Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis.

BACKGROUND: Central nervous system tuberculosis (CNS-TB) may be fatal even with treatment. Neutrophils are the key mediators of TB immunopathology, and raised CSF matrix metalloproteinase-9 (MMP-9) which correlates to neutrophil count in CNS-TB is associated with neurological deficit and death. The mechanisms by which neutrophils drive TB-associated CNS matrix destruction are not clearly defined. METHODS: Human brain biopsies with histologically proven CNS-TB were stained for neutrophils, neutrophil elastase, and MMP-9. Neutrophil MMP-9 secretion and gene expression were analyzed using Luminex and real-time PCR. Type IV collagen degradation was evaluated using confocal microscopy and quantitative fluorescent assays. Intracellular signaling pathways were investigated by immunoblotting and chemical inhibitors. RESULTS: MMP-9-expressing neutrophils were present in tuberculous granulomas in CNS-TB and neutrophil-derived MMP-9 secretion was upregulated by Mycobacterium tuberculosis (M.tb). Concurrent direct stimulation by M.tb and activation via monocyte-dependent networks had an additive effect on neutrophil MMP-9 secretion. Destruction of type IV collagen, a key component of the blood-brain barrier, was inhibited by neutralizing neutrophil MMP-9. Monocyte-neutrophil networks driving MMP-9 secretion in TB were regulated by MAP-kinase and Akt-PI3 kinase pathways and the transcription factor NF-kB. TNFα neutralization suppressed MMP-9 secretion to baseline while dexamethasone did not. CONCLUSIONS: Multiple signaling paths regulate neutrophil-derived MMP-9 secretion, which is increased in CNS-TB. These paths may be better targets for host-directed therapies than steroids currently used in CNS-TB

Photofunctional metal-organic framework thin films for sensing, catalysis and device fabrication

Metal Organic Frameworks (MOFs) constitute a developing class of materials constructed by metallic ions or inorganic clusters bridged by organic ligands, generating 2D or 3D extended porous crystalline structures. Their physical and chemical properties can be dramatically changed since the huge database of metal centers and type of ligands available for the design and construction MOFs. Besides, the implementation of anchored MOF onto different substrates opens up to an emerging field of device fabrication for specific applications. In this review we surveyed the recent progress and developments on MOF for sensing, catalylisis, photovoltaics, up conversion, and LED fabrication.Fil: Gomez, Germán Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; ArgentinaFil: Roncaroli, Federico. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Clinical and Pathological Aspects of Silent Pituitary Adenomas.

CONTEXT: Silent pituitary adenomas are anterior pituitary tumors with hormone synthesis but without signs or symptoms of hormone hypersecretion. They have been increasingly recognized and represent challenging diagnostic issues. EVIDENCE ACQUISITION: A comprehensive literature search was performed using MEDLINE and EMBASE databases from January 2000 to March 2018 with the following key words: (i) pituitary adenoma/tumor and nonfunctioning; or (ii) pituitary adenoma/tumor and silent. All titles and abstracts of the retrieved articles were reviewed, and recent advances in the field of silent pituitary adenomas were summarized. EVIDENCE SYNTHESIS: The clinical and biochemical picture of pituitary adenomas reflects a continuum between functional and silent adenomas. Although some adenomas are truly silent, others will show some evidence of biochemical hypersecretion or could have subtle clinical signs and, therefore, can be referred to as clinically silent or "whispering" adenomas. Silent tumors seem to be more aggressive than their secreting counterparts, with a greater recurrence rate. Transcription factors for pituitary cell lineages have been introduced into the 2017 World Health Organization guidelines: steroidogenic factor 1 staining for gonadotroph lineage; PIT1 (pituitary-specific positive transcription factor 1) for growth hormone, prolactin, and TSH lineage, and TPIT for the corticotroph lineage. Prospective studies applying these criteria will establish the value of the new classification. CONCLUSIONS: A concise review of the clinical and pathological aspects of silent pituitary adenomas was conducted in view of the new World Health Organization classification of pituitary adenomas. New classifications, novel prognostics markers, and emerging imaging and therapeutic approaches need to be evaluated to better serve this unique group of patients.J.D. was supported by a grant from the Brazilian Federal Agency for Support and Evaluation of Postgraduate Education (CAPES). The studies of M.K. on pituitary adenomas were supported by the Medical Research Council, Rosetrees Trust, and Wellcome Trust

TSPO expression in brain tumours: is TSPO a target for brain tumour imaging?

