161 resultados para BLOOD BRAIN BARRIER


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Mycoplasma pneumoniae (M. pneumoniae) frequently causes community-acquired respiratory tract infection and often presents as atypical pneumonia. Following airborne infection and a long incubation period, affected patients mostly suffer from mild or even asymptomatic and self-limiting disease. In particular in school-aged children, M. pneumoniae is associated with a wide range of extrapulmonary manifestations including central nervous system (CNS) disease. In contrast to children, severe CNS manifestations are rarely observed in adults. We report a case of a 37 year-old previously healthy immunocompetent adult with fulminant M. pneumoniae-induced progressive encephalomyelitis who was initially able to walk to the emergency department. A few hours later, she required controlled mechanical ventilation for ascending transverse spinal cord syndrome, including complete lower extremity paraplegia. Severe M. pneumoniae-induced encephalomyelitis was postulated, and antimicrobial, anti-inflammatory and immunosuppressive therapy was applied on the intensive care unit. Despite early and targeted therapy using four different immunosuppressive strategies, clinical success was limited. In our patient, locked-in syndrome developed followed by persistent minimally conscious state. The neurological status was unchanged until day 230 of follow-up. Our case underlines that severe M. pneumoniae- related encephalomyelitis must not only be considered in children, but also in adults. Moreover, it can be fulminant and fatal in adults. Our case enhances the debate for an optimal antimicrobial agent with activity beyond the blood-brain barrier. Furthermore, it may underline the difficulty in clinical decision making regarding early antimicrobial treatment in M. pneumoniae disease, which is commonly self-limited.

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BACKGROUND The monoclonal antibody natalizumab (NAT) inhibits the migration of lymphocytes throughout the blood-brain barrier by blocking very late antigen (VLA)-4 interactions, thereby reducing inflammatory central nervous system (CNS) activity in patients with multiple sclerosis (MS). We evaluated the effects of different NAT treatment regimens. METHODS We developed and optimised a NAT assay to measure free NAT, cell-bound NAT and VLA-4 expression levels in blood and cerebrospinal fluid (CSF) of patients using standard and prolonged treatment intervals and after the cessation of therapy. RESULTS In paired CSF and blood samples of NAT-treated MS patients, NAT concentrations in CSF were approximately 100-fold lower than those in serum. Cell-bound NAT and mean VLA-4 expression levels in CSF were comparable with those in blood. After the cessation of therapy, the kinetics of free NAT, cell-bound NAT and VLA-4 expression levels differed. Prolonged intervals greater than 4 weeks between infusions caused a gradual reduction of free and cell-bound NAT concentrations. Sera from patients with and without NAT-neutralising antibodies could be identified in a blinded assessment. The NAT-neutralising antibodies removed NAT from the cell surface in vivo and in vitro. Intercellular NAT exchange was detected in vitro. CONCLUSIONS Incorporating assays to measure free and cell-bound NAT into clinical practice can help to determine the optimal individual NAT dosing regimen for patients with MS.

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Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93-1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.

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Disruption of the blood-brain and blood-spinal cord barriers (BBB and BSCB, respectively) and immune cell infiltration are early pathophysiological hallmarks of multiple sclerosis (MS), its animal model experimental autoimmune encephalomyelitis (EAE), and neuromyelitis optica (NMO). However, their contribution to disease initiation and development remains unclear. In this study, we induced EAE in lys-eGFP-ki mice and performed single, nonterminal intravital imaging to investigate BSCB permeability simultaneously with the kinetics of GFP(+) myeloid cell infiltration. We observed a loss in BSCB integrity within a day of disease onset, which paralleled the infiltration of GFP(+) cells into the CNS and lasted for ∼4 d. Neutrophils accounted for a significant proportion of the circulating and CNS-infiltrating myeloid cells during the preclinical phase of EAE, and their depletion delayed the onset and reduced the severity of EAE while maintaining BSCB integrity. We also show that neutrophils collected from the blood or bone marrow of EAE mice transmigrate more efficiently than do neutrophils of naive animals in a BBB cell culture model. Moreover, using intravital videomicroscopy, we demonstrate that the IL-1R type 1 governs the firm adhesion of neutrophils to the inflamed spinal cord vasculature. Finally, immunostaining of postmortem CNS material obtained from an acutely ill multiple sclerosis patient and two neuromyelitis optica patients revealed instances of infiltrated neutrophils associated with regions of BBB or BSCB leakage. Taken together, our data provide evidence that neutrophils are involved in the initial events that take place during EAE and that they are intimately linked with the status of the BBB/BSCB.

