Inositol-trisphosphate-dependent intercellular calcium signaling in and between astrocytes and endothelial cells

Interactions between astrocytes and endothelial cells are believed to play an important role in the control of blood-brain barrier permeability and transport. Astrocytes and endothelial cells respond to a variety of stimuli with an increase of intracellular free calcium ([Ca²⁺]_i) that is propagated to adjacent cells as an intercellular Ca²⁺ wave. We hypothesized that intercellular Ca²⁺ signaling also occurs between astrocytes and endothelial cells, and we investigated this possibility in co-cultures of primary astrocytes and an endothelial cell line using caged messengers. Intercellular Ca²⁺ waves, induced by mechanical stimulation of a single cell, propagated from astrocytes to endothelial cells and vice versa. Intercellular Ca²⁺ waves could also be induced by flash photolysis of pressure-injected caged inositol trisphosphate (IP₃) and also by applying the flash to remote noninjected cells. Ca²⁺ waves induced by flash photolysis propagated from endothelial cells to astrocytes but not from astrocytes to endothelial cells even though caged IP₃ diffused between the two cell types. Flash photolysis of caged Ca²⁺ (NP-EGTA) resulted in an increase of [Ca²⁺]_i but did not initiate an intercellular Ca²⁺ wave. We conclude that an increase of IP₃ in a single cell is sufficient to initiate an intercellular Ca²⁺ wave that is propagated by the diffusion of IP₃ to neighboring cells and that can be communicated between astrocytes and endothelial cells in co-culture. By contrast, Ca²⁺ diffusion via gap junctions does not appear to be sufficient to propagate an intercellular Ca²⁺ wave. We suggest that intercellular Ca²⁺ waves may play a role in astrocyte-endothelial interactions at the blood-brain barrier. GLIA 24:398–407, 1998. © 1998 Wiley-Liss, Inc.     

Optical coherence tomography: a quantitative tool to screen for papilledema in craniosynostosis

Purpose

Our aim was to evaluate if optical coherence tomography (OCT) can be used as an alternative for fundoscopy to screen for increased intracranial pressure (ICP) in children with craniosynostosis

Methods

We performed a prospective cohort study at the Dutch Craniofacial Centre. We included 38 patients with nonsyndromic scaphocephaly and Crouzon’s syndrome aged 3–8 years old, in whom we scored complaints suggestive of increased ICP and performed fundoscopy and OCT. Main outcome measures total retinal thickness (TRT) which was measured on 58 OCT scans.

Results

Forty-three percent of fundoscopies revealed pathologic changes of the papil in at least one eye. Retinal thickness was increased in patients with an abnormal fundoscopy as compared to patients with a normal papil (TRT p?<?0.001). Patients with Crouzon’s syndrome had a significantly increased retinal thickness as compared to patients with scaphocephaly (TRT p?<?0.001).

Conclusions

The current study demonstrates that OCT in children with craniosynostosis is feasible. It confirms that retinal thickness increases in case of papilledema. Given the quantitative character, OCT has a high potential as an alternative tool to screen for papilledema in craniosynostosis and other pediatric populations.     

Preclinical evaluation and quantification of [18F]MK-9470 as a radioligand for PET imaging of the type 1 cannabinoid receptor in rat brain

Purpose

[¹⁸F]MK-9470 is an inverse agonist for the type 1 cannabinoid (CB1) receptor allowing its use in PET imaging. We characterized the kinetics of [¹⁸F]MK-9470 and evaluated its ability to quantify CB1 receptor availability in the rat brain.

Methods

Dynamic small-animal PET scans with [¹⁸F]MK-9470 were performed in Wistar rats on a FOCUS-220 system for up to 10?h. Both plasma and perfused brain homogenates were analysed using HPLC to quantify radiometabolites. Displacement and blocking experiments were done using cold MK-9470 and another inverse agonist, SR141716A. The distribution volume (V _T) of [¹⁸F]MK-9470 was used as a quantitative measure and compared to the use of brain uptake, expressed as SUV, a simplified method of quantification.

