar) or multiple-lesion pattern, and vascular (single, multiple or junctional) territory. Brain parenchyma was evaluated, based on visualization of macrobleeds, microbleeds, white-matter hyperintensities or stroke sequelae. Etiology was classified according to TOAST criteria. RESULTS: Among 596 ischemic stroke patients included, 534 (295 men, 239 women; mean age, 71 [range 23-110] years) underwent MRI (median delay 1 day). Four hundred and eighty-eight had single-type lesion (14.8% cortical, 42.4% cortical-subcortical, 14.5% subcortical, 16.6% lacunar), involving anterior cerebral (4%), middle cerebral (63.7%), posterior cerebral artery (10.4%) or basilar trunk (11.7%) territories, with 10.3% simultaneously involving multiple territories and 4.9% junctional infarction. Etiologies were LAA (11.2%), SVD (10.7%), CE (29.6%), rare (4.5%) or undetermined (44.1%). CONCLUSION: Our prospective, consecutive, ischemic stroke series gives a comprehensive description of ischemic stroke imaging patterns and etiologic distributions in an Afro-Caribbean population with high socio-economic status. Our patients' stroke characteristics are close to those of European-descent populations.

Inter-hemispheric Claustral Connections in Human Brain: A Constrained Spherical Deconvolution-Based Study.

PURPOSE: Complex claustral connection network was widely demonstrated both in humans and animals. Moreover, several studies have suggested that claustral connections directly involve also the contralateral hemisphere. Detection of contralateral cortico-claustral and inter-claustral connections was reported mainly in animals and only partially in humans. The main purpose of this study was to provide more robust tractography-driven support of the existence of inter-hemispheric claustral connections in humans, by means of a dedicated optimized tractographic protocol. METHODS: Fifteen healthy subjects were examined by means of an advanced magnetic resonance imaging-based probabilistic constrained spherical deconvolution tractographic protocol. Moreover, quantitative diffusion parameters were extracted by each reconstructed pathway. RESULTS: In this study, further imaging-based support on the possible existence in humans of contralateral cortico-claustral and inter-claustral connections was provided. These connections were found to involve almost all the superior portion of each claustrum, showing a topographical organization. Moreover, the detection of inter-claustral connections passing through the anterior commissure was reported, for the first time, in humans. CONCLUSIONS: The possible existence of inter-claustral and cortico-claustral contralateral pathways might provide the morphological basis for the complex functional phenomena observed in previous studies. Furthermore, these connections might have several important clinical implications, since they might explain how the inter-hemispheric coordination governed by the claustrum, as well as the functional recovery subsequent to damages involving one claustrum, takes place.

MRI Tractography of Corticospinal Tract and Arcuate Fasciculus in High-Grade Gliomas Performed by Constrained Spherical Deconvolution: Qualitative and Quantitative Analysis.

BACKGROUND AND PURPOSE: MR imaging tractography is increasingly used to perform noninvasive presurgical planning for brain gliomas. Recently, constrained spherical deconvolution tractography was shown to overcome several limitations of commonly used DTI tractography. The purpose of our study was to evaluate WM tract alterations of both the corticospinal tract and arcuate fasciculus in patients with high-grade gliomas, through qualitative and quantitative analysis of probabilistic constrained spherical deconvolution tractography, to perform reliable presurgical planning. MATERIALS AND METHODS: Twenty patients with frontoparietal high-grade gliomas were recruited and evaluated by using a 3T MR imaging scanner with both morphologic and diffusion sequences (60 diffusion directions). We performed probabilistic constrained spherical deconvolution tractography and tract quantification following diffusion tensor parameters: fractional anisotropy; mean diffusivity; linear, planar, and spherical coefficients. RESULTS: In all patients, we obtained tractographic reconstructions of the medial and lateral portions of the corticospinal tract and arcuate fasciculus, both on the glioma-affected and nonaffected sides of the brain. The affected lateral corticospinal tract and the arcuate fasciculus showed decreased fractional anisotropy (z = 2.51, n = 20, P = .006; z = 2.52, n = 20, P = .006) and linear coefficient (z = 2.51, n = 20, P = .006; z = 2.52, n = 20, P = .006) along with increased spherical coefficient (z = -2.51, n = 20, P = .006; z = -2.52, n = 20, P = .006). Mean diffusivity values were increased only in the lateral corticospinal tract (z = -2.53, n = 20, P = .006). CONCLUSIONS: In this study, we demonstrated that probabilistic constrained spherical deconvolution can provide essential qualitative and quantitative information in presurgical planning, which was not otherwise achievable with DTI. These findings can have important implications for the surgical approach and postoperative outcome in patients with glioma.

