Amyloid plaques and normal ageing have differential effects on microglial Ca2+ activity in the mouse brain.

In microglia, changes in intracellular calcium concentration ([Ca2+]i) may regulate process motility, inflammasome activation, and phagocytosis. However, while neurons and astrocytes exhibit frequent spontaneous Ca2+ activity, microglial Ca2+ signals are much rarer and poorly understood. Here, we studied [Ca2+]i changes of microglia in acute brain slices using Fluo-4-loaded cells and mice expressing GCaMP5g in microglia. Spontaneous Ca2+ transients occurred ~ 5 times more frequently in individual microglial processes than in their somata. We assessed whether microglial Ca2+ responses change in Alzheimer's disease (AD) using AppNL-G-F knock-in mice. Proximity to Aß plaques strongly affected microglial Ca2+ activity. Although spontaneous Ca2+ transients were unaffected in microglial processes, they were fivefold more frequent in microglial somata near Aß plaques than in wild-type microglia. Microglia away from Aß plaques in AD mice showed intermediate properties for morphology and Ca2+ responses, partly resembling those of wild-type microglia. By contrast, somatic Ca2+ responses evoked by tissue damage were less intense in microglia near Aß plaques than in wild-type microglia, suggesting different mechanisms underlying spontaneous vs. damage-evoked Ca2+ signals. Finally, as similar processes occur in neurodegeneration and old age, we studied whether ageing affected microglial [Ca2+]i. Somatic damage-evoked Ca2+ responses were greatly reduced in microglia from old mice, as in the AD mice. In contrast to AD, however, old age did not alter the occurrence of spontaneous Ca2+ signals in microglial somata but reduced the rate of events in processes. Thus, we demonstrate distinct compartmentalised Ca2+ activity in microglia from healthy, aged and AD-like brains.

Modelling homeostatic plasticity in the auditory cortex results in neural signatures of tinnitus.

Tinnitus is a clinical condition where a sound is perceived without an external sound source. Homeostatic plasticity (HSP), serving to increase neural activity as compensation for the reduced input to the auditory pathway after hearing loss, has been proposed as a mechanism underlying tinnitus. In support, animal models of tinnitus show evidence of increased neural activity after hearing loss, including increased spontaneous and sound-driven firing rate, as well as increased neural noise throughout the auditory processing pathway. Bridging these findings to human tinnitus, however, has proven to be challenging. Here we implement hearing loss-induced HSP in a Wilson-Cowan Cortical Model of the auditory cortex to predict how homeostatic principles operating at the microscale translate to the meso- to macroscale accessible through human neuroimaging. We observed HSP-induced response changes in the model that were previously proposed as neural signatures of tinnitus, but that have also been reported as correlates of hearing loss and hyperacusis. As expected, HSP increased spontaneous and sound-driven responsiveness in hearing-loss affected frequency channels of the model. We furthermore observed evidence of increased neural noise and the appearance of spatiotemporal modulations in neural activity, which we discuss in light of recent human neuroimaging findings. Our computational model makes quantitative predictions that require experimental validation, and may thereby serve as the basis of future human studies of hearing loss, tinnitus, and hyperacusis.

On the Role of Theory and Modeling in Neuroscience.

In recent years, the field of neuroscience has gone through rapid experimental advances and a significant increase in the use of quantitative and computational methods. This growth has created a need for clearer analyses of the theory and modeling approaches used in the field. This issue is particularly complex in neuroscience because the field studies phenomena that cross a wide range of scales and often require consideration at varying degrees of abstraction, from precise biophysical interactions to the computations they implement. We argue that a pragmatic perspective of science, in which descriptive, mechanistic, and normative models and theories each play a distinct role in defining and bridging levels of abstraction, will facilitate neuroscientific practice. This analysis leads to methodological suggestions, including selecting a level of abstraction that is appropriate for a given problem, identifying transfer functions to connect models and data, and the use of models themselves as a form of experiment.

Periaxonal and nodal plasticities modulate action potential conduction in the adult mouse brain.

