Hyperechoic Area Under Insular Gliomas: A Potentially Hazardous Intraoperative Ultrasound Artifact.

BACKGROUND: Intraoperative ultrasound (IOUS) images can be distorted by various artifacts. During surgeries for insular low-grade gliomas (LGGs), we repeatedly observed a distinct hyperechoic artifact adjacent to medial tumor borders, localized in brain regions with normal appearance on magnetic resonance imaging (MRI) that has not been reported before. METHODS: We retrospectively evaluated saved 3-dimensional (3D) IOUS images of 20 patients harboring insular LGGs. Twelve patients were operated on between 2010 and 2015 using an older navigated 3D IOUS system. Additionally, 3D-IOUS images of 8 patients operated on between 2021 and 2023 using a new high-end 3D-IOUS system were evaluated. The investigated region was the area under medial tumor borders, which were defined using preoperative MRI. RESULTS: In 17 out of 20 cases (85%), a distinct hyperechoic area adjacent to medial tumor borders localized in brain regions with normal appearance on preoperative MRI was found; in the remaining 3 cases the saved images were suboptimal and did not allow evaluation of the area under the medial tumor borders. CONCLUSIONS: Although the causes of this bright artifact are unclear, we can hypothesize that the reverberation in between different parallel layers of white and gray matter localized under the insula could play a role in its appearance. Importantly, as this hyperechoic area was depicted already before any tumor resection, it may lead to erroneous conclusion that the tumor spreads more medially. Potential resection in this region may cause significant neurologic sequelae.

Morphological peculiarities of the autonomic nervous system in the thoracic region.

BACKGROUND: The aim of the work is to define the morphological peculiarities of the autonomic nervous system (ANS) in the thoracic region. MATERIAL AND METHODS: An anatomical study was performed on 20 cadavers, 17 men and 3 women. We studied cadavers within 24 h of death. We observed the vertebral and prevertebral section of the truncus sympathicus, their morphological peculiarities depending on the type of ANS. To show the intimate relationship of both systems, we also focused on the details of the structure related to the connections of the ANS with the spinal nervous system. RESULTS: In the thoracic region, the segmental arrangement of the truncus sympathicus ganglia prevailed in 16 (80%) cases. Rami communicantes gave anastomoses to spinal nerves. Small ganglia were observed on the rami communicantes to the spinal nerves. In the case of the concentrated type, in 4 cases (20%), we observed a reduction in the number of ganglia, as well as the absence of small ganglia on the connecting branches. Connections between n. vagus and sympathetic branches were poorly developed. We observed right-left asymmetry and differences in the formation of ganglia and anastomoses in the truncus sympathicus in the vertebral and prevertebral section. Variations of distance of n. splanchnicus major were observed in 16 cases (80%). CONCLUSION: This study allowed us to identify and describe the morphological peculiarities of the thoracic ANS. The variations were numerous; their preoperative diagnosis is difficult to impossible. The knowledge gained can be helpful in clarifying clinical signs and symptoms.

Navigated 3D-ultrasound power Doppler and visualization of lenticulostriate arteries during resections of insular gliomas.

•Preservation of LSAs is extremely important during resections of insular gliomas.•Navigated 3D-US power Doppler may enable intraoperative visualization of LSAs.•Quality of ultrasound scanner is important when LSAs should be visualized.•Reliability of LSAs depiction by 3D-US power Doppler is still investigated.

Current Limitations of Intraoperative Ultrasound in Brain Tumor Surgery.

While benefits of intraoperative ultrasound (IOUS) have been frequently described, data on IOUS limitations are relatively sparse. Suboptimal ultrasound imaging of some pathologies, various types of ultrasound artifacts, challenging patient positioning during some IOUS-guided surgeries, and absence of an optimal IOUS probe depicting the entire sellar region during transsphenoidal pituitary surgery are some of the most important pitfalls. This review aims to summarize prominent limitations of current IOUS systems, and to present possibilities to reduce them by using ultrasound technology suitable for a specific procedure and by proper scanning techniques. In addition, future trends of IOUS imaging optimization are described in this article.

Unusual aetiology of a type 2 myocardial infarction: a case-based review.

Organophosphate pesticide (OP) poisoning is quite common and can cause cardiovascular complications and even direct myocardial injury. However, no guideline has included an acute poisoning as a potential cause for a type 2 myocardial infarction (MI) so far. Here we present a case of a 61-year-old woman brought by ambulance to emergency department one hour after accidental ingestion of an unknown quantity of a solution she used against flea infestation. The patient presented with dizziness, myosis, excessive sweating, hypersalivation, sphincteric incontinence, muscle fasciculation, tremor of the extremities, pale skin, alcoholic and pesticide breath odour. Even though we had no guidelines to fall back on, we successfully treated the patient with low-molecular-weight heparin, antiplatelets, statin, diltiazem, antidote therapy, and supportive care. Physicians should be aware that OP poisoning can induce type 2 MI as a complication within a few hours since exposure, and emergency management should always include close cardiac monitoring.

A novel pregnane X receptor-mediated and sterol regulatory element-binding protein-independent lipogenic pathway.