HspB1 dynamic phospho-oligomeric structure dependent interactome as cancer therapeutic target.

Human HspB1 (Hsp27), a molecular chaperone bearing tumorigenic and metastatic roles, is characterized by its dynamic phosphorylation and heterogenous oligomerization in response to changes in cell physiology. The phenomenon is particularly intense and specific when cells are exposed to different death inducers. This favors the hypothesis that the structural organization of HspB1 acts as a sensor which, through reversible modifications, allows cells to adapt and/or mount a protective response. A large number of HspB1 interacting partners have already been described in the literature. Specific changes in oligomerphosphorylation organization may therefore allow HspB1 to interact with the more appropriate polypeptides and to subsequently modulate their folding/activity and/or half-life. This could indirectly link HspB1 to multiple cellular functions and could explain the apparently unrelated effects associated to its over- or underexpression. In cancer, HspB1 is tumorigenic, stimulates metastasis and provide cancer cells with resistance to many anti-cancer drugs, so compounds aimed at disrupting HspB1 deleterious pro-cancer activity are actively looked for. One example, is brivudine that impairs HspB1 ability to recognize pathological protein substrates and appears as a promising anti-cancer drug. Similarly, we have observed that peptide aptamers that specifically interfere with HspB1 structural organization reduced its anti-apoptotic and tumorigenic activities. We propose that, in addition to RNA interference approaches, the tumorigenic activity of HspB1 could be inhibited by altering HspB1 structural organization and consequently its interaction with inappropriate procancerous polypeptide partners. Hence, developping HspB1 structure-based interfering strategies could lead to new anti-cancer drugs discovery.

Targeting heat shock protein 27 (HspB1) interferes with bone metastasis and tumour formation in vivo.

BACKGROUND: The small stress heat shock protein 27 (Hsp27) has recently turned as a promising target for cancer treatment. Hsp27 upregulation is associated with tumour growth and resistance to chemo- and radio-therapeutic treatments, and several ongoing drugs inhibiting Hsp27 expression are under clinical trial. Hsp27 is now well described to counteract apoptosis and its elevated expression is associated with increased aggressiveness of several primary tumours. However, its role in the later stage of tumour progression and, more specifically, in the later and most deadly stage of tumour metastasis is still unclear. METHODS/RESULTS: In the present study, we showed by qRT-PCR that Hsp27 gene is overexpressed in a large fraction of the metastatic breast cancer area in 53 patients. We further analysed the role of this protein in mice during bone metastasis invasion and establishment by using Hsp27 genetically depleted MDA-MB231/B02 human breast cancer cell line as a model. We demonstrate that Hsp27 silencing led to reduced cell migration and invasion in vitro and that in vivo it correlated with a decreased ability of breast cancer cells to metastasise and grow in the skeleton. CONCLUSION: Altogether, these data characterised Hsp27 as a potent therapeutic target in breast cancer bone metastasis and skeletal tumour growth.

Pathology-dependent effects linked to small heat shock proteins expression: an update.

Small heat shock proteins (small Hsps) are stress-induced molecular chaperones that act as holdases towards polypeptides that have lost their folding in stress conditions or consequently of mutations in their coding sequence. A cellular protection against the deleterious effects mediated by damaged proteins is thus provided to cells. These chaperones are also highly expressed in response to protein conformational and inflammatory diseases and cancer pathologies. Through specific and reversible modifications in their phospho-oligomeric organization, small Hsps can chaperone appropriate client proteins in order to provide cells with resistance to different types of injuries or pathological conditions. By helping cells to better cope with their pathological status, their expression can be either beneficial, such as in diseases characterized by pathological cell degeneration, or deleterious when they are required for tumor cell survival. Moreover, small Hsps are actively released by cells and can act as immunogenic molecules that have dual effects depending on the pathology. The cellular consequences linked to their expression levels and relationships with other Hsps as well as therapeutic strategies are discussed in view of their dynamic structural organization required to interact with specific client polypeptides.

Inhibition of heat shock protein 27 (HspB1) tumorigenic functions by peptide aptamers.