Central nervous system myelination increases action potential conduction velocity. However, it is unclear how myelination is coordinated to ensure the temporally precise arrival of action potentials and facilitate information processing within cortical and associative circuits. Here, we show that myelin sheaths, supported by mature oligodendrocytes, remain plastic in the adult mouse brain and undergo subtle structural modifications to influence action potential conduction velocity. Repetitive transcranial magnetic stimulation and spatial learning, two stimuli that modify neuronal activity, alter the length of the nodes of Ranvier and the size of the periaxonal space within active brain regions. This change in the axon-glial configuration is independent of oligodendrogenesis and robustly alters action potential conduction velocity. Because aptitude in the spatial learning task was found to correlate with action potential conduction velocity in the fimbria-fornix pathway, modifying the axon-glial configuration may be a mechanism that facilitates learning in the adult mouse brain.

New Method toward a Robust Covalently Attached Cross-Linked Nanofiltration Membrane.

As nanofiltration applications increase in diversity, there is a need for new fabrication methods to prepare chemically and thermally stable membranes with high retention performance. In this work, thio-bromo "click" chemistry was adapted for the fabrication of a robust covalently attached and ultrathin nanofiltration membrane. The selective layer was formed on a pre-functionalized porous ceramic surface via a novel, liquid-vapor interfacial polymerization method. Compared to the most common conventional interfacial polymerization procedure, no harmful solvents and a minimal amount of reagents were used. The properties of the membrane selective layer and its free-standing equivalent were characterized by complementary physicochemical analysis. The stability of the thin selective layer was established in water, ethanol, non-polar solvents, and up to 150 °C. The potential as a nanofiltration membrane was confirmed through solvent permeability tests (water, ethanol, hexane, and toluene), PEG-in-water molecular weight cut-off measurements (≈700 g mol-1), and dye retention measurements.

Melamine-Based Microporous Organic Framework Thin Films on an Alumina Membrane for High-Flux Organic Solvent Nanofiltration.

Microporous polymer frameworks have attracted considerable attention to make novel separation layers owing to their highly porous structure, high permeability, and excellent molecular separation. This study concerns the fabrication and properties of thin melamine-based microporous polymer networks with a layer thickness of around 400 nm, supported on an α-alumina support and their potential use in organic solvent nanofiltration. The modified membranes show excellent solvent purification performances, such as n-heptane permeability as high as 9.2 L m-2 h-1 bar -1 in combination with a very high rejection of approximately 99 % for organic dyes with molecular weight of ≥457 Da. These values are higher than for the majority of the state-of-the-art membranes. The membranes further exhibit outstanding long-term operation stability. This work significantly expands the possibilities of using ceramic membranes in organic solvent nanofiltration.

Harnessing Microglia and Macrophages for the Treatment of Glioblastoma.

Glioblastoma multiforme (GBM) is the most malignant form of brain tumors, with a dismal prognosis. During the course of the disease, microglia and macrophages both infiltrate the tumor microenvironment and contribute considerably in glioma development. Thus, tumor-associated microglia and macrophages have recently emerged as potentially key therapeutic targets. Here, we review the physiology of microglia and their responses in brain cancer. We further discuss current treatment options for GBM using radiotherapy, and novel advances in our knowledge of microglia physiology, with emphasis on the recently discovered pathway that controls the baseline motility of microglia processes. We argue that the latter pathway is an interesting therapeutic avenue to pursue for the treatment of glioblastoma.

Host plant defenses of black (Solanum nigrum L.) and red nightshade ( Solanum villosum Mill.) against specialist Solanaceae herbivore Leptinotarsa decemlineata (Say).