The pregnane X receptor (PXR) was isolated as a xenosensor regulating xenobiotic responses. In this study, we show that PXR plays an endobiotic role by impacting lipid homeostasis. Expression of an activated PXR in the livers of transgenic mice resulted in an increased hepatic deposit of triglycerides. This PXR-mediated lipid accumulation was independent of the activation of the lipogenic transcriptional factor SREBP-1c (sterol regulatory element-binding protein 1c) and its primary lipogenic target enzymes, including fatty-acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC-1). Instead, the lipid accumulation in transgenic mice was associated with an increased expression of the free fatty acid transporter CD36 and several accessory lipogenic enzymes, such as stearoyl-CoA desaturase-1 (SCD-1) and long chain free fatty acid elongase. Studies using transgenic and knock-out mice showed that PXR is both necessary and sufficient for Cd36 activation. Promoter analyses revealed a DR-3-type of PXR-response element in the mouse Cd36 promoter, establishing Cd36 as a direct transcriptional target of PXR. The hepatic lipid accumulation and Cd36 induction were also seen in the hPXR "humanized" mice treated with the hPXR agonist rifampicin. The activation of PXR was also associated with an inhibition of pro-beta-oxidative genes, such as peroxisome proliferator-activated receptor alpha (PPARalpha) and thiolase, and an up-regulation of PPARgamma, a positive regulator of CD36. The cross-regulation of CD36 by PXR and PPARgamma suggests that this fatty acid transporter may function as a common target of orphan nuclear receptors in their regulation of lipid homeostasis.

Traditional Chinese medicines Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch) activate pregnane X receptor and increase warfarin clearance in rats.

The traditional Chinese medicines (TCMs) are essential components of alternative medicines. Many TCMs are known to alter the expression of hepatic drug-metabolizing enzymes and transporters. The molecular mechanism by which TCMs and/or their constituents regulate enzyme and transporter expression, however, has remained largely unknown. In this report, we show that two TCMs, Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch), and their selected constituents activate the xenobiotic orphan nuclear receptor pregnane X receptor (PXR). Treatment with TCM extracts and the Schisandrol and Schisandrin constituents of Wu Wei Zi induced the expression of drug-metabolizing enzymes and transporters in reporter gene assays and in primary hepatocyte cultures. The affected enzymes and transporters include CYP3A and 2C isozymes and the multidrug resistance-associated protein 2. In transient transfection and reporter gene assays, the Schisandrin constituents of Wu Wei Zi had an estimated EC50 of 2 and 1.25 microM on hPXR and mPXR, respectively. Interestingly, mutations that were intended to alter the pore of the ligand-binding cavity of PXR had species-specific effects on the activities of the individual Schisandrols and Schisandrins. In rats, the administration of Wu Wei Zi and Gan Cao increased the metabolism of the coadministered warfarin, reinforcing concerns involving the safe use of herbal medicines and other nutraceuticals to avoid PXR-mediated drug-drug interactions. Meanwhile, the activation of PXR and induction of detoxifying enzymes provide a molecular mechanism for the hepatoprotective effects of certain TCMs.

Orphan nuclear receptor pregnane X receptor sensitizes oxidative stress responses in transgenic mice and cancerous cells.

Efficient handling of oxidative stress is critical for the survival of organisms. The orphan nuclear receptor pregnane X receptor (PXR) is important in xenobiotic detoxification through its regulation of phase I and phase II drug-metabolizing/detoxifying enzymes and transporters. In this study we unexpectedly found that the expression of an activated human PXR in transgenic female mice resulted in a heightened sensitivity to paraquat, an oxidative xenobiotic toxicant. Heightened paraquat sensitivity was also seen in wild-type mice treated with the mouse PXR agonist pregnenolone-16alpha-carbonitrile. The PXR-induced paraquat sensitivity was associated with decreased activities of superoxide dismutase and catalase, enzymes that scavenge superoxide and hydrogen peroxide, respectively. Paradoxically, the general expression and activity of glutathione S-transferases, a family of phase II enzymes that detoxify electrophilic and cytotoxic substrates, was also induced in the transgenic mice. PXR regulates glutathione S-transferase expression in an isozyme-, tissue-, and sex-specific manner, and this regulation is independent of the nuclear factor-erythroid 2 p45-related factor 2/Kelch-like Ech-associated protein 1 pathway. In cell cultures, expression of activated human PXR sensitizes the cancerous colon and liver cells to the cytotoxic effect of paraquat, which is associated with an increased production of the reactive oxygen species. The current study reveals a novel function of PXR in the mammalian oxidative stress response, and this regulatory pathway may be implicated in carcinogenesis by sensitizing normal and cancerous tissues to oxidative cellular damage.

A pregnane X receptor agonist with unique species-dependent stereoselectivity and its implications in drug development.