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Intensive efforts in recent years to develop and commercialize in vitro alternatives in the field of risk assessment have yielded new promising two- and three dimensional (3D) cell culture models. Nevertheless, a realistic 3D in vitro alveolar model is not available yet. Here we report on the biofabrication of the human air-blood tissue barrier analogue composed of an endothelial cell, basement membrane and epithelial cell layer by using a bioprinting technology. In contrary to the manual method, we demonstrate that this technique enables automatized and reproducible creation of thinner and more homogeneous cell layers, which is required for an optimal air-blood tissue barrier. This bioprinting platform will offer an excellent tool to engineer an advanced 3D lung model for high-throughput screening for safety assessment and drug efficacy testing.

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During a mammary immune response, the integrity of the blood-milk barrier is negatively affected and becomes leaky. The aim of the present study was to demonstrate the blood origin, and to investigate changes in the concentration, of various constituents including immunoglobulins in blood and milk during the early phase of lipopolysaccharide (LPS)-induced mastitis. Five lactating dairy cows received continuous β-hydroxybutyrate (BHBA) clamp infusions to maintain elevated BHBA blood concentrations (1.5 to 2.0 mmol/L) from 48 h before and 8h after LPS administration. One udder quarter was infused with 200 μg of Escherichia coli LPS. A second quarter served as control. Milk and blood samples were taken hourly for 8h postchallenge (PC). The somatic cell count in LPS-challenged quarters was increased from 4h PC to the end of the experiment compared with control quarters. In LPS-challenged quarters, l-lactate, BHBA, lactate dehydrogenase (LDH), IgG(1), and IgG(2) were increased at 3h PC and remained elevated until the end of experiment (8h PC) compared with control quarters. In addition, the optical density values in milk in a nonquantitative ELISA for antibodies directed against bluetongue virus (used as a measure of nonspecific antibody transfer; all animals were vaccinated) increased and, thus, indicates an increase in these antibodies in response to LPS treatment. l-Lactate concentration also increased in blood 2h PC and in the milk of control quarters during the experiment from 3h PC. A second experiment was conducted in vitro to investigate a possible contribution from destructed milk cells to l-lactate concentration and activity of LDH in milk. Aliquots of milk samples (n=8) were frozen (-20°C) or disrupted with ultrasound, respectively. Freeze thawing and ultrasound treatment increased LDH in milk samples, but had no effect on l-lactate concentrations. Results suggest that intramammary infusion of LPS induces a systemic response, as evidenced by an elevation of blood l-lactate concentration. The concomitant changes of all investigated components suggest that they were blood derived. However, the increase in blood components in the milk is not necessarily supportive of the mammary immune system, and likely a side effect of reduced blood-milk barrier integrity.

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PURPOSE The aim of this study was to evaluate the antibiotic treatment of postoperative endophthalmitis with combined systemic meropenem and linezolid. METHODS A retrospective analysis of endophthalmitis treated with systemic meropenem and linezolid compared to conventional systemic antibiotics by evaluation of outcome and adverse effects was carried out. RESULTS 26 patients with unilateral postoperative endophthalmitis with a systemic combination regimen of meropenem (2 g TID, mean duration of treatment 5.5 days) and linezolid (600 mg BID, mean duration of treatment 8.9 days) (group 1, mean follow-up time 140 days) were included in this study and compared to 45 postoperative endophthalmitis patients treated with conventional systemic antibiotics (group 2; mean follow-up time 320 days). In group 1, 69.2 % of eyes additionally received intravitreal amikacin and vancomycin (vs. 24.4 % in group 2; p < 0.001), in 92.3 % pars plana vitrectomy was performed (vs. 68.9 % in group 2, p = 0.047). Mean best corrected visual acuity improved from a baseline of 1.76 logMar for group 1 and 1.83 logMar for group 2 to 0.91 logMar (p = 0.0001) and 0.90 logMar (p < 0.0001), respectively, at the end of the follow-up, revealing no significant differences between the two groups at any time point (p > 0.05). Ocular complications were observed in 34.6 % of eyes in group 1 (vs. 37.8 % in group 2; p > 0.05). Adverse drug effects occurred significantly more frequently in group 1 (26.9 % vs. 4.4 % p = 0.02). CONCLUSION In spite of the reported better penetration through the blood-ocular barrier and the broader antibacterial spectrum of meropenem and linezolid, no benefit in outcome was found in the present study. In contrast, adverse effects and costs of the combination regimen were significantly higher.

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We studied development of the ostrich lung using light microscopy as well as electron microscopy techniques. At E24, the lung comprised a few epithelial tubes, interspersed with abundant mesenchyme with scattered profiles of incipient blood vessels. Between E24 and E39, the epithelial thickness was reduced by 90% from 13.5 ± 0.41 μm to 1.33 ± 0.014 μm (mean ± SD, respectively). Atria were evident at E32, and by E35, the first portions of the blood-gas barrier (BGB) measuring 3.41 ± 1.12 μm were encountered. Gas exchange tissue was well formed by E39 with atria, infundibulae, air capillaries and a mature blood-gas barrier (BGB). BGB formation proceeded through the complex processes of secarecytosis and peremerecytosis, which entailed decapitation of epithelial cells by cutting or pinching off respectively and by E39, the BGB was thin at 2.21 ± 1.21 μm. Vascular remodeling by intussusceptive angiogenesis was a late stage process mediated by intraluminal pillars in the pulmonary vasculature.