Black nightshade (Solanum nigrum, S. nigrum L.) and red nightshade ( Solanum villosum, S. villosum Mill.) are medicinal plants from the Solanaceae family that synthesize glycoalkaloids and other secondary metabolites. To recognize the potential insecticide activity of these compounds, leaf extracts (containing glycoalkaloid and methanol fractions) were tested for enzyme inhibition, antifeedant activity and toxicity. For in-vitro glutathione S-transferase (GST) inhibition activity, we used insecticide-resistant Colorado potato beetle, Leptinotarsa decemlineata ( L. decemlineata; Say) midgut and fat-body homogenate. In-vivo toxicity and the antifeedant activity were performed using larval bioassays. The methanol extracts had greater GST inhibitory activity compared to the glycoalkaloids, as well as greater 2nd instar larvae mortality and antifeedant activity. Furthermore, the green leaf volatile compound, cis-hex-3-enyl acetate, at the concentration of 5 ppm, caused 50% mortality of 2nd instar larvae. Our findings suggest the potential usefulness of S. nigrum and S. villosum extracts to control L. decemlineata.

MIL-53(Al) and NH2-MIL-53(Al) modified α-alumina membranes for efficient adsorption of dyes from organic solvents.

To the best of our knowledge, for the first time MIL-53(Al) and NH2-MIL-53(Al) modified α-alumina membranes are investigated for the adsorption of organic dyes from organic solvents. These new, modified membranes show excellent adsorption of high concentrations of Rose Bengal dye in methanol and isopropanol solutions.

Pivotal role of carnosine in the modulation of brain cells activity: Multimodal mechanism of action and therapeutic potential in neurodegenerative disorders.

Carnosine (ß-alanyl-l-histidine), a dipeptide, is an endogenous antioxidant widely distributed in excitable tissues like muscles and the brain. Although discovered more than a hundred years ago and having been extensively studied in the periphery, the role of carnosine in the brain remains mysterious. Carnosinemia, a rare metabolic disorder with increased levels of carnosine in urine and low levels or absence of carnosinase in the blood, is associated with severe neurological symptoms in humans. This review deals with the role of carnosine in the brain in both physiological and pathological conditions, with a focus on preclinical evidence suggesting a high therapeutic potential of carnosine in neurodegenerative disorders. We review carnosine and carnosinemia's discoveries and the extensive research on the role and benefits of carnosine in the periphery. We then turn to carnosine's biochemistry and distribution in the brain. Using an array of recent observations as a foundation, we draw a parallel with the role of carnosine in muscles and speculate on the role of carnosine in promoting the metabolic support of neurons by glial cells. Finally, carnosine has been shown to exert a multimodal activity including inhibition of protein cross-linking and aggregation of amyloid-ß and related proteins, free radical generation, nitric oxide detoxification, and an anti-inflammatory activity. It could thus play an important role in the prevention and treatment of neurodegenerative diseases such as Alzheimer's disease. We discuss the potential of carnosine in this context and speculate on new preclinical research directions.

Results of Toccata® resurfacing PIP joint arthroplasty. A series of 32 cases at a mean follow-up of 5.9 years.

The objective of this study was to evaluate the long-term results of proximal interphalangeal (PIP) resurfacing arthroplasty for treating osteoarthritis: the PIP Toccata implant®. This was a retrospective study of 32 out of 33 PIP arthroplasty cases performed with a dorsolateral or a Chamay approach by two surgeons after a minimum follow-up of 24 months. Patients were reviewed using a standardized assessment of pain, function, mobility and radiological changes. The average follow-up was 5.9 years. The mean active range of motion was 67° (15-95). Radiographic analysis found osteointegration of the implant in all patients except one, in whom distal migration had no clinical consequence. Heterotopic ossifications (HO) developed in 10 of the 20 cases where the implant was inserted through a lateral approach. Intra-articular bone debris was identified in the first postoperative X-ray in most of these cases. The presence of HO was significantly correlated with decreased range of motion (P<0.05). Six patients required surgical revision and two needed implant removal and arthrodesis. Our results are comparable to other published studies of PIP resurfacing arthroplasty. It is important to remove all bone debris when using the dorsolateral approach. The PIP Toccata® implant is a reliable solution for treating PIP osteoarthritis but this arthroplasty procedure is demanding.

[A report of the SFGM-TC on the interactions between national transplant coordination and local coordinators in allogeneic stem cell transplantation activity]. / Interactions entre coordination nationale de greffe et coordinateurs locaux.

