Familial Liability to Psychosis Is Associated With Attenuated Dopamine Stress Signaling in Ventromedial Prefrontal Cortex

Objective: Patients diagnosed with a psychotic disorder and their first-degree relatives display increased reactivity to stress. Theory predicts that experience of psychosocial stress is associated both with ventromedial prefrontal and mesolimbic dopamine neurotransmission. However, while there is evidence of aberrant striatal dopamine processing in psychotic disorder, the role of the prefrontal cortex remains under-researched. This study aimed at investigating stress-induced in vivo dopamine release in ventromedial prefrontal cortex (vmPFC) of individuals at familial risk for psychosis. Method: Fourteen healthy first-degree relatives of patients with a diagnosis of psychotic disorder and 10 control subjects underwent a single dynamic positron emission tomography (PET) scanning session after intravenous administration of 183.2 (SD = 7.6) MBq [¹⁸F]fallypride. Psychosocial stress was initiated at 100min postinjection using a computerized mental arithmetic task with social evaluative threat components. PET data were analyzed using the linearized simplified reference region model. Regression analyses were performed to compare the spatial extent of task-related ligand displacement between control subjects and relatives and to find how it related to self-rated experiences of psychosocial stress and psychosis. Results: First-degree relatives displayed hyporeactive dopamine signaling in the vmPFC in response to stress. Increased levels of subjectively rated stress were associated with increased intensity of psychotic experiences. This effect was particularly pronounced in first-degree relatives. Conclusion: Although previous studies have hypothesized a role for prefrontal dopamine dysfunction in psychosis, this study, to our knowledge, is the first in vivo human imaging study showing attenuated (ie, hyporeactive) dopamine stress neuromodulation in vmPFC of individuals at familial risk for psychosis.Key words: schizophrenia, positron emission tomography, neuromodulation, relatives, mesolimbic, salience     

Metabolism and Health Effects of Rare Sugars in a CACO-2/HepG2 Coculture Model

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease worldwide and is impacted by an unhealthy diet with excessive calories, although the role of sugars in NAFLD etiology remains largely unexplored. Rare sugars are natural sugars with alternative monomers and glycosidic bonds, which have attracted attention as sugar replacers due to developments in enzyme engineering and hence an increased availability. We studied the impact of (rare) sugars on energy production, liver cell physiology and gene expression in human intestinal colorectal adenocarcinoma (Caco-2) cells, hepatoma G2 (HepG2) liver cells and a coculture model with these cells. Fat accumulation was investigated in the presence of an oleic/palmitic acid mixture. Glucose, fructose and galactose, but not mannose, l-arabinose, xylose and ribose enhanced hepatic fat accumulation in a HepG2 monoculture. In the coculture model, there was a non-significant trend (p = 0.08) towards higher (20–55% increased) median fat accumulation with maltose, kojibiose and nigerose. In this coculture model, cellular energy production was increased by glucose, maltose, kojibiose and nigerose, but not by trehalose. Furthermore, glucose, fructose and l-arabinose affected gene expression in a sugar-specific way in coculture HepG2 cells. These findings indicate that sugars provide structure-specific effects on cellular energy production, hepatic fat accumulation and gene expression, suggesting a health potential for trehalose and l-arabinose, as well as a differential impact of sugars beyond the distinction of conventional and rare sugars.     

Multislice spiral computed tomography coronary angiography in patients with stable angina pectoris

OBJECTIVES: This study was designed to prospectively evaluate the diagnostic performance of multislice spiral computed tomography (MSCT) coronary angiography for the detection of significant lesions in all segments of the coronary tree potentially suitable for revascularization. BACKGROUND: Noninvasive MSCT coronary angiography is a promising coronary imaging technique. METHODS: Sixteen-row MSCT coronary angiography was performed in 128 patients (89% men, mean age 58.9 +/- 11.7 years) in sinus rhythm with stable angina pectoris scheduled for conventional coronary angiography. Sixty percent (77 of 128) of patients received pre-scan oral beta-blockers, resulting in a mean heart rate of 57.7 +/- 7.7 beats/min. The diagnostic performance of MSCT for detection of significant lesions (> or =50% diameter reduction) was compared with that of quantitative coronary angiography (QCA). RESULTS: The sensitivity of MSCT for detection of significant lesions was 92% (216 of 234, 95% confidence interval [CI]: 88 to 95). Specificity was 95% (1,092 of 1,150, 95% CI: 93 to 96), positive predictive value 79% (216 of 274, 95% CI: 73 to 88), and negative predictive value 98% (1,092 of 1,110, 95% CI: 97 to 99). Two > or =50% lesions were missed because of motion artifacts and two because of severe coronary calcifications. The rest (78%, 14 of 18) were detected but incorrectly classified as <50% obstructions. All patients with and 86% (18 of 21) of patients without significant lesions on QCA were correctly classified by MSCT. All patients with significant left main disease or total occlusions were correctly identified on MSCT. CONCLUSIONS: Sixteen-row MSCT coronary angiography permits reliable detection of significant obstructive coronary artery disease in patients with stable angina in sinus rhythm.     

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.