Fever-like temperature modification differentially affects in vitro signaling of bradykinin B-1 and B-2 receptors

The bradykinin (BK) B-2 and B-1 receptors (B2R, B1R) belong to the rhodopsin-like G protein-coupled receptors (GPCRs) and are involved in (patho)physiological processes such as blood pressure regulation or inflammation. They mediate the effects of the pro-inflammatory peptides bradykinin/kallidin and desArg(9)-BK/desArg(10)-kallidin, respectively. Whereas the B2R is constitutively expressed and gets internalized upon activation, the B1R is especially induced by inflammatory mediators and responds to stimulation with increased surface receptor numbers. Stimulation of both receptors activates phospholipase C beta (PLC beta) and mitogen activated protein kinase (MAPK) signaling. Because inflammatory processes are characterized by heat (fever), we analyzed the effect of increased temperature (41 degrees C vs. 37 degrees C) on B1R and B2R signaling in HEK 293 and IMR 90 cells. Our results show that signaling of both receptors is temperature-sensitive, however to a different extent and with regard to the investigated pathways. Comparing PLCb activity and Ca2+-regulated signals, a temperature-dependent increase was only observed for B1R but not for B2R activation, whereas MAPK activities were doubled at 41 degrees C for both receptors. Taken together, our findings suggest that the observed temperature sensitivity of B1R-induced PLCb activation is B1R-specific. In contrast, the enhanced stimulation of MAPK activity under hyperthermic conditions appears to be a common phenomenon for GPCRs

Psychiatric comorbidity and psychosocial impairment among patients with vertigo and dizziness

Background: Vertigo and dizziness are often not fully explained by an organic illness, but instead are related to psychiatric disorders. This study aimed to evaluate psychiatric comorbidity and assess psychosocial impairment in a large sample of patients with a wide range of unselected organic and non-organic (ie, medically unexplained) vertigo/dizziness syndromes. Methods: This cross-sectional study involved a sample of 547 patients recruited from a specialised interdisciplinary treatment centre for vertigo/dizziness. Diagnostic evaluation included standardised neurological examinations, structured clinical interview for major mental disorders (SCID-I) and self-report questionnaires regarding dizziness, depression, anxiety, somatisation and quality of life. Results: Neurological diagnostic workup revealed organic and non-organic vertigo/dizziness in 80.8% and 19.2% of patients, respectively. In 48.8% of patients, SCID-I led to the diagnosis of a current psychiatric disorder, most frequently anxiety/phobic, somatoform and affective disorders. In the organic vertigo/dizziness group, 42.5% of patients, particularly those with vestibular paroxysmia or vestibular migraine, had a current psychiatric comorbidity. Patients with psychiatric comorbidity reported more vertigo-related handicaps, more depressive, anxiety and somatisation symptoms, and lower psychological quality of life compared with patients without psychiatric comorbidity. Conclusions: Almost half of patients with vertigo/dizziness suffer from a psychiatric comorbidity. These patients show more severe psychosocial impairment compared with patients without psychiatric disorders. The worst combination, in terms of vertigo-related handicaps, is having non-organic vertigo/dizziness and psychiatric comorbidity. This phenomenon should be considered when diagnosing and treating vertigo/dizziness in the early stages of the disease

Critical evaluation of P2X7 receptor antagonists in selected seizure models

The ATP-gated P2X7 receptor (P2X7R) is a non-selective cation channel which senses high extracellular ATP concentrations and has been suggested as a target for the treatment of neuroinflammation and neurodegenerative diseases. The use of P2X7R antagonists may therefore be a viable approach for treating CNS pathologies, including epileptic disorders. Recent studies showed anticonvulsant potential of P2X7R antagonists in certain animal models. To extend this work, we tested three CNS-permeable P2X7R blocker (Brilliant Blue G, AFC-5128, JNJ-47965567) and a natural compound derivative (tanshinone IIA sulfonate) in four well-characterized animal seizure models. In the maximal electroshock seizure threshold test and the pentylenetetrazol (PTZ) seizure threshold test in mice, none of the four compounds demonstrated anticonvulsant effects when given alone. Notably, in combination with carbamazepine, both AFC-5128 and JNJ-47965567 increased the threshold in the maximal electroshock seizure test. In the PTZ-kindling model in rats, useful for testing antiepileptogenic activities, Brilliant Blue G and tanshinone exhibited a moderate retarding effect, whereas the potent P2X7R blocker AFC-5128 and JNJ-47965567 showed a significant and long-lasting delay in kindling development. In fully kindled rats, the investigated compounds revealed modest effects to reduce the mean seizure stage. Furthermore, AFC-5128- and JNJ-47965567-treated animals displayed strongly reduced Iba 1 and GFAP immunoreactivity in the hippocampal CA3 region. In summary, our results show that P2X7R antagonists possess no remarkable anticonvulsant effects in the used acute screening tests, but can attenuate chemically-induced kindling. Further studies would be of interest to support the concept that P2X7R signalling plays a crucial role in the pathogenesis of epileptic disorders