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. The main aim of this session was to describe the relations between the national transplant coordination office of the French registry and local stem cell transplantation coordinators throughout France.

Urinary neopterin is a valuable tool in monitoring Crohn's disease activity.

BACKGROUND: The aim was to investigate the relation between urinary neopterin and the Crohn's Disease Activity Index (CDAI) and to compare its ability to discriminate active versus inactive CD with serum C-reactive protein (CRP). METHODS: In all, 217 urinary samples for neopterin measurement were obtained in a cohort of 93 consecutive patients with CD and 66 samples in 33 healthy volunteers. Clinical parameters were recorded and blood samples for CRP were collected as well. RESULTS: Whereas patients with inactive CD showed similar levels of urinary neopterin excretion than healthy volunteers (163 +/- 8 versus 142 +/- 7 nmol/mol of creatinine, respectively; P = 0.1), urinary neopterin excretion from mild to severe active CD was significantly higher (302 +/- 15 nmol/mol of creatinine; P < 0.001). Serum CRP levels were higher in active CD (14.8 +/- 2.1 mg/L) compared with inactive CD (5.6 +/- 0.8 mg/L; P < 0.001). Urinary neopterin excretion, and to a lesser degree CRP, were positively and significantly correlated with CDAI (r = 0.64 and 0.43, respectively, P < 0.001). Based on the cutoff of 183 nmol/mol of creatinine for urinary neopterin, the sensitivity and specificity of urinary neopterin to discriminate between active and inactive CD were 73% and 82%, respectively, and the positive and negative predictive values were 80% and 78%, respectively. CONCLUSIONS: Urinary neopterin excretion is an objective, valuable, simple, and noninvasive biomarker to detect and follow fluctuations of CD activity. Further work is warranted to study its clinical value and relation to mucosal healing.

Campylobacter fetus bloodstream infection: risk factors and clinical features.

In this paper, we report 21 cases of Campylobacter fetus bloodstream infection observed in our institution over a 9-year period. The median age of the patients was 78 years. Most of them (62%) had a significant underlying disease, such as diabetes, immunodeficiency or cardiovascular disease. The main clinical features were fever with (62% of cases) or without (38%) extra-intestinal symptoms. These included mycotic aneurysm of the abdominal aorta (24%) and cellulitis (19%). Antibiotic treatment was mainly based on amoxicilline-clavulanate (57%) or imipenem (21%), for a median duration of 28 days. A favourable outcome was observed in 72% of cases. Death directly attributable to infection was observed for three patients, due to the rupture of an infected aneurysm or relapsing bloodstream infection with septic shock. All patients initially treated with imipenem had a favourable outcome. This report adds evidence that C. fetus bloodstream infection should be suspected in elderly patients with fever, immunodeficiency and cardiovascular damages. Imipenem seems to be the most active drug, especially in severe cases.

Investigation of the ability of the Pneumonia Severity Index to accurately predict clinically relevant outcomes: a European study.

In order to confirm the validity of the Pneumonia Severity Index (PSI) for patients in Europe, data from adults with pneumonia who were enrolled in two prospective multicentre studies, conducted in France (Pneumocom-1, n = 925) and Spain (Pneumocom-2, n = 853), were compared with data from the original North American study (Pneumonia PORT, n = 2287). The primary outcome was 28-day mortality; secondary outcomes were subsequent hospitalisation for outpatients, and intensive care unit admission and length of stay for inpatients. All outcomes within individual risk classes, and mortality rates in low-risk (PSI I-III) and higher-risk patients, were compared across the three cohorts. Overall mortality rates were 4.7% in Pneumonia PORT, 6.3% in Pneumocom-2 and 10.6% in Pneumocom-1 (p <0.01), ranging from 0.4% to 1.6% (p 0.06) for low-risk patients and from 13.0% to 19.1% (p 0.24) for high-risk patients. Despite significant differences in baseline patient characteristics, none of the study outcomes differed within the low-risk classes. The sensitivity and negative predictive value of low-risk classification for mortality exceeded 93% and 98%, respectively. Thus, in two independent European cohorts, the PSI predicted patient outcomes accurately and reliably, particularly for low-risk patients. These findings confirm the validity of the PSI when applied to patients from Europe.

