Implication of long non-coding RNA NEAT1 in the pathogenesis of bacterial meningitis-induced blood-brain barrier damage.

PURPOSE: Blood-brain barrier (BBB) damage is closely related to various neurological disorders, including bacterial meningitis (BM). Determining a reliable strategy to prevent BBB damage in the context of infection would be highly desirable. In the present study, we investigated the implications of the long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) in moderating BBB damage. METHODS: In vitro BBB models were developed by co-culturing hCMEC/D3 cells with glioma cells, whereupon the glioma-exposed endothelial cells (GECs) were treated with a series of mimics, inhibitors, overexpression plasmids, and shRNAs for evaluating whether NEAT1, microRNA-135a (miR-135a) and hypoxia-inducible factor 1α (HIF1α) mediated BBB integrity and permeability. Furthermore, the in vivo biological function of NEAT1 was validated in a mouse model of BBB damage. RESULTS: NEAT1 and HIF1α were determined to be up-regulated, while miR-135a was under-expressed in GECs. As demonstrated by chromatin immunoprecipitation and dual-luciferase reporter assays, NEAT1 could bind to miR-135a, and HIF1α was confirmed as a target of miR-135a. Either overexpression of NEAT1 or depletion of miR-135a impaired the integrity and augmented the permeability of BBB. However, HIF1α silencing could reverse the BBB damage induced by NEAT1 overexpression or by inhibition of miR-135a. In vivo experiments substantiated that knockdown of NEAT1 could alleviate BBB damage in living mice. CONCLUSIONS: Hence, NEAT1 knockdown prevents BBB disruption and exerts promise as a potential target for BM treatment.

Fatal Disseminated Mycobacterium chelonae Infection in an Immunocompromised Host--A Unique Presentation.

Disseminated disease due to rapidly growing non tuberculous mycobacteria especially in the immunocompromised host is being increasingly reported. The usual manifestations of disease being skin and soft tissue infection, post operative wound infection and pulmonary disease. We present a case of a disseminated infection due to Mycobacterium chelonae with features of chronic meningitis and knee joint arthritis in a patient with systemic lupus erythematosus on systemic steroids and mycophenolate. M chelonae was isolated from both synovial and cerebrospinal fluid and anti microbial therapy was initiated as per sensitivity results. However the patient's clinical condition continued to worsen and she succumbed to her illness.

Cerebral sinovenous thrombosis in a child with Crohn's disease, otitis media, and meningitis.

Pediatric cerebral sinovenous thrombosis (CSVT) is associated with high morbidity and mortality. Severe long-term sequelae are reported in up to 48% of children. The most frequent location of CSVT in children is the superficial venous system. We present the neuroimaging findings using both computed tomography and magnetic resonance imaging (MRI) in a 10-year-old child with extensive superficial CSVT. Our report aims to stress the importance of awareness of risk factors in suspecting and rapidly diagnosing CSVT. The application of targeted conventional and advanced MRI sequences is the diagnostic tool of choice in children at risk of or with clinically suspected CSVT.

A neuropharmacokinetic assessment of bafetinib, a second generation dual BCR-Abl/Lyn tyrosine kinase inhibitor, in patients with recurrent high-grade gliomas.