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BACKGROUND: Little is known about the ocular penetration of echinocandin antifungals. We studied the ocular distribution of systemically administered caspofungin in a rabbit uveitis model. METHODS: Caspofungin (1 mg/kg per day) was given intravenously to rabbits as a single dose or as repeated daily doses on 7 days starting 24 h after induction of unilateral uveitis by intravitreal endotoxin injection. Caspofungin concentrations were determined by high-performance liquid chromatography in the cornea, aqueous humor, vitreous humor, and serum 4, 8, 16, and 24 h after administration of a single dose and 24 h after the last of seven doses. RESULTS: The mean caspofungin concentration in the aqueous of the inflamed eye 4 and 8 h after single-dose administration was 1.30 +/- 0.39 mug/ml and 1.12 +/- 0.34 mug/ml, respectively. Drug concentrations decreased to 0.24 +/- 0.09 mug/ml at 16 h and 0.26 +/- 0.14 mug/ml at 24 h. In the vitreous of inflamed eyes drug levels were undetectable at all time points. No drug was found in the aqueous of inflamed eyes 24 h after the last of seven repeated doses, and the vitreous only contained trace amounts. In the corneas of inflamed eyes concentrations reached 1.64 +/- 0.48 mug/g at 4 h, peaked at 2.16 +/- 1.14 mug/g at 8 h, and declined to 1.87 +/- 0.52 mug/g and 1.49 +/- 0.48 mug/g at 16 and 24 h, respectively. After repeated dosing, corneal concentrations of caspofungin were 0.8 and 1.0 mug/g and below the limit of detection in two of four animals. In non-inflamed eyes no drug was detectable in the aqueous and vitreous humor, and the corneas at any time point. CONCLUSIONS: In our model, caspofungin reached therapeutically relevant levels in the aqueous and cornea but not in the vitreous humor of inflamed eyes. Intraocular drug deposition was critically dependent on a disrupted blood-eye barrier. These findings suggest a limited role for caspofungin in the treatment of fungal endophthalmitis.

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A morphological and morphometric study of the lung of the newborn quokka wallaby (Setonix brachyurus) was undertaken to assess its morphofunctional status at birth. Additionally, skin structure and morphometry were investigated to assess the possibility of cutaneous gas exchange. The lung was at canalicular stage and comprised a few conducting airways and a parenchyma of thick-walled tubules lined by stretches of cuboidal pneumocytes alternating with squamous epithelium, with occasional portions of thin blood-gas barrier. The tubules were separated by abundant intertubular mesenchyme, aggregations of developing capillaries and mesenchymal cells. Conversion of the cuboidal pneumocytes to type I cells occurred through cell broadening and lamellar body extrusion. Superfluous cuboidal cells were lost through apoptosis and subsequent clearance by alveolar macrophages. The establishment of the thin blood-gas barrier was established through apposition of the incipient capillaries to the formative thin squamous epithelium. The absolute volume of the lung was 0.02 +/- 0.001 cm(3) with an air space surface area of 4.85 +/- 0.43 cm(2). Differentiated type I pneumocytes covered 78% of the tubular surface, the rest 22% going to long stretches of type II cells, their precursors or low cuboidal transitory cells with sparse lamellar bodies. The body weight-related diffusion capacity was 2.52 +/- 0.56 mL O(2) min(-1) kg(-1). The epidermis was poorly developed, and measured 29.97 +/- 4.88 microm in thickness, 13% of which was taken by a thin layer of stratum corneum, measuring 4.87 +/- 0.98 microm thick. Superficial capillaries were closely associated with the epidermis, showing the possibility that the skin also participated in some gaseous exchange. Qualitatively, the neonate quokka lung had the basic constituents for gas exchange but was quantitatively inadequate, implying the significance of percutaneous gas exchange.

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Sensorineural hearing loss (SNHL) is the most common sequel of bacterial meningitis (BM) and is observed in up to 30% of survivors when the disease is caused by Streptococcus pneumoniae. BM is the single most important origin of acquired SNHL in childhood. Anti-inflammatory dexamethasone holds promises as potential adjuvant therapy to prevent SNHL associated with BM. However, in infant rats, pneumococcal meningitis (PM) increased auditory brainstem response (ABR) thresholds [mean difference = 54 decibels sound pressure level (dB SPL)], measured 3 wk after infection, irrespective to treatment with ceftriaxone plus dexamethasone or ceftriaxone plus saline (p < 0.005 compared with mock-infected controls). Moreover, dexamethasone did not attenuate short- and long-term histomorphologic correlates of SNHL. At 24 h after infection, blood-labyrinth barrier (BLB) permeability was significantly increased in infected animals of both treatment groups compared with controls. Three weeks after the infection, the averaged number of type I neurons per square millimeter of the Rosenthal's canal dropped from 0.3019 +/- 0.0252 in controls to 0.2227 +/- 0.0635 in infected animals receiving saline (p < 0.0005). Dexamethasone was not more effective than saline in preventing neuron loss (0.2462 +/- 0.0399; p > 0.05). These results suggest that more efficient adjuvant therapies are needed to prevent SNHL associated with pediatric PM.