Diagnosing Developmental Dyscalculia on the Basis of Reliable Single Case FMRI Methods: Promises and Limitations

FMRI-studies are mostly based on a group study approach, either analyzing one group or comparing multiple groups, or on approaches that correlate brain activation with clinically relevant criteria or behavioral measures. In this study we investigate the potential of fMRI-techniques focusing on individual differences in brain activation within a test-retest reliability context. We employ a single-case analysis approach, which contrasts dyscalculic children with a control group of typically developing children. In a second step, a support-vector machine analysis and cluster analysis techniques served to investigate similarities in multivariate brain activation patterns. Children were confronted with a non-symbolic number comparison and a non-symbolic exact calculation task during fMRI acquisition. Conventional second level group comparison analysis only showed small differences around the angular gyrus bilaterally and the left parieto-occipital sulcus. Analyses based on single-case statistical procedures revealed that developmental dyscalculia is characterized by individual differences predominantly in visual processing areas. Dyscalculic children seemed to compensate for relative under-activation in the primary visual cortex through an upregulation in higher visual areas. However, overlap in deviant activation was low for the dyscalculic children, indicating that developmental dyscalculia is a disorder characterized by heterogeneous brain activation differences. Using support vector machine analysis and cluster analysis, we tried to group dyscalculic and typically developing children according to brain activation. Fronto-parietal systems seem to qualify for a distinction between the two groups. However, this was only effective when reliable brain activations of both tasks were employed simultaneously. Results suggest that deficits in number representation in the visual-parietal cortex get compensated for through finger related aspects of number representation in fronto-parietal cortex. We conclude that dyscalculic children show large individual differences in brain activation patterns. Nonetheless, the majority of dyscalculic children can be differentiated from controls employing brain activation patterns when appropriate methods are used

bFGF and EGF modulate trauma-induced proliferation and neurogenesis in juvenile organotypic hippocampal slice cultures

Since postnatal and adult mammalian brains have been shown to retain an ability to generate neurons from endogenous stem cells throughout life, these cells could play a central role in regeneration after neuronal loss. Therefore, we studied cell proliferation, glio- and neurogenesis respectively after brain injury in organotypic hippocampal slice cultures using a focal trauma by transecting Schaffer collaterals in the cornu ammonis (CA) 2 region mechanically. After determination of cell death using propidium iodide, neuroregenerative processes were quantitatively analyzed by various immunohistochemical techniques at different time points post injury. As this endogenous insult-induced neurogenesis is rather inefficient, we investigated if it can be enhanced by application of exogenous growth factors.Exogenous basic fibroblast growth factor (bFGF) enhanced neurogenesis significantly in the dentate gyrus (DG) region. A neutralizing antibody against endogenous bFGF revealed a significant decrease of basal and trauma-induced proliferation. Reverse transcription polymerase chain reaction (RT-PCR) studies exhibited a downregulation of FGF messenger ribonucleic acid (mRNA) transcription after the antibody treatment. In contrast, epidermal growth factor (EGF) increased proliferation, but not neurogenesis. A combination of bFGF and EGF displayed an EGF-like effect on proliferation and no effect on neurogenesis. These results demonstrate, that in our model bFGF but not EGF sustains neurogenesis, whereas together the two growth factors permit an increased proliferation but not neurogenesis in organic hippocampal slice cultures