Human heat shock protein 27 (Hsp27, HspB1) is an anti-apoptotic protein characterized for its tumorigenic and metastatic properties, and now referenced as a major therapeutic target in many types of cancer. Hsp27 biochemical properties rely on a structural oligomeric and dynamic organization. Downregulation by small interfering RNA or inhibition with dominant-negative mutant have proven their efficiency to counteract the anti-apoptotic and protective properties of Hsp27. In this study, we report the isolation and characterization of Hsp27-targeted molecules interfering with its structural organization. Using the peptide aptamer (PA) strategy, we isolated PAs that specifically interact with Hsp27 and not with the other members of the small heat shock protein family. In mammalian cell cultures, PAs expression perturbed the dimerization and oligomerization of Hsp27, and acted as negative regulators of the anti-apoptotic and cytoprotective activities of this protein. Further studies analyzing SQ20B cell xenografts in immunocompromised mice showed that PAs strongly reduced tumor development through cell cycle arrest. Our data suggest that PAs could provide a potential tool to develop strategies for the discovery of Hsp27 chemical inhibitors.

Expression and functions of heat shock proteins in the normal and pathological mammalian eye.

Heat shock proteins (Hsps) are expressed in mammalian embryonic, adult and aging lens, cornea and retina. These proteins, particularly those belonging to the family of small Hsps, such as αA-crystallin (HspB4) and αB-crystallin (HspB5), play important roles in the differentiation of lens cells and are essential for the maintenance and protection of the supraorganization of proteins in differentiated corneal and lens fiber cells. Hsps are molecular chaperones characterized by their protective activity against different types of stress. They also have anti-apoptotic and anti-oxidant functions that help lens and corneal cells to better cope with the oxidative conditions that result from light induced injuries. They are also effective to protect the retina against the high rate of oxidative metabolism observed in this tissue. The goal of this review is to highlight recent works describing the expression and function(s) of the different Hsps as an attempt to better understand their roles in the normal and pathological eye. Particular emphasis is given to the α-crystallin polypeptides which, in addition to their protective functions, are key structural polypeptides that are essential for the refractive and light focusing properties of the lens, a property demonstrated by the caractogenic potential of their mutation.

Diastematomyelia in adults. A report of two cases incidentally discovered.

We describe two cases of incidentally discovered split cord malformations in adults undergoing MR for symptoms unrelated to that malformation. Case 1 is an 80-year-old woman with pain due to a D7 and D8 vertebral body compression fracture resistant to medical treatment where we performed D7 and D8 percutaneous vertebroplasty with no complications and satisfactory pain control. Case 2 is a 59-year-old woman with L5 radiculopathy due to L5-S1 spondilolysthesis who had a satisfactory pain relief under medical treatment. The implementation and worldwide diffusion of MR revealed that diastematomyelia, split cord malformations traditionally seen in children, may be less rare than we thought in adults and can remain asymptomatic.

A saturated N-acylethanolamine other than N-palmitoyl ethanolamine with anti-inflammatory properties: a neglected story...

N-acylethanolamines, which include the endocannabinoid anandamide and the cannabinoid receptor-inactive saturated compounds N-palmitoyl ethanolamine and N-stearoyl ethanolamine, are ethanolamines of long-chain fatty acids degraded by fatty acid amide hydrolase (FAAH) known to accumulate in degenerating tissues and cells. Whilst much evidence supports a protective anti-inflammatory role of both anandamide and N-palmitoyl ethanolamine, very little information is available with regard to the bioactivity of N-stearoyl ethanolamine. Employing a murine model of passive IgE-induced cutaneous anaphylaxis, we have found that N-stearoyl ethanolamine is endowed with marked anti-inflammatory properties in vivo, supporting the hypothesis that endogenous N-stearoyl ethanolamine is, in analogy to N-palmitoyl ethanolamine, a bioactive signalling lipid capable of downregulating allergic inflammation in the skin. This effect, although mimicked by synthetic, non-selective, CB(1)/CB(2) receptor agonists, such as WIN55, 212-2, was not sensitive to CB(1) or CB(2) receptor antagonists, but rather was fully reversed by capsazepine, a competitive antagonist of the TRPV1 receptor. Moreover, CB(1) receptor antagonists, although effective in antagonising the WIN55,212-2-induced hypothermia, did not reduce the anti-inflammatory effect of WIN55,212-2, whilst CB(2) receptor antagonists, per se inactive, potentiated the WIN55,212-2 effect, suggesting an involvement of non-CB(1)/CB(2) receptors in the anti-inflammatory action of WIN55,212-2. All this, together with demonstration of FAAH as a major regulator of the in vivo concentrations of saturated N-stearoyl ethanolamine, in addition to N-palmitoyl ethanolamine, raise the speculation that pharmacological treatments with saturated N-acylethanolamines such as N-stearoyl ethanolamine, or alternatively FAAH inhibitors able to increase their local concentration, rather than selective CB receptor agonists, might be of promising therapeutic benefit in reducing allergic inflammation in the skin.

