Cerebral arterial gas embolism in swine. Comparison of two sites for air injection

Cerebral arterial gas embolism is a risk in diving and occurs as a complication in surgery and interventional radiology. Swine models for cerebral arterial gas embolism have been used in the past. However, injection of air into the main artery feeding the pig brain - the ascending pharyngeal artery - might be complicated by the presence of the carotid rete, an arteriolar network at the base of the brain. On the other hand, anastomoses between external and internal carotid territories are present in the pig. In order to determine the most appropriate vessel for air injection, we performed experiments in which air was injected into either the ascending pharyngeal artery or the external carotid artery. We injected 0.25 ml/kg of room air selectively into the ascending pharyngeal artery or the external carotid artery of 35-40 kg Landrace pigs (n=8). We assessed the effect on cerebral metabolism by measuring intracranial pressure, brain oxygen tension and brain glucose and lactate concentrations using cerebral microdialysis. Intracranial pressure and brain oxygen tension changed significantly in both groups, but did not differ between groups. Brain lactate increased significantly more in pigs in which air was injected into the ascending pharyngeal artery. Intracranial pressure, brain oxygen tension and brain lactate correlated after injection of air into the ascending pharyngeal artery, but not after injection into the external carotid artery. Our model is suitable for investigation of cerebral arterial gas embolism. The ascending pharyngeal artery is the most appropriate vessel for air injection.     

Effects of handedness (left vs right) and cannabis abuse on intermanual coordination and negative symptoms in schizophrenic patients of the paranoid type

Intermanual coordination as an index of interhemispheric transfer and negative symptoms were investigated in 50 left- and 42 right-handed schizophrenic inpatients of the paranoid type, also including drug abusers. The primary objective was to show that there were higher values in intermanual coordination and fewer manifestations of negative symptoms in the left-handed compared to the right-handed patients. This assumption was based on previous studies. Most importantly, right- and left-handed patients showed a different behaviour in intermanual coordination, when the duration of illness was taken into consideration. Thus, long-term left-handed paranoid patients performed better in intermanual coordination and showed fewer manifestations of negative symptoms than did long-term right-handed patients. These results were true for the large group of all patients, and among them for the subgroup of patients without drug abuse. Consequently, higher scores in intermanual coordination in left-handed patients may be related to a better interhemispheric crosstalk resulting in less pronounced negative symptoms. Secondary objectives assessed by explorative data analysis included the effects of cannabis abuse. While cannabis abuse may be more prevalent in left-handed patients, its effects may be more pronounced in right-handed patients, scoring higher in intermanual coordination and lower in manifestations of negative symptoms.     

Intracellular transport of Toxoplasma gondii through the blood-brain barrier

Toxoplasma gondii establishes latent infection in the central nervous system of immunocompentent hosts. Toxoplasmic encephalitis is a life threatening reactivation of latent infection in the brain of immunocompromised patients. To further understand the mechanisms of entry into the brain of T. gondii we investigated host molecules and cells involved in the passage of the parasite through the blood-brain barrier. First, using microarrays brain endothelial cells were found to upregulate, among others, chemokines and adhesion molecules following infection with tachyzoites. Using flow cytometry we observed upregulated ICAM-1 expression on the surface of brain endothelial cells following infection; ICAM-1 expression was further increased after pre-incubation with IFN-γ. Compared to RH tachyzoites, ME49 tachyzoites induced a stronger upregulation of ICAM-1 and an earlier and stronger IL-6 and MCP-1 secretion by brain endothelial cells. Using an in vitro coculture model of the BBB (primary glia cells and brain endothelial cells) we found a stronger migration of infected antigen-presenting cells compared to lymphocytes (4.63% vs. 0.6% of all cells) across the BBB. Among all antigen-presenting cells CD11b(+)/CD11c(+) cells showed the highest infection rate, whereas the majority of infected cells that migrated through the blood-brain barrier were CD11b(+)/CD11c(-) cells. Infection of PBMCs with type I or type II Toxoplasma strains resulted in similar patterns of cell migration across the in vitro BBB model. In conclusion, these results suggest that T. gondii modulates gene expression of brain endothelial cells to promote its own migration through the blood-brain barrier in a 'Trojan horse' manner. Cells expressing CD11b either with or without CD11c are likely candidate cells for the intracellular transport of T. gondii across the BBB. T. gondii type I and type II strains induced similar migration patterns of antigen-presenting cells across the in vitro BBB.     

