An Allograft Glioma Model Reveals the Dependence of Aquaporin-4 Expression on the Brain Microenvironment

Aquaporin-4 (AQP4), the main water channel of the brain, is highly expressed in animal glioma and human glioblastoma in situ. In contrast, most cultivated glioma cell lines don’t express AQP4, and primary cell cultures of human glioblastoma lose it during the first passages. Accordingly, in C6 cells and RG2 cells, two glioma cell lines of the rat, and in SMA mouse glioma cell lines, we found no AQP4 expression. We confirmed an AQP4 loss in primary human glioblastoma cell cultures after a few passages. RG-2 glioma cells if grafted into the brain developed AQP4 expression. This led us consider the possibility of AQP4 expression depends on brain microenvironment. In previous studies, we observed that the typical morphological conformation of AQP4 as orthogonal arrays of particles (OAP) depended on the extracellular matrix component agrin. In this study, we showed for the first time implanted AQP4 negative glioma cells in animal brain or flank to express AQP4 specifically in the intracerebral gliomas but neither in the extracranial nor in the flank gliomas. AQP4 expression in intracerebral gliomas went along with an OAP loss, compared to normal brain tissue. AQP4 staining in vivo normally is polarized in the astrocytic endfoot membranes at the glia limitans superficialis and perivascularis, but in C6 and RG2 tumors the AQP4 staining is redistributed over the whole glioma cell as in human glioblastoma. In contrast, primary rat or mouse astrocytes in culture did not lose their ability to express AQP4, and they were able to form few OAPs

Assessing fidelity of delivery of smoking cessation behavioural support in practice.

Effectiveness of evidence-based behaviour change interventions is likely to be undermined by failure to deliver interventions as planned. Behavioural support for smoking cessation can be a highly cost-effective, life-saving intervention. However, in practice, outcomes are highly variable. Part of this may be due to variability in fidelity of intervention implementation. To date, there have been no published studies on this. The present study aimed to: evaluate a method for assessing fidelity of behavioural support; assess fidelity of delivery in two English Stop-Smoking Services; and compare the extent of fidelity according to session types, duration, individual practitioners, and component behaviour change techniques (BCTs)

17 years of experience with shunt systems in normal pressure hydrocephalus - From differential pressure to gravitational valves

Objective: Complication rate of shunting for normal pressure hydrocephalus (NPH) has significantly improved over the last decades. Especially the use of overdrainage protection has reduced the incidence of subdural hematoma and collections. However, gravitational valves were associated with other complications of shunt dysfunction. We present our 17 years of experience with patients with normal pressure hydrocephalus who changed from a differential pressure valve to a gravitational valve system. Methods: We retrospectively identified all patients with the diagnosis of normal pressure hydrocephalus, in whom primary shunt implantation was performed between 2004 and 2020. Shunt implantation was performed as per our internal standard. Review of imaging, charts and patient reports was performed. Results: In total, 409 patients were included in the analysis. Mean age was 73.0 ± 7.1years. Between 2004 and 2010, predominantly Hakim valves (n = 100, 24.4%) were implanted, whilst from 2009 until 2020, proGAV valves (n = 296, 72.4%) were used. Mean follow-up was 8.9 ± 4.5 years. Initial subjective improvement of symptoms was reported in 69.9%, whilst this number decreased at the last follow-up to 29.8%. No significant differences were observed between the valves in the frequency of surgery for subdural hematoma. Shunt assistant implantation was performed in 17% of patients with Hakim valve, in 9.5% of patients with proGAV, a shunt assistant was added. Shunt obstruction was significantly higher in proGAV valves (p < 0.001). Conclusions: Our findings confirm the observation of frequent overdrainage in shunts without anti-siphon/gravitational component. Gravitational valves on the other hand may be associated with more obstruction

Is Upregulation of Aquaporin 4-M1 Isoform Responsible for the Loss of Typical Orthogonal Arrays of Particles in Astrocytomas?

The astrocytic endfoot membranes of the healthy blood-brain barrier—contacting the capillary—are covered with a large number of the water channel aquaporin 4 (AQP4). They form orthogonal arrays of particles (OAPs), which consist of AQP4 isoform M1 and M23. Under pathologic conditions, AQP4 is distributed over the whole cell and no or only small OAPs are found. From cell culture experiments, it is known that cells transfected only with AQP4-M1 do not form OAPs or only small ones. We hypothesized that in astrocytomas the situation may be comparable to the in vitro experiments expecting an upregulation of AQP4-M1. Quantitative Real-time PCR (qRT-PCR) of different graded astrocytomas revealed an upregulation of both isoforms AQP4 M1 and M23 in all astrocytomas investigated. In freeze fracture replicas of low-grade malignancy astrocytomas, more OAPs than in high-grade malignancy astrocytomas were found. In vitro, cultured glioma cells did not express AQP4, whereas healthy astrocytes revealed a slight upregulation of both isoforms and only a few OAPs in freeze fracture analysis. Taken together, we found a correlation between the decrease of OAPs and increasing grade of malignancy of astrocytomas but this was not consistent with an upregulation of AQP4-M1 in relation to AQP4 M23