PURPOSE: The primary objective of this study was to use intracerebral microdialysis (ICMD) to determine the neuropharmacokinetics of bafetinib, a dual BCR-Abl/Lyn tyrosine kinase inhibitor that may have activity against gliomas. METHODS: A microdialysis catheter was placed into either peritumoural or enhancing brain tissue of seven patients at the time of tumour resection or biopsy. Twenty-four hours later, bafetinib was administered, 240 or 360 mg po, repeating the same dose 12 h later. Dialysate samples were continuously collected for 24h, with plasma samples obtained in parallel. One to two weeks after finishing ICMD, patients were allowed to resume taking bafetinib continuously while being observed for toxicity and tumour response. RESULTS: Twenty-six dialysate samples per patient were collected (n=6) and analysed for bafetinib by tandem mass spectrometry. Bafetinib concentrations in the brain were below the lower limit of detection of the assay (0.1 ng/ml) in all samples except one from a single subject that was 0.52 ng/ml. The mean plasma bafetinib maximum concentrations after dose 1 and 2 were 143±99 and 247±73 ng/ml, respectively. Only one patient remained on treatment past two cycles, and no radiographic responses were seen. CONCLUSIONS: Bafetinib does not sufficiently cross intact or disrupted blood-brain barrier, and therefore, systemic administration of bafetinib is not recommended when investigating this drug as a treatment for brain tumours. ICMD can be a valuable research tool in early drug development. Lead-in ICMD studies can be performed relatively quickly, requiring only a small number of patients, and without significantly disrupting standard cancer care.

Cerebral vasculitis complicating postoperative meningitis: the role of steroids revisited.

Meningitis due to Streptococcus pneumoniae is a rare complication of trans-sphenoidal surgery. We present the case of a patient who developed pneumococcal meningitis with associated bacteraemia after elective endoscopic trans-sphenoidal resection of a pituitary macro-adenoma. After initial treatment with ceftriaxone and dexamethasone, the patient made a good recovery and dexamethasone was discontinued. Two days later the patient's condition deteriorated rapidly, presenting focal and diffuse neurological deficits. Cerebral MRI revealed widespread punctate ischaemic-type lesions affecting both anterior and posterior vascular territories bilaterally and involving features consistent with cerebral vasculitis. Antibiotic treatment was broadened to include meropenem and dexamethasone was restarted, but the patient remained in a comatose state and died 14 days later. Steroid treatment may play a dual role in this poorly characterised infectious complication of trans-sphenoidal pituitary surgery. This possibility is discussed and the options for prophylaxis are reviewed.

Central nervous system is a sanctuary site for chronic myelogenous leukaemia treated with imatinib mesylate.

Imatinib mesylate (IM) is currently used as the first therapeutic choice against chronic myelogenous leukaemia (CML). Because IM poorly penetrates the blood-brain barrier, IM-treated CML patients may have a potential risk of central nervous system (CNS) involvement. Here we report a case with lymphoid blast crisis isolated only in CNS after bacterial meningitis, although the patient achieved and maintained complete cytogenetic response by IM therapy. It is important to consider isolated CNS blast crisis as a possible event in IM-treated CML patients.

Two cases of bacterial meningitis accompanied by thalidomide therapy in patients with multiple myeloma: is thalidomide associated with bacterial meningitis?

Morbidity and mortality in multiple myeloma is often attributed to life-threatening infections. A defect in humoral immunity has been proposed for the predisposition to bacterial infections. Most of the infections are of bacterial origin, and the most serious are septicemia, meningitis, and pneumonia. Thalidomide is a drug with pleiotropic effects. The immunomodulatory effects of thalidomide are at least partially mediated through its ability to down-regulate the pathogenic over-production of tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is a cytokine that plays a central role in the regulation of the host immune and inflammatory response to infection. In the central nervous system, TNF-alpha is involved in induction of a fever response and triggers the release of other cytokines, and may also influence transport of compounds into the brain, leading to cerebrospinal fluid leukocytosis, increased protein influx, and lactate accumulation. Thalidomide has been shown to down-regulate the production of TNF-alpha. On the other hand, knowledge of the effects of thalidomide on granulocyte functions is limited. Thalidomide has been shown to attenuate neutrophil adhesion and chemotaxis. We present herein two cases of Streptococcus pneumoniae bacterial meningitis that developed soon after the initiation of thalidomide treatment, and discuss the effect of thalidomide on the immune system. Although, it is not clear whether thalidomide caused the development of the bacterial infections and meningitis, or what its pathogenetic mechanisms are, physicians should be alert for signs and symptoms of meningitis in patients with multiple myeloma who are treated with thalidomide, especially those in neutropenic states.