Pregnane X receptor (PXR) is an orphan nuclear receptor that regulates the expression of genes encoding drug-metabolizing enzymes and transporters. In addition to affecting drug metabolism, potent and selective PXR agonists may also have therapeutic potential by removing endogenous and exogenous toxins. In this article, we report the synthesis and identification of novel PXR agonists from a library of peptide isosteres. Compound S20, a C-cyclopropylalkylamide, was found to be a PXR agonist with both enantiomer- and species-specific selectivity. S20 has three chiral carbons and was resolved into its two enantiomers. The individual S20 enantiomers exhibited striking mouse/human-specific PXR activation, whereby enantiomer (+)-S20 preferentially activated hPXR, and enantiomer (-)-S20 was a better activator for mPXR. As a human PXR (hPXR) agonist, (+)-S20 was more potent and efficacious than rifampicin. Mutagenesis studies revealed that the ligand binding domain residue Phe305 is critical for the preference for the (-)-S20 enantiomer by the rodent PXR. Treatment of S20 induced the expression of drug-metabolizing enzymes and transporters in reporter gene assays, in primary human hepatocytes, and in "humanized" hPXR transgenic mice. To our knowledge, S20 represents the first compound whose enantiomers have opposite species preference in activating a xenobiotic receptor. The stereoselectivity may be used to guide the development of safer drugs to avoid drug-drug interactions or to achieve human-specific therapeutic effects when a xenobiotic receptor is being used as a drug target.

Dual role of orphan nuclear receptor pregnane X receptor in bilirubin detoxification in mice.

The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are implicated in xenobiotic and endobiotic detoxification, including the clearance of toxic bilirubin. Previous studies have suggested both overlapping and preferential regulation of target genes by these receptors, but the mechanism of cross-talk remains elusive. Here we reveal a dual role of PXR in bilirubin detoxification in that both the loss and activation of PXR led to protection from hyperbilirubinemia induced by bilirubin infusion or hemolysis. The increased bilirubin clearance in PXR-null mice was associated with selective upregulation of detoxifying enzymes and transporters, and the pattern of regulation is remarkably similar to that of transgenic mice expressing the activated CAR. Interestingly, the increased bilirubin clearance and associated gene regulation were absent in the CAR-null or double-knockout mice. In cell cultures, ligand-free PXR specifically suppressed the ability of CAR to induce the multidrug resistance associated protein 2 (MRP2), a bilirubin-detoxifying transporter. This suppression was, at least in part, the result of the disruption of ligand-independent recruitment of coactivator by CAR. In conclusion, PXR plays both positive and negative roles in regulating bilirubin homeostasis, and this provides a novel mechanism that may govern receptor cross-talk and the hierarchy of xenobiotic and endobiotic regulation. PXR is a potential therapeutic target for clinical treatment of jaundice. (HEPATOLOGY 2005;41:497-505.).

Combined loss of orphan receptors PXR and CAR heightens sensitivity to toxic bile acids in mice.

Efficient detoxification of bile acids is necessary to avoid pathological conditions such as cholestatic liver damage and colon cancer. The orphan nuclear receptors PXR and CAR have been proposed to play an important role in the detoxification of xeno- and endo-biotics by regulating the expression of detoxifying enzymes and transporters. In this report, we showed that the combined loss of PXR and CAR resulted in a significantly heightened sensitivity to bile acid toxicity in a sex-sensitive manner. A regimen of lithocholic acid treatment, which was tolerated by wild-type and PXR null mice, caused a marked accumulation of serum bile acids and histological liver damage as well as an increased hepatic lipid deposition in double knockout males. The increased sensitivity in males was associated with genotype-specific suppression of bile acid transporters and loss of bile acid-mediated downregulation of small heterodimer partner, whereas the transporter suppression was modest or absent in females. The double knockout mice also exhibited gene- and tissue-specific dysregulation of PXR and CAR target genes in response to PXR and CAR agonists. In conclusion, althoughthe cross-regulation of target genes by PXR and CAR has b een proposed, the current study represents in vivo evidence of the combined loss of both receptors causing a unique pattern of gene regulation that can be translated into physiological events such as sensitivity to toxic bile acids.

A novel constitutive androstane receptor-mediated and CYP3A-independent pathway of bile acid detoxification.

Cytosolic sulfotransferase (SULT)-mediated sulfation plays an essential role in the detoxification of bile acids and is necessary to avoid pathological conditions, such as cholestasis, liver damage, and colon cancer. In this study, using transgenic mice bearing conditional expression of the activated constitutive androstane receptor (CAR), we demonstrate that activation of CAR is both necessary and sufficient to confer resistance to the hepatotoxicity of lithocholic acid (LCA). Surprisingly, the CAR-mediated protection is not attributable to the expected and previously characterized CYP3A pathway; rather, it is associated with a robust induction of SULT gene expression and increased LCA sulfation. We have also provided direct evidence that CAR regulates SULT expression by binding to the CAR response elements found within the SULT gene promoters. Interestingly, activation of CAR was also associated with an increased expression of the 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2), an enzyme responsible for generating the sulfate donor 3'-phosphoadenosine-5'-phosphosulfate. Analysis of gene knockout mice revealed that CAR is also indispensable for ligand-dependent activation of SULT and PAPSS2 in vivo. Therefore, we establish an essential and unique role of CAR in controlling the mammalian sulfation system and its implication in the detoxification of bile acids.