Positron emission tomography (PET) alone or in combination with MRI is increasingly assuming a central role in the development of diagnostic and therapeutic strategies for brain tumours with the aim of addressing tumour heterogeneity, assisting in patient stratification, and contributing to predicting treatment response. The 18 kDa translocator protein (TSPO) is expressed in high-grade gliomas, while its expression is comparatively low in normal brain. In addition, the evidence of elevated TSPO in neoplastic cells has led to studies investigating TSPO as a transporter of anticancer drugs for brain delivery and a selective target for tumour tissue. The TSPO therefore represents an ideal candidate for molecular imaging studies. Knowledge of the biology of TSPO in normal brain cells, in-depth understanding of TSPO functions and biodistribution in neoplastic cells, accurate methods for quantification of uptake of TSPO tracers and pharmacokinetic data regarding TSPO-targeted drugs are required before introducing TSPO PET and TSPO-targeted treatment in clinical practice. In this review, we will discuss the impact of preclinical PET studies and the application of TSPO imaging in human brain tumours, the advantages and disadvantages of TSPO imaging compared to other imaging modalities and other PET tracers, and pathology studies on the extent and distribution of TSPO in gliomas. The suitability of TSPO as molecular target for treatment of brain tumours will also be the appraised

Da Verona a Mayerling: riflessioni sul fenomeno dell’omicidio-suicidio partendo da alcuni casi storico-artistici

The phenomenon of homicide-suicide, particularly if carried out between two lovers, has been the subject of several artistic productions. Some stories, then, such as the history of Shakespeare’s Romeo and Juliet, and the case of the lovers of Mayerling, gave inspiration to many literary and motion picture works. Whether it comes to historical events, as in the matter of Crown Prince Rudolf of Austria and Baroness Maria Vetsera, or to dramatic works, as in the matter of Romeo Montagues and Juliet Capulets, the more or less voluntary death of two lovers is always a very interesting case to criminological sciences. This interest is due to many reasons: in criminology reconstructing a crime is meant also as a symbolic activity, which is - at least for some aspects - similar to an artistic production; artworks often do show in a clear way those psychopathological situations, which can cause deeds such as homicide-suicide; the crime description, from an artistic point of view, may help reconstructing the emotional atmosphere in which the crime was carried out and with which the specialist has to empathize. The Authors aim then at deepening some aspects concerning both the causesand the dynamics of homicide-suicide, making reference to the above mentioned historical and literary cases. In fact, the death of the lovers of Verona involves those dynamics we also find in suicide pacts, in which a life plan based on love is paradoxically performed through a double and simultaneous voluntary death.With regards to this and to the tragedy of Mayerling,we remark the need of distinguishing between a suicide pact and a suicide carried out only after an homicide and inspired by reasons which are far away from those of a shared death. Sometimes the range of interpretation as regards to this phenomenon may be very wide, either because of the emotional involvement caused in the observer by an homicide-suicide, since it reaches the existential dimension of the observer himself, either because of the enigmatic feature often characterizing a voluntary death, particularly when performed at the same time (or almost at the same time) by two people linked by an emotional relationship. In many cases there are only partial answers to questions, since reconstructing the path leading to such deed is difficult, because rarely there are survivors. Therefore, from this point of view, reflecting both on the symptoms and on the dynamics of the stories of either the lovers of Mayerling and those of Verona helps us to a better understanding of such a complex, and for some aspects always mysterious case as that of homicide-suicide. That is the place, in the end, beyond the different definitions and classifications proposed in the scientific field, where the search for the meaning of life is necessarily linked to that for the end of life, if we admit that the fundamental concern of human beings is avoiding the distress caused by death.Il fenomeno dell’omicidio-suicidio, specie se consumato tra due amanti, è stato oggetto di diverse produzioni artistiche ed alcune vicende, come quelle dei personaggi shakespeariani di Romeo e Giulietta, o quelle degli amanti di Mayerling, hanno ispirato molte opere letterarie e cinematografiche. Che si tratti di fatti storici, come nel caso del principe Rodolfo d’Asburgo e della baronessa Maria Vetzera, oppure di narrazioni teatrali, come nel caso di Romeo Montecchi e Giulietta Capuleti, la morte più o meno volontaria di due amanti rappresenta sempre una fattispecie di particolare interesse per le discipline criminologiche. Le ragioni di ciò sono molteplici: in criminologia, la ricostruzione dei delitti viene anche intesa come un’attività simbolica simile, almeno per certi aspetti, ad una produzione artistica; spesso l’opera d’arte illustra chiaramente quelle situazioni psicopatologiche che possono essere all’origine di gesti come l’omicidio-suicidio; le narrazioni stesse dei reati, dal punto di vista artistico, possono aiutare a ricostruisce l’atmosfera emotiva nella quale il delitto si è consumato e nella quale l’esperto deve concretamente calarsi. Facendo quindi riferimento ai predetti casi storico-letterari, gli Autori si propongono di approfondire alcuni aspetti criminogenetici e criminodinamici dell’omicidio-suicidio. La morte degli amanti di Verona, infatti, chiama in causa quelle dinamiche che si ravvisano anche nei patti suicidari, nei quali un progetto di vita basato sull’amore viene paradossalmente ad essere realizzato mediante una duplice e contestuale morte volontaria. In proposito, come la tragedia di Mayerling insegna, si rileva la necessità di differenziare tra l’eventualità di un patto suicidario e quello di un suicidio agito in epoca successiva ad un omicidio ed ispirato da motivazioni ben diverse da quelle di una morte condivisa. Talora, i m argini di interpretazione di questo fenomeno possono essere molto ampi, sia per il coinvolgimento emotivo che l’omicidio-suicidio suscita nell’osservatore, chiamando in causa anche la dimensione esistenziale del medesimo, sia per la connotazione enigmatica che spesso assume la morte volontaria, soprattutto se questa viene ad essere realizzata contemporaneamente, o quasi, da due soggettilegati da un rapporto di tipo affettivo. In molti casi, le domande trovano risposte solo parziali, dato che la ricostruzione del percorso che motiva tale gesto risente del fatto che non vi sono quasi mai superstiti. In questa prospettiva, quindi, riflettere sui prodromi e sui dinamismi delle vicende degli amanti di Mayerling e di Verona aiuta a chiarire meglio una fattispecie così complessa e, per certi versi, sempre misteriosa come quella dell’omicidio- suicidio. In essa, del resto, al di là delle diverse definizioni e classificazioni proposte in ambito scientifico, la ricerca del senso della vita si intreccia necessariamente a quella della conclusione della stessa, se è vero che la preoccupazione fondamentale dell’essere umano è quella di evitare l’angoscia suscitata dalla morte