Anthrax toxins inhibit neutrophil signaling pathways in brain endothelium and contribute to the pathogenesis of meningitis.

BACKGROUND: Anthrax meningitis is the main neurological complication of systemic infection with Bacillus anthracis approaching 100% mortality. The presence of bacilli in brain autopsies indicates that vegetative bacteria are able to breach the blood-brain barrier (BBB). The BBB represents not only a physical barrier but has been shown to play an active role in initiating a specific innate immune response that recruits neutrophils to the site of infection. Currently, the basic pathogenic mechanisms by which B. anthracis penetrates the BBB and causes anthrax meningitis are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Using an in vitro BBB model, we show for the first time that B. anthracis efficiently invades human brain microvascular endothelial cells (hBMEC), the single cell layer that comprises the BBB. Furthermore, transcriptional profiling of hBMEC during infection with B. anthracis revealed downregulation of 270 (87%) genes, specifically key neutrophil chemoattractants IL-8, CXCL1 (Gro alpha) and CXCL2 (Gro beta), thereby strongly contrasting hBMEC responses observed with other meningeal pathogens. Further studies using specific anthrax toxin-mutants, quantitative RT-PCR, ELISA and in vivo assays indicated that anthrax toxins actively suppress chemokine production and neutrophil recruitment during infection, allowing unrestricted proliferation and dissemination of the bacteria. Finally, mice challenged with B. anthracis Sterne, but not the toxin-deficient strain, developed meningitis. CONCLUSIONS/SIGNIFICANCE: These results suggest a significant role for anthrax toxins in thwarting the BBB innate defense response promoting penetration of bacteria into the central nervous system. Furthermore, establishment of a mouse model for anthrax meningitis will aid in our understanding of disease pathogenesis and development of more effective treatment strategies.

Impaired anti-pneumococcal polysaccharide antibody production and invasive pneumococcal infection following heart transplantation.

An increased risk of invasive pneumococcal infection has been described among adult heart transplant (HT) recipients. Vaccination has been recommended before HT but the appropriate time for revaccination is not known. In a preliminary analysis of a prospective study involving a cohort of 32 HT recipients receiving daclizumab and triple immunosuppresion therapy, a progressive decline in pneumococcal polysaccharide antibody (anti-PPS) levels was observed during the first year after HT. One of the patients who was found to have a decrease in the levels of anti-PPS developed severe pneumococcal meningitis 20 months after HT. Before HT he had received non-conjugated 23-valent pneumococcal vaccine and showed a normal post-immunization anti-PPS production. The data suggest that long-term immunologic monitoring might be useful to recognize impairment of antibody responses under immunosuppressive therapy in HT.

Iatrogenic (para-) spinal abscesses and meningitis following injection therapy for low back pain.

Low back pain is often treated with paraspinal injections of analgesics and steroids. Infectious complications of these techniques are rare but they can potentially hold high risks for the patients. History and clinical data of all patients admitted to a neurological unit suffering from community acquired purulent meningitis were prospectively analyzed during an 8 year interval (1992 and 2000) with special regard to the previous medical history. One hundred and twenty eight patients were included in the study. Eight out of 128 patients (6.25%) had a history of single or repeated paravertebral (4/8), facet-joint (2/8), peridural (1/8) or spinal (1/8) injections 2-21 days before admission to the hospital. In six out of eight patients either Staphylococcus aureus (4/8) or coagulase-negative staphylococci (2/8) were found in the cerebro spinal fluid (CSF), in two patients no causative organism was detected. One patient died, three survived with sequel. Repeated paraspinal, peridural or spinal injections with analgesic drugs in combination with corticosteroids hold a risk for parameningeal inoculation of bacteria resulting in paraspinal, spinal, and epidural abscesses or meningitis. The absolute frequency of these complications may be rare but they are responsible for a considerable proportion of community acquired purulent CNS infections.