Variations in extracellular levels of dopamine, noradrenaline, glutamate, and aspartate across the sleep--wake cycle in the medial prefrontal cortex and nucleus accumbens of freely moving rats.

We used intracerebral microdialysis coupled with electrophysiologic recordings to determine relative changes in the concentrations of several neurotransmitters in the medial prefrontal cortex and nucleus accumbens of freely moving rats during waking, slow-wave sleep, and rapid eye movement (REM) sleep. The concentrations of noradrenaline, dopamine, glutamate, and aspartate in 2-min dialysate samples were analyzed by capillary electrophoresis combined with laser-induced fluorescence detection. Changes in glutamate and aspartate concentrations were found only in the nucleus accumbens, in which a decrease was obtained during both slow-wave sleep and REM sleep compared to waking. A progressive reduction in the release of noradrenaline was observed from waking to REM sleep in both structures. In contrast, dopamine concentrations were higher during waking and REM sleep compared to that during slow-wave sleep. The latter results demonstrate that contrary to the findings of earlier electrophysiologic studies carried out on ventral tegmental area dopaminergic neurons, changes in the release of dopamine in projection areas occur across the sleep-wake cycle. The elevated levels of dopamine during waking and REM sleep in the medial prefrontal cortex and the nucleus accumbens could result from changes during these two states in afferent modulation at the level of cell bodies or at the level of dopaminergic terminals.

Campylobacter fetus meningitis in a diabetic adult cured by imipenem.

Reported here is the successful management of a severe case of Campylobacter fetus subspecies fetus meningitis, complicated by septic shock, in a patient without overt immunosuppression who was cured by imipenem. Meningitis caused by C. fetus has rarely been reported in adults, and only exceptionally in non-immunocompromised patients, and septic shock has not previously been reported as a complication of such meningitis. The best antibiotic regimen for treating this condition remains to be determined. Imipenem has displayed high in vitro activity against C. fetus but has been used rarely in clinical practice. It was administered in this case with good results.

Toward brain imaging of serotonin 5-HT1A autoreceptor internalization.

Enhancing cerebral serotonin (5-hydroxytryptamine, 5-HT) neurotransmission is a common property of antidepressant treatments and the basis for their efficacy. 5-HT1A receptors located on the cell body and dendrites of 5-HT neurons (autoreceptors) play a key role in this regard. Because they normally mediate an inhibition of neuronal firing, their desensitization is a prerequisite to the delayed enhancement of 5-HT neurotransmission upon treatment with monoamine oxidase (MAOI) inhibitors or specific serotonin reuptake inhibitors (SSRI). Using beta-sensitive microprobes in vivo, we measured a significant decrease (-30%) in binding sites for the 5-HT1A PET radioligand [18F]MPPF associated with an equivalent reduction (-34%) in the cell surface density of 5-HT1A receptor immunoreactivity (internalization), in the nucleus raphe dorsalis (autoreceptors), but not hippocampus (heteroreceptors), of rats given a single dose of the specific 5-HT1A receptor agonist, 8-OH-DPAT (0.5 mg/kg, iv). This effect was completely blocked by pretreatment with the selective 5-HT1A antagonist WAY 100635. Having ruled out that this decreased density of [18F]MPPF binding in the nucleus raphe dorsalis of 8-OH-DPAT-treated rats resulted from a local blood flow effect, we obtained autoradiographic evidence indicating that the total amount of specific binding of [18F]MPPF in tissue sections was unaffected by the 8-OH-DPAT treatment in either NRD or hippocampus. It was therefore concluded that the internalization of 5-HT1A autoreceptors accounted for the decreased binding in vivo of [18F]MPPF in the nucleus raphe dorsalis of rats treated with 8-OH-DPAT. Thus, PET imaging might provide a mean to measure 5-HT1A receptor internalization in human brain and thus assess responsiveness to antidepressant treatment.