Glial-conditional deletion of aquaporin-4 (Aqp4) reduces blood-brain water uptake and confers barrier function on perivascular astrocyte endfeet

Tissue- and cell-specific deletion of the Aqp4 gene is required to differentiate between the numerous pools of aquaporin-4 (AQP4) water channels. A glial-conditional Aqp4 knockout mouse line was generated to resolve whether astroglial AQP4 controls water exchange across the blood-brain interface. The conditional knockout was driven by the glial fibrillary acidic protein promoter. Brains from conditional Aqp4 knockouts were devoid of AQP4 as assessed by Western blots, ruling out the presence of a significant endothelial pool of AQP4. In agreement, immunofluorescence analysis of cryostate sections and quantitative immunogold analysis of ultrathin sections revealed no AQP4 signals in capillary endothelia. Compared with litter controls, glial-conditional Aqp4 knockout mice showed a 31% reduction in brain water uptake after systemic hypoosmotic stress and a delayed postnatal resorption of brain water. Deletion of astroglial Aqp4 did not affect the barrier function to macromolecules. Our data suggest that the blood-brain barrier (BBB) is more complex than anticipated. Notably, under certain conditions, the astrocyte covering of brain microvessels is rate limiting to water movement.     

Secretory products of multiple sclerosis B cells are cytotoxic to oligodendroglia in vitro

B cells are important in the pathogenesis of multiple sclerosis (MS) and some of the effects are not dependent on maturation of B cells into immunoglobulin (Ig) producing plasmablasts and plasma cells. B cells present antigen, activate T cells, and are involved in immunoregulation and cytokine secretion. To determine if B cells from MS patients secrete products that have deleterious effects on glial cells not mediated by Ig, and to compare effects with secretory products of normal controls (NC), we isolated B cells from 7 patients with relapsing remitting MS (RRMS) and 4 NC. B cells were cultured alone or after stimulation with CD40 ligand (CD40L), CD40L+cross-linking of the B cell antigen receptor (xBCR) and CD40L+xBCR+stimulation of toll like receptor 9 (TLR9). Supernatants were harvested and incubated with mixed central nervous system (CNS) neonatal rat glial cells. Supernatants from unstimulated NC B cells induced on average death of 7% (range 0-24%) of differentiated oligodendrocytes (OL); in contrast, supernatants from unstimulated B cells from RRMS patients induced death of 57% (range 35-74%) of OL. Supernatants of stimulated B cells from NC did not increase the minimal OL death whereas stimulation of B cells from RRMS had variable results compared to unstimulated B cells. Supernatants from both NC and RRMS induced microglial enlargement and loss of normal resting bipolar morphology. OL death did not correlate with levels of tumor necrosis alpha (TNF-α), lymphotoxin alpha (LT-α), interleukin 6 (IL-6), IL-10, transforming growth factor beta 1 (TGF-β1) or any combination or ratio of these cytokines. Analysis of 26 supernatants from NC and RRMS patients failed to detect IgM. There were very low levels of IgG in 8 of the 26 supernatants, and no correlation between of OL death and presence or absence of IgG. Sera used in both the B cell and glial cell cultures were heated, which inactivates complement. The effects of B cell supernatants on OL could be direct and/or indirect involving either microglia and/or astrocytes. The identity of the toxic factor(s) is as yet unknown. Thus we have demonstrated that B cells from patients with RRMS but not NC secrete one or more factors toxic to OL. It is possible that such factors produced by peripheral blood B cells when within the CNS could contribute to demyelination in MS patients.     

Neurological features in adult Triple-A (Allgrove) syndrome

Triple-A or Allgrove syndrome is a rare multisystem disease classically associated with esophageal achalasia, adrenal insufficiency and alacrima. Here, we describe the poorly understood neurological characteristics often associated with this condition, through the clinical and electrophysiological analysis of eight patients. All patients were genetically confirmed and had a mutation in the ALADIN gene. They all displayed a classical picture of Triple-A syndrome: all suffered from achalasia and alacrima and half of them from adrenal insufficiency. However, all harbored a neurological picture characterized by a recognizable pattern of peripheral neuropathy. Other neurological features included cognitive deficits, pyramidal syndrome, cerebellar dysfunction, dysautonomia, neuro-ophthalmological signs and bulbar and facial symptoms. This neurological picture was prominent in all patients and misled the initial diagnosis in six of them, which had a late onset. We then review the previous neurological reports of this disease, to improve the understanding of this rare condition. Diagnosis of late-onset Triple-A syndrome is difficult when the clinical picture is mainly neurological and when endocrine or gastrointestinal signs are minor. The characteristics of the peripheral neuropathy, among other neurological signs, can be of help.     