CD15s/CD62E interaction mediates the adhesion of non-small cell lung cancer cells on brain endothelial cells:implications for cerebral metastasis

Expression of the cell adhesion molecule (CAM), Sialyl Lewis X (CD15s) correlates with cancer metastasis, while expression of E-selectin (CD62E) is stimulated by TNF-α. CD15s/CD62E interaction plays a key role in the homing process of circulating leukocytes. We investigated the heterophilic interaction of CD15s and CD62E in brain metastasis-related cancer cell adhesion. CD15s and CD62E were characterised in human brain endothelium (hCMEC/D3), primary non-small cell lung cancer (NSCLC) (COR-L105 and A549) and metastatic NSCLC (SEBTA-001 and NCI-H1299) using immunocytochemistry, Western blotting, flow cytometry and immunohistochemistry in human brain tissue sections. TNF-α (25 pg/mL) stimulated extracellular expression of CD62E while adhesion assays, under both static and physiological flow live-cell conditions, explored the effect of CD15s-mAb immunoblocking on adhesion of cancer cell–brain endothelium. CD15s was faintly expressed on hCMEC/D3, while high levels were observed on primary NSCLC cells with expression highest on metastatic NSCLC cells (p < 0.001). CD62E was highly expressed on hCMEC/D3 cells activated with TNF-α, with lower levels on primary and metastatic NSCLC cells. CD15s and CD62E were expressed on lung metastatic brain biopsies. CD15s/CD62E interaction was localised at adhesion sites of cancer cell–brain endothelium. CD15s immunoblocking significantly decreased cancer cell adhesion to brain endothelium under static and shear stress conditions (p < 0.001), highlighting the role of CD15s–CD62E interaction in brain metastasis

B cell rich meningeal inflammation associates with increased spinal cord pathology in multiple sclerosis