Protection against heat and staurosporine mediated apoptosis by the HSV-1 US11 protein.

US11 protein, one of herpes simplex virus type 1 (HSV-1) true late gene products, plays a role in the virally induced post-transcriptional control of gene expression. In addition, US11 expression also interferes with the cellular response to HSV-1 infection that can lead to apoptosis. We have previously shown that US11 expression enhanced the recovery of cellular protein synthesis and increased cell survival in response to thermal stress. Since heat shock can activate apoptosis, we tested for a possible anti-apoptotic behavior of US11. Here, we show that, in HeLa cells, US11 expression strongly reduced heat induced apoptosis, a phenomenon independent of Hsp expression and characterized by a delayed cytochrome c efflux from mitochondria and reduced caspase 3 activation. Moreover, US11 expression also protected against staurosporine induced apoptosis. Hence, our results favor an anti-apoptotic activity of US11 polypeptide that appears to be located at the level of mitochondria or upstream signaling pathways.

Neurological complications of liver cirrhosis and orthotopic liver transplant.

Neurological complications are common in cirrhotic patients with end-stage liver failure. They comprise a wide array of etiologies, which may originate before, during, or after liver transplantation. The objective of this study was to describe the nature of the main neurological complications in patients with end-stage liver failure. Several toxins including ammonia, manganese, benzodiazepine-like substances, gamma-aminobutyric acid-like substances, and impaired dopaminergic neurotransmission are at the top of the list of candidates for hepatic encephalopathy, subclinical encephalopathy, and extrapyramidal signs before liver transplantation. Central pontine myelinolysis, cerebrovascular autoregulation impairment, and paradoxical cerebral embolism are probably responsible for the neurological complications during liver transplantation. Neurological complications represented by alterations of mental status, seizures, and focal motor deficits have been described after liver transplantation. These complications have been attributed to several pathogenetic factors, such as a poorly functioning graft, an intracranial hemorrhage, a cerebral infarction, an infection, or the toxicity of immunosuppressants.

Dithiocarbamate fungicide thiram detection: comparison of bioluminescent and fluorescent whole-cell bioassays based on hsp22 stress promoter induction.

Detection of toxic substances interfering with endocrine system is one of the major preoccupations of the European community. A whole-cell bioassay for pollution detection based on stress induction has been designed. Well characterized toxicants, cadmium chloride and thiram (a dithiocarbamate fungicide), were used to optimize the detection conditions such as time-course conditions, cell line and reporter gene to be used. HeLa cells containing the firefly luciferase (luc) reporter gene under the control of the Drosophila melanogaster hsp22 promoter were compared to liver cells (HepG2) containing the same stress gene promoter fused either to the luc or the EGFP (Enhanced-Green Fluorescent Protein) gene. The sensitivity of the obtained bioassay was found to be enhanced by the concomitant use of liver cells and EGFP reporter gene. The detection limits of the toxicants were then lowered from 1 to 0.1 microM and from 1 to 0.01 microM for CdCl(2) and thiram, respectively.

Chemical stress sensitive luminescent human cells: molecular biology approach using inducible Drosophila melanogaster hsp22 promoter.

A whole-cell bioassay has been developed for the total toxicity testing of liquid samples. The method is based on the induction of the bioluminescent activity of genetically manipulated mammalian cells. For that purpose, transfection was used to introduce, in HeLa cells, a DNA sensing element that responds to chemical stress agents (heavy metals, genotoxic agents, and endocrine-disrupting chemicals). Such element was designed to direct the expression of a reporting gene (firefly luciferase) through the activation of Drosophila melanogaster hsp22 promoter. A molecular approach was conducted to optimize hsp22 promoter element in order to decrease the background expression level of the reporting gene and to increase the sensitivity of the bioassay for testing endocrine disruptors. As a result, in the presence of 20-100 microM cadmium chloride, a 6-fold increase in luciferase expression was obtained using a specially designed truncated hsp22 promoter construction. The following chemicals known to be found in the polluted samples were tested: CdCl2, Cd(NO3)2, NaAsO2, alachlore, fentine acetate, thiram, and maneb. The stressing effect of each of them was sensitively detected by the present bioassay in the 0.05-50 microM concentration range.