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Anthropogenic nano-sized particles (NSP), ie, particles with a diameter of less than 100 nm, are generated with or without purpose as chemically and physically well-defined materials or as a consequence of combustion processes respectively. Inhalation of NSP occurs on a regular basis due to air pollution and is associated with an increase in respiratory and cardiovascular morbidity and mortality. Manufactured NSP may intentionally be inhaled as pharmaceuticals or unintentionally during production at the workplace. Hence the interactions of NSP with the respiratory tract are currently under intensive investigation. Due to special physicochemical features of NSP, its biological behaviour may differ from that of larger sized particles. Here we review two important themes of current research into the effects of NSP on the lungs: 1) The potential of NSP to cross the blood-air barrier of the lungs, thus gaining access to the circulation and extrapulmonary organs. It is currently accepted that a small fraction of inhaled NSP may translocate to the circulation. The significance of this translocation requires further research. 2) The entering mechanisms of NSP into different cell types. There is evidence that NSP are taken up by cells via well-known pathways of endocytosis but also via different mechanisms not well understood so far. Knowledge of the quantitative relationship between the different entering mechanisms and cellular responses is not yet available but is urgently needed in order to understand the effects of intentionally or unintentionally inhaled NSP on the respiratory tract.

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The reproducibility of metabolite content determined by MR spectroscopy (MRS) is usually at best a few percent for the prominent singlets. When studying low-concentration metabolites, like phenylalanine (Phe), where tissue content can be <100 micromol/kg, better reproducibility is paramount-particularly in view of using MRS results for potential individual treatment advice. An optimized, targeted spectroscopy method was established at 1.5T and reproducibility was established in 21 patients with phenylketonuria (PKU) where three spectra were recorded in each of three independent sessions, two of which were in immediate succession to minimize physiologic variation. Intersession variation was found to be only 7 micromol/kg Phe for back-to-back repetition of sessions, in close agreement with the variation of 16 micromol/kg observed for single spectra within a session. Analysis of variance proved the individuality of the blood/brain Phe ratio-though this ratio seems to be influenced by physiologic factors that are not stable in time. The excellent reproducibility was achieved through optimization of various factors, including signal-to-noise ratio, repositioning, and prescan calibrations, but also by enforcing as much prior information as possible (e.g., lineshape and phase from reference scans, constant prior-knowledge-locked baseline). While the application of maximum general prior knowledge is a general method to reduce fluctuations, one should remember that it may introduce systematic errors.

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Mastitis induced by Escherichia coli is often characterized by severe clinical signs, indicating a more powerful combat of the immune system against the pathogen compared with Staphylococcus aureus infections, which are often represented by chronic and subclinical diseases. The aim of this study was to test the major pathogenic component lipopolysaccharide (LPS) from E. coli and lipoteichoic acid (LTA) from Staph. aureus for their effects on blood-milk barrier integrity and the related transfer of immunoglobulins and lactate from blood into milk. A similar somatic cell count (SCC) increase was achieved by intramammary challenge of 1 quarter of 5 cows with 20 µg of LTA, and 8 cows with 0.2 µg of LPS (maximum log SCC/mL: 7). Milk IgG(1) concentrations increased in LPS- but not in LTA-challenged quarters. Milk IgG(2) concentrations were increased in treated quarters at 3h after LPS, and 6h after LTA challenge. Higher maximum levels of IgG(2) were reached in milk of LPS-treated quarters (173 ± 58 μg/mL) than of LTA-challenged quarters (62 ± 13 μg/mL). Immunoglobulin G(1) and IgG(2) levels did not change in control quarters. l-Lactate concentrations in milk increased 4h after LPS and 5h after LTA challenge and reached higher maximum levels in LPS- (221 ± 48 mg/L) than in LTA-treated quarters (77 ± 18 mg/L). In conclusion, a mammary inflammation on a quantitatively similar level based on SCC increase achieves a more efficient transfer of blood components such as IgG(2) via the blood-milk barrier if induced by LPS from E. coli than by LTA from Staph. aureus. This pathogen-specific difference may play an important role in the cure rate of the respective intramammary infection, which is usually lower in Staph. aureus- than in E. coli-induced mastitis.