Chronic vagus nerve stimulation for treatment-resistant depression increases regional cerebral blood flow in the dorsolateral prefrontal cortex

The purpose of the present study was to assess the effects of vagus nerve stimulation (VNS) therapy on regional cerebral blood flow (rCBF) in depressed patients. Regional cerebral blood flow (rCBF) was assessed by [^99mTc]-HMPAO-single photon emission computed tomography (SPECT) before and after 10 weeks of VNS in patients participating in an open, uncontrolled European multi-center study investigating efficacy and safety of VNS. Patients suffered from major depression, with a baseline score of ≥ 20 on the 24-item Hamilton Depression Rating Scale (HDRS) and had been unsuccessfully treated with at least two adequately prescribed antidepressant drugs. Data of 15 patients could be analyzed using SPM 2. After 10 weeks of VNS (20 Hz, 500 μs pulse width, stimulation during 30 s every 5 min at the maximal comfortable level) rCBF was increased in the left dorsolateral/ventrolateral prefrontal cortex (Brodmann areas 46 and 47) and decreased in the right posterior cingulate area, the lingual gyrus and the left insula. Our findings are in line with earlier results which showed that VNS increases rCBF in the left dorsolateral prefrontal cortex. The modulation of the activity in this region could be associated with the antidepressant efficacy of VNS.     

Systematic Literature Review of Spinal Cord Stimulation in Patients With Chronic Back Pain Without Prior Spine Surgery

ObjectiveLow back pain is the leading cause of disability worldwide and one of the most common reasons for seeking health care. Despite numerous care strategies, patients with low back pain continue to exhibit poor outcomes. Spinal cord stimulation (SCS) is an evidence-based therapeutic modality for patients with failed back surgery syndrome. For patients without a surgical lesion or history, minimally invasive interventions that provide long-term reduction of chronic back pain are needed. Therefore, we conducted a systematic review of the evidence on SCS therapy in patients with chronic back pain who have not undergone spinal surgery.Materials and MethodsA systematic literature search was performed to identify studies reporting outcomes for SCS in chronic back pain patients (with or without secondary radicular leg pain) without prior surgery using date limits from database inception to February 2021. Study results were analyzed and described qualitatively.ResultsA total of ten primary studies (16 publications) were included. The included studies consistently demonstrated favorable outcomes in terms of pain reduction and functional improvement following SCS therapy. Improvements also occurred in quality of life scores; however, not all studies reported statistically significant findings. Additionally, the studies reported that SCS resulted in high patient satisfaction, reductions in opioid use, and an acceptable safety profile, although these data were more limited.ConclusionFindings suggest that SCS is a promising, safe, minimally invasive, and reversible alternative option for managing chronic back pain in patients who have not undergone spinal surgery.     

Phenotypic spectrum and genetics of SCN2A‐related disorders,treatment options,and outcomes in epilepsy and beyond

Pathogenic variants in the SCN2A gene are associated with a variety of neurodevelopmental phenotypes, defined in recent years through multicenter collaboration. Phenotypes include benign (self‐limited) neonatal and infantile epilepsy and more severe developmental and epileptic encephalopathies also presenting in early infancy. There is increasing evidence that an important phenotype linked to the gene is autism and intellectual disability without epilepsy or with rare seizures in later childhood. Other associations of SCN2A include the movement disorders chorea and episodic ataxia. It is likely that as genetic testing enters mainstream practice that new phenotypic associations will be identified. Some missense, gain of function variants tend to present in early infancy with epilepsy, whereas other missense or truncating, loss of function variants present with later‐onset epilepsies or intellectual disability only. Knowledge of both mutation type and functional consequences can guide precision therapy. Sodium channel blockers may be effective antiepileptic medications in gain of function, neonatal and infantile presentations.     

Distinct glutaminyl cyclase expression in Edinger–Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-Aβ pathology in Alzheimer’s disease

Glutaminyl cyclase (QC) was discovered recently as the enzyme catalyzing the pyroglutamate (pGlu or pE) modification of N-terminally truncated Alzheimer’s disease (AD) Aβ peptides in vivo. This modification confers resistance to proteolysis, rapid aggregation and neurotoxicity and can be prevented by QC inhibitors in vitro and in vivo, as shown in transgenic animal models. However, in mouse brain QC is only expressed by a relatively low proportion of neurons in most neocortical and hippocampal subregions. Here, we demonstrate that QC is highly abundant in subcortical brain nuclei severely affected in AD. In particular, QC is expressed by virtually all urocortin-1-positive, but not by cholinergic neurons of the Edinger–Westphal nucleus, by noradrenergic locus coeruleus and by cholinergic nucleus basalis magnocellularis neurons in mouse brain. In human brain, QC is expressed by both, urocortin-1 and cholinergic Edinger–Westphal neurons and by locus coeruleus and nucleus basalis Meynert neurons. In brains from AD patients, these neuronal populations displayed intraneuronal pE-Aβ immunoreactivity and morphological signs of degeneration as well as extracellular pE-Aβ deposits. Adjacent AD brain structures lacking QC expression and brains from control subjects were devoid of such aggregates. This is the first demonstration of QC expression and pE-Aβ formation in subcortical brain regions affected in AD. Our results may explain the high vulnerability of defined subcortical neuronal populations and their central target areas in AD as a consequence of QC expression and pE-Aβ formation.     