Results

The percentage of intact [¹⁸F]MK-9470 in arterial plasma samples was 80?±?23?% at 10?min, 38?±?30?% at 40?min and 13?±?14?% at 210?min. A polar radiometabolite fraction was detected in plasma and brain tissue. The brain radiometabolite concentration was uniform across the whole brain. Displacement and pretreatment studies showed that 56?% of the tracer binding was specific and reversible. V _T values obtained with a one-tissue compartment model plus constrained radiometabolite input had good identifiability (≤10?%). Ignoring the radiometabolite contribution using a one-tissue compartment model alone, i.e. without constrained radiometabolite input, overestimated the [¹⁸F]MK-9470 V _T, but was correlated. A correlation between [¹⁸F]MK-9470 V _T and SUV in the brain was also found (R ²?=?0.26–0.33; p?≤?0.03).

Conclusion

While the presence of a brain-penetrating radiometabolite fraction complicates the quantification of [¹⁸F]MK-9470 in the rat brain, its tracer kinetics can be modelled using a one-tissue compartment model with and without constrained radiometabolite input.     

Are psychotic symptoms related to vagus nerve stimulation in epilepsy patients?

Four patients with refractory epilepsy presented with psychotic symptoms following treatment with vagus nerve stimulation (VNS) to control seizures. Besides its anti-epileptic effect VNS has been shown to have an effect on various cognitive and behavioural functions. VNS is known to increase alertness and reduce sedation, which is independent from seizure control. VNS has also been shown to positively affect cognition and to exert strong antidepressant effects. Co-morbidity in epilepsy often comprises psychiatric illnesses. Increased psychiatric symptoms have mainly been described in association with successful outcome following epilepsy surgery as a result of 'forced normalisation'. Different hypotheses on the underlying aetiology of VNS-induced psychotic symptoms other than the previously described 'forced normalisation' are discussed.     

Evidence for involvement of a tumor suppressor gene on 1p in malignant peripheral nerve sheath tumors

Malignant peripheral nerve sheath tumors (MPNST) are rare soft-tissue malignancies. The genetic basis of these tumors is still poorly understood. Cytogenetic analyses predominantly revealed complex karyotypes, precluding the identification of recurrent chromosomal changes. We report loss of 1p material in a near-diploid karyotype with few or no additional structural chromosome changes in two sporadic cases of MPNST, indicating an important role of 1p loss in MPNST development. In one of these two tumors, a distal 1p deletion (1p31.2 approximately pter) was detected suggesting involvement of a tumor suppressor gene located within this distal region of 1p. Further evidence for recurrent 1p loss in MPNST was obtained by interphase fluorescence in situ hybridization, which showed loss of 1p material in 3 out of 13 tumors. These findings together with data from the literature suggest that loss of a tumor suppressor gene located within distal 1p is implicated in the pathogenesis of MPNST.     

Hydatidiform mole and triploidy: the role of genomic imprinting in placental development

Genomic imprinting, the differential expression of paternal and maternal alleles, is involved in the regulation of embryonic and fetal growth and development. In this review, we focus on the genetics of a disorder caused by a global defect in genomic imprinting, the hydatidiform mole. The ratio between the maternal and paternal genomes is critical in determining the development of both the embryonic and extraembryonic tissues, with an excess of paternally derived chromosomes leading to a complete (no maternal genome) or partial (lower amount of maternal chromosomes) mole. The recent identification and molecular studies in biparental complete moles may yield more insight into the regulation of imprinting during gametogenesis.     

Predictive testing for Huntington's disease: relationship with partners after testing

This study focuses on the partner relationship of tested persons, 5 years after their predictive test result for Huntington's disease (HD). We describe changes in marital status, quality of the relationship, and perceived changes in the relationship. Twenty-six carriers, 14 of their partners, 33 non-carriers, and 17 of their partners participated in the study. Qualitative and quantitative methods were used. For the majority of tested persons (about 70%), the marital status was unchanged 5 years post test. Overall, carriers rated the quality of the relationship higher than their partners did and they perceived more positive changes. Qualitative data show that a test result leading to changed roles may induce significant marital distress. Another consequence of the test may be the changes in dynamics in asymptomatic carrier couples. A pre-test discussion of the possible impact of the test result on the relationship should result in a better preparation for and more understanding of the reactions after testing. Counselling after testing should stimulate an open communication between partners with consideration of needs and anxieties of both partners.