Strategies to advance translational research into brain barriers

There is a paucity of therapies for most neurological disorders--from rare lysosomal storage diseases to major public health concerns such as stroke and Alzheimer's disease. Advances in the targeting of drugs to the CNS are essential for the future success of neurotherapeutics; however, the delivery of many potentially therapeutic and diagnostic compounds to specific areas of the brain is restricted by the blood-brain barrier, the blood-CSF barrier, or other specialised CNS barriers. These brain barriers are now recognised as a major obstacle to the treatment of most brain disorders. The challenge to deliver therapies to the CNS is formidable, and the solution will require concerted international efforts among academia, government, and industry. At a recent meeting of expert panels, essential and high-priority recommendations to propel brain barrier research forward in six topical areas were developed and these recommendations are presented here.     

Critical role of connexin 43 in secondary expansion of traumatic spinal cord injury

Spinal cord injury (SCI) is often complicated by secondary injury as a result of the innate inflammatory response to tissue trauma and swelling. Previous studies have shown that excessive ATP release from peritraumatic regions contributes to the inflammatory response to SCI by activation of low-affinity P2X7 receptors. Because connexin hemichannels constitute an important route for astrocytic ATP release, we here evaluated the impact on post-traumatic ATP release of deletion of connexins (Cx30/Cx43) in astrocytes. In vivo bioluminescence imaging showed a significant reduction in ATP release after weight-drop injury in mice with deletion of Cx43 compared with Cx43-expressing littermates, both on a Cx30 knockout background. Moreover, astrogliosis and microglia activation were reduced in peritraumatic areas of those mice lacking Cx43; motor recovery was also significantly improved, and the traumatic lesion was smaller. Combined, these observations are consistent with a contribution by astrocytic hemichannels to post-traumatic ATP release that aggravates secondary injury and restrains functional recovery after experimental spinal cord injury. Connexins may thereby constitute a new therapeutic target in spinal cord injury.     

Acute pulmonary aspergillosis in immunocompetent subjects after exposure to bark chippings

We describe 2 cases of immunocompetent males with acute community-acquired invasive pulmonary aspergillosis developing shortly after spreading bark chippings. One patient with a fatal outcome was initially diagnosed as allergic alveolitis rather than infection and received steroid treatment illustrating the obvious challenges in the differential diagnosis between these disease entities.     

Health related quality of life and impact of infectious comorbidity in outpatient management of patients with acute leukemia

Abstract Although survival has improved among patients with acute leukemia, there is still a considerable risk of severe complications throughout the course of treatment. This contrast increases the interest in monitoring health related quality of life (HRQOL) in these patients. This study presents a longitudinal HRQOL evaluation (European Organisation for Research and Treatment of Cancer core 30-item questionnaire; EORTC-QLQ C-30) and the impact of infectious comorbidity among 60 patients with leukemia (median age 47) treated in an outpatient management program at Copenhagen University Hospital. Significant improvement was seen on several HRQOL scores during follow-up. Explorative general linear models (GLMs) suggest that high cumulative severity of infectious comorbidity significantly reduces physical functioning and overall quality of life at treatment completion.     

Molecular scaffolds underpinning macroglial polarization: An analysis of retinal Müller cells and brain astrocytes in mouse

Key roles of macroglia are inextricably coupled to specialized membrane domains. The perivascular endfoot membrane has drawn particular attention, as this domain contains a unique complement of aquaporin‐4 (AQP4) and other channel proteins that distinguishes it from perisynaptic membranes. Recent studies indicate that the polarization of macroglia is lost in a number of diseases, including temporal lobe epilepsy and Alzheimer's disease. A better understanding is required of the molecular underpinning of astroglial polarization, particularly when it comes to the significance of the dystrophin associated protein complex (DAPC). Here, we employ immunofluorescence and immunogold cytochemistry to analyze the molecular scaffolding in perivascular endfeet in macroglia of retina and three regions of brain (cortex, dentate gyrus, and cerebellum), using AQP4 as a marker. Compared with brain astrocytes, Müller cells (a class of retinal macroglia) exhibit lower densities of the scaffold proteins dystrophin and α‐syntrophin (a DAPC protein), but higher levels of AQP4. In agreement, depletion of dystrophin or α‐syntrophin—while causing a dramatic loss of AQP4 from endfoot membranes of brain astrocytes—had only modest or insignificant effect, respectively, on the AQP4 pool in endfoot membranes of Müller cells. In addition, while polarization of brain macroglia was less affected by dystrophin depletion than by targeted deletion of α‐syntrophin, the reverse was true for retinal macroglia. These data indicate that the molecular scaffolding in perivascular endfeet is more complex than previously assumed and that macroglia are heterogeneous with respect to the mechanisms that dictate their polarization. © 2012 Wiley Periodicals, Inc.     

In vivo NADH fluorescence imaging indicates effect of aquaporin-4 deletion on oxygen microdistribution in cortical spreading depression

Using in vivo two-photon imaging, we show that mice deficient in aquaporin-4 (AQP4) display increased fluorescence of nicotinamide adenine dinucleotide (NADH) when subjected to cortical spreading depression. The increased NADH signal, a proxy of tissue hypoxia, was restricted to microwatershed areas remote from the vasculature. Aqp4 deletion had no effects on the hyperemia response, but slowed [K⁺]_o recovery. These observations suggest that K⁺ uptake is suppressed in Aqp4^−/− mice as a consequence of decreased oxygen delivery to tissue located furthest away from the vascular source of oxygen, although increased oxygen consumption may also contribute to our observations.     

In Vivo Emergence of Aspergillus terreus with Reduced Azole Susceptibility and a Cyp51a M217I Alteration

Azole resistance in Aspergillus terreus isolates was explored. Twenty related (MB) and 6 unrelated A. terreus isolates were included. CYP51A sequencing and RAPD genotyping was performed. Five MB isolates were itraconazole susceptible, whereas the minimum inhibitory concentrations (MICs) for 15 MB isolates were elevated (1-2?mg/L). Voriconazole and posaconazole MICs were 0.5-4 and 0.06-0.5?mg/L, respectively, for MB isolates but 0.25-0.5 and <0.03-0.06?mg/L, respectively, for controls. Sequencing identified a Cyp51Ap M217I alteration in all 15 isolates with elevated itraconazole MICs. Genotyping showed that 18 of 20 MB isolates were identical and unique, suggesting endogenous origin. In conclusion, itraconazole resistance in A. terreus was linked to an M217I Cyp51A alteration.     

Hyperglycaemia protects against neuronal injury around experimental brain infarcts

Regional glucose utilization was measured in the rat brain after occlusion of the middle cerebral artery. Normoglycaemic rat had increased glucose use in the cerebral codex adjacent, to the infarct. A fraction of the nerve cells were irreversibly injured in this region. In hyperglycaemic rats, the glucose metabolism remained normal and no nerve cell loss was found around the infarct. The findings indicate that hyperglycaemia protects against nerve cell injury in the areas next to experimental brain infarcts.