Amygdala activation during reading of emotional adjectives--an advantage for pleasant content

This event-related functional magnetic resonance imaging (fMRI)study investigated brain activity elicited by emotional adjectivesduring silent reading without specific processing instructions.Fifteen healthy volunteers were asked to read a set of randomlypresented high-arousing emotional (pleasant and unpleasant)and low-arousing neutral adjectives. Silent reading of emotionalin contrast to neutral adjectives evoked enhanced activationsin visual, limbic and prefrontal brain regions. In particular,reading pleasant adjectives produced a more robust activationpattern in the left amygdala and the left extrastriate visualcortex than did reading unpleasant or neutral adjectives. Moreover,extrastriate visual cortex and amygdala activity were significantlycorrelated during reading of pleasant adjectives. Furthermore,pleasant adjectives were better remembered than unpleasant andneutral adjectives in a surprise free recall test conductedafter scanning. Thus, visual processing was biased towards pleasantwords and involved the amygdala, underscoring recent theoreticalviews of a general role of the human amygdala in relevance detectionfor both pleasant and unpleasant stimuli. Results indicate preferentialprocessing of pleasant information in healthy young adults andcan be accounted for within the framework of appraisal theory.     

Genetic variation in the schizophrenia‐risk gene neuregulin 1 correlates with brain activation and impaired speech production in a verbal fluency task in healthy individuals

Impaired performance in verbal fluency tasks is an often replicated finding in schizophrenia. In functional neuroimaging studies, this dysfunction has been linked to signal changes in prefrontal and temporal areas. Since schizophrenia has a high heritability, it is of interest whether susceptibility genes for the disorder, such as NRG1, modulate verbal fluency performance and its neural correlates. Four hundred twenty‐nine healthy individuals performed a semantic and a lexical verbal fluency task. A subsample of 85 subjects performed an overt semantic verbal fluency task while brain activation was measured with functional magnetic resonance imaging (MRI). NRG1 (SNP8NRG221533; rs35753505) status was determined and correlated with verbal fluency performance and brain activation. For the behavioral measure, there was a linear effect of NRG1 status on semantic but not on lexical verbal fluency. Performance decreased with number of risk‐alleles. In the fMRI experiment, decreased activation in the left inferior frontal and the right middle temporal gyri as well as the anterior cingulate gyrus was correlated with the number of risk‐alleles in the semantic verbal fluency task. NRG1 genotype does influence language production on a semantic level in conjunction with the underlying neural systems. These findings are in line with results of studies in schizophrenia and may explain some of the cognitive and brain activation variation found in the disorder. More generally, NRG1 might be one of several genes that influence semantic language capacities. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Stem-cell-like glioma cells are resistant to TRAIL/Apo2L and exhibit down-regulation of caspase-8 by promoter methylation

Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising cancer drug. However, many tumours are resistant to TRAIL-based therapies. Glioma cells with stem cell features (SCG), such as CD133 expression and neurosphere formation, have been recently identified to be more resistant to cytotoxic drugs than glioma cells lacking stem-cell-like features (NSCGs). Here we report that SCGs are completely resistant to 100–2,000 ng/ml TRAIL, whereas NSCGs revealed a moderate sensitivity to TRAIL. We found that SCGs exhibited only low levels of caspase-8 mRNA and protein, known to be indispensable for TRAIL-induced apoptosis. In addition, we detected hypermethylation of CASP8 promoter in SCGs, whereas NSCGs exhibited a non-methylated CASP8 promoter. Reexpression of caspase-8 by 5-Aza-2′-deoxycytidine was not sufficient to restore TRAIL sensitivity in SCGs cells, suggesting that additional factors cause TRAIL resistance in SCGs. Our data suggest that therapy with TRAIL, either as monotherapy or in combination with demethylating agents, is not effective in treating glioblastoma because SCGs are not targeted by such treatment.