Aquaporin-4 regulates extracellular space volume dynamics during high-frequency synaptic stimulation: a gene deletion study in mouse hippocampus

Little is known about the physiological roles of aquaporin-4 (AQP4) in the central nervous system. AQP4 water channels are concentrated in endfeet membranes of astrocytes but also localize to the fine astrocytic processes that abut central synapses. Based on its pattern of expression, we predicted that AQP4 could be involved in controlling water fluxes and changes in extracellular space (ECS) volume that are associated with activation of excitatory pathways. Here, we show that deletion of Aqp4 accentuated the shrinkage of the ECS that occurred in the mouse hippocampal CA1 region during activation of Schaffer collateral/commissural fibers. This effect was found in the stratum radiatum (where perisynaptic astrocytic processes abound) but not in the pyramidal cell layer (where astrocytic processes constitute but a minor volume fraction). For both genotypes the ECS shrinkage was most pronounced in the pyramidal cell layer. Our data attribute a physiological role to AQP4 and indicate that this water channel regulates extracellular volume dynamics in the mammalian brain.     

Identification of human herpesviruses 1 to 8 in Tunisian multiple sclerosis patients and healthy blood donors

Members of the human Herpesviridae family are candidates for representing the macroenvironmental factors associated with multiple sclerosis (MS) pathogenesis. To verify the possible role of human herpesviruses (HHVs) as triggering or aggravating factors in relapsing–remitting multiple sclerosis clinical outcome, we studied the prevalence of all eight human herpesviruses in whole blood samples collected from 51 MS patients and from 51 healthy controls. The presence of DNA of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicella zoster virus (VZV), Epstein–Barr virus (EBV), human cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7) and human herpesvirus 8 (HHV-8) was searched by specific nested polymerase chain reaction. HHVs were significantly more prevalent in the blood of MS patients than in those of the controls (P < 10⁻⁴). HSV-1, HSV-2, HCMV and HHV-8 were negative in both MS patients and controls samples. In MS patients, EBV, HHV-7, HHV-6 and VZV were detected in 31.3%, 33.3%, 5.8% and 7.8% of samples, respectively, compared with 3.9%, 9.8%, 1.96% and 1.96%, respectively, of samples from controls. We found a statistically significant difference only for EBV DNA and for HHV-7 DNA prevalence (P < 0.001 and P = 0.03). Although these results indicate lack of apparent association in terms of gender, type of diagnosis, symptoms, disease score and β interferon treatment between EBV or HHV-7 to MS among Tunisian patients, heterogeneity related to genetic polymorphism as well as geographical distribution of the disease and of pathogens may be of significance.     

Mental health of asylum seekers: a cross-sectional study of psychiatric disorders

ABSTRACT: BACKGROUND: Asylum procedures are known to be protracted, stretching to over ten years in many host countries. International research shows high levels of distress for asylum seekers. Little is known about actual psychiatric morbidity in this population, especially during the first few years postmigration. METHODS: The mental health status of two groups of asylum seekers was assessed: Group 1 (n = 43) had arrived in Switzerland 2.9 (SD 1.1) months prior to assessment, while Group 2 (n = 43) had arrived 15.5 (SD 3.2) months prior to assessment. Psychiatric disorders were diagnosed using the Mini International Neuropsychiatric Interview (MINI). Symptom severity of posttraumatic stress disorder (Posttraumatic Diagnostic Scale), anxiety (Hopkins Symptom Checklist), depression (Hopkins Symptom Checklist), and pain (Verbal Rating Scale) were assessed using self-report questionnaires. Post-migratory factors such as German language proficiency and social contacts were also assessed. Interviews were conducted with the assistance of trained interpreters. RESULTS: Four out of ten participants met diagnostic criteria for at least one DSM-IV disorder. Groups did not differ with respect to psychiatric morbidity or symptom levels. Major depression (31.4%) and PTSD (23.3%) were diagnosed most frequently. The number of experienced traumatic event types was highly correlated with psychiatric morbidity. CONCLUSIONS: Psychiatric morbidity in asylum seekers in the first two years after arrival is high, with no indication of a decrease in mental distress over time. Traumatic experiences seem to play a major role in morbidity during this time. Considering the magnitude of clinically relevant distress, a short psychological screening upon arrival with a focus on traumatic experiences may be warranted.     

Infant feeding behaviours and attitudes to feeding amongst mothers with eating disorders: A longitudinal study

This study aims to investigate breastfeeding, infant feeding behaviours, and attitudes to feeding amongst women with eating disorders (ED) and healthy controls (HC). Women with active ED (C‐ED; N = 25), past ED (P‐ED; N = 28), and HC (N = 46) were recruited in pregnancy and followed up longitudinally. Post‐natally infant feeding behaviour was investigated at 8 weeks, 6 months, and 1 year and parental modelling at 1 and 2 years. Women with P‐ED and C‐ED reported higher concerns about their infant being/becoming overweight compared with HC, respectively, at 8 weeks and 6 months and 6 months only post‐partum. Women with P‐ED showed less awareness of infant hunger and satiety cues compared with HC at 8 weeks. Despite few differences between ED and HC, both P‐ED and C‐ED predicted maternal attitudes and worries about child's eating. These are likely to impact on child's growth and later eating behaviours and might impact on the intergenerational transmission of ED.