Increased inflammation in the cerebral meninges is associated with extensive subpial cortical grey matter pathology in the forebrain and a more severe disease course in a substantial proportion of secondary progressive multiple sclerosis (SPMS) cases. It is not known whether this relationship extends to spinal cord pathology. We assessed the contribution of meningeal and parenchymal immune infiltrates to spinal cord pathology in SPMS cases characterised by the presence (F+) or absence (F-) of lymphoid-like structures in the forebrain meninges. Transverse cryosections of cervical, thoracic and lumbar cord of 22 SPMS and 5 control cases were analysed for CD20+ B cells, CD4+ and CD8+ T cells, microglia/macrophages (IBA-1+), demyelination (myelin oligodendrocyte glycoprotein+) and axon density (neurofilament-H+). Lymphoid-like structures containing follicular dendritic cell networks and dividing B cells were seen in the spinal meninges of three out of 11 F+SPMS cases. CD4+ and CD20+ cell counts were increased in F+SPMS compared to F-SPMS and controls, whilst axon loss was greatest in motor and sensory tracts of the F+SPMS cases (p<0.01). The density of CD20+ B cells of the spinal leptomeninges correlated with: CD4+ T cells and total B and T cells of the meninges; with the density of white matter perivascular CD20+ and CD4+ lymphocytes (p<0.05); with white matter lesion area (p<0.05); and the extent of axon loss (p<0.05) in F+SPMS cases only. We show that the presence of lymphoid-like structures in the forebrain is associated with a profound spinal cord pathology, and local B cell rich meningeal inflammation associates with the extent of cord pathology. Our work supports a principal role for B cells in sustaining inflammation and tissue injury throughout the CNS in the progressive disease stage

Galectin-3 expression is ubiquitous in tumors of the sellar region, nervous system, and mimics - An immunohistochemical and RT-PCR study

Galectin-3 expression has been reported in spindle cell oncocytoma, certain pituitary adenoma subtypes, astrocytomas, oligodendrogliomas, and meningiomas. We evaluated galectin-3 protein expression by immunohistochemistry in 201 cases of a variety of nervous system and sellar tumors, as well as mRNA expression by reverse transcription-polymerase chain reaction in formalin-fixed paraffin-embedded tissue in a subset (20 cases). Immunohistochemical results were evaluated in a semiquantitative fashion on a 4-tiered scale (0 to 3). Strong (3+) immunoreactivity was seen in most of the cases (61%), followed by 2+(22%), and 1+(13%) staining. Only 4% of the lesions studied were immunonegative. Galectin-3 mRNA was present in 15 of the 18 cases (83%) in which reverse transcription-polymerase chain reaction was successful. Significant differences in protein expression were noted in the following 2 settings: specific meningioma subtypes (P=0.004, Fisher exact test) wherein clear cell meningioma demonstrated weak protein expression when compared with other meningioma variants. No significant difference was noted with respect to World Health Organization grade. Galectin-3 was also strongly expressed in benign nerve sheath tumors but only moderately expressed in malignant peripheral nerve sheath tumors (P=0.0009, Fisher exact test). Although galectin-3 positivity is a key feature of the immunophenotype of spindle cell oncocytoma, its consistent expression in other morphologically similar tumors (meningioma, pituicytoma, nerve sheath tumors, granular cell tumor, metastases) makes it of little use in the differential diagnosis of sellar region tumors, a setting in which it should be discouraged. Diagnostic uses of this marker may be limited to specific settings, including some meningioma subtypes and nerve sheath tumors

Mean expression of the X-chromosome is associated with neuronal density

peer reviewedBackground: Neurodegenerative diseases are characterized by key features such as loss of neurons, astrocytosis, and microglial activation/proliferation. These changes cause differences in the density of cell types between control and disease subjects, confounding results from gene expression studies. Chromosome X (ChrX) is known to be specifically important in the brain. We hypothesized the existence of a chromosomal signature of gene expression associated with the X-chromosome for neurological conditions not normally associated with that chromosome. The hypothesis was investigated using publicly available microarray datasets from studies on Parkinson's disease, Alzheimer's disease, and Huntington's disease. Data were analyzed using Chromowave, an analytical tool for detecting spatially extended expression changes along chromosomes. To examine associations with neuronal density and astrocytosis, the expression of cell specific reporter genes was extracted. The association between these genes and the expression patterns extracted by Chromowave was then analyzed. Further analyses of the X:Autosome ratios for laser dissected neurons, microglia cultures and whole tissue were performed to detect cell specific differences. Results: We observed an extended pattern of low expression of ChrX consistent in all the neurodegenerative disease brain datasets. There was a strong correlation between mean ChrX expression and the pattern extracted from the autosomal genes representing neurons, but not with mean autosomal expression. No chromosomal patterns associated with the neuron specific genes were found on other chromosomes. The chromosomal expression pattern was not present in datasets from blood cells. The X:Autosome expression ratio was also higher in neuronal cells than in tissues with a mix of cell types. Conclusions: The results suggest that neurological disorders show as a reduction in mean expression of many genes along ChrX. The most likely explanation for this finding relates to the documented general up-regulation of ChrX in brain tissue which, this work suggests, occurs primarily in neurons. If validated, this cell specific ChrX expression warrants further research as understanding the biological reasons and mechanisms for this expression, may help to elucidate a connection with the development of neurodegenerative disorders