Surgical outcomes of patients with inferior vena cava leiomyosarcoma.

INTRODUCTION: Primary vascular leiomyosarcomas are incredibly rare and have a poor prognosis. The purpose of this study was to analyze the surgical outcomes of patients with primary inferior vena cava (IVC) leiomyosarcoma. METHODS: We performed a retrospective review of IVC leiomyosarcoma resections performed at a single tertiary care hospital from 2014 to 2023. A total of 13 cases were analyzed, including 10 women and 3 men. The presenting symptoms, tumor characteristics, operative management, postoperative complications, and survival rates were assessed for each patient. RESULTS: The median patient age was 59 years (quartile [Q]1, 52 years; Q3, 68 years). The median tumor size was 7.0 cm (Q1, 6 cm; Q3, 12 cm). The median mitotic rate was 6 per 10 high-power fields (Q1, 2.5; Q3, 15.5). All 13 patients underwent grossly negative tumor resection, with 9 (69%) having microscopically negative margins (R0). No patient had lymph node involvement. The IVCs were managed with ligation in four patients for tumors already occluding the IVC and bovine pericardial patch angioplasty in seven patients or primary repair in two patients for patent IVCs. Concomitant right nephrectomy was performed in seven patients. Left renal vein ligation was performed in three patients, but no left nephrectomies were performed. Significant postoperative complications included one patient with lower extremity compartment syndrome, two patients with severe leg swelling, and one patient with arm swelling. The 30-day mortality rate was zero. Using the Kaplan-Meier product limit method, disease-specific survival was estimated to be 93%. CONCLUSIONS: Surgical resection is a feasible and effective oncologic treatment option for patients with IVC leiomyosarcoma. The IVC can be safely managed by ligation, primary repair, or patch angioplasty, depending on the prior patency of the IVC.

Is there a biochemical basis for purinergic P2X3 and P2X4 receptor antagonists to be considered as anti-seizure medications?

Patients with epilepsy require improved medications. Purinergic receptors were identified as late as 1976 and are slowly emerging as potential drug targets for the discovery of antiseizure medications. While compounds interacting with these receptors have been approved for use as medicines (e.g., gefapixant for cough) and continue to be explored for a number of diseases (e.g., pain, cancer), there have been no purinergic receptor antagonists that have been advanced for epilepsy. There are very few studies on the channel conducting receptors, P2X3 and P2X4, that suggest their possible role in seizure generation or control. However, the limited data available provides some compelling reasons to believe that they could be valuable antiseizure medication drug targets. The data implicating P2X3 and P2X4 receptors in epilepsy includes the role played by ATP in neuronal excitability and seizures, receptor localization, increased receptor expression in epileptic brain, the involvement of these receptors in seizure-associated inflammation, crosstalk between these purinergic receptors and neuronal processes involved in seizures (GABAergic and glutamatergic neurotransmission), and the significant attenuation of seizures and seizure-like activity with P2X receptor blockade. The discovery of new and selective antagonists for P2X3 and P2X4 receptors is ongoing, armed with new structural data to guide rational design. The availability of safe, brain-penetrant compounds will likely encourage the clinical exploration of epilepsy as a disease entity.

Mechanistic and therapeutic relationships of traumatic brain injury and γ-amino-butyric acid (GABA).

Traumatic brain injury (TBI) is a highly prevalent medical condition for which no medications specific for the prophylaxis or treatment of the condition as a whole exist. The spectrum of symptoms includes coma, headache, seizures, cognitive impairment, depression, and anxiety. Although it has been known for years that the inhibitory neurotransmitter γ-amino-butyric acid (GABA) is involved in TBI, no novel therapeutics based upon this mechanism have been introduced into clinical practice. We review the neuroanatomical, neurophysiological, neurochemical, and neuropharmacological relationships of GABA neurotransmission to TBI with a view toward new potential GABA-based medicines. The long-standing idea that excitatory and inhibitory (GABA and others) balances are disrupted by TBI is supported by the experimental data but has failed to invent novel methods of restoring this balance. The slow progress in advancing new treatments is due to the complexity of the disorder that encompasses multiple dynamically interacting biological processes including hemodynamic and metabolic systems, neurodegeneration and neurogenesis, major disruptions in neural networks and axons, frank brain lesions, and a multitude of symptoms that have differential neuronal and neurohormonal regulatory mechanisms. Although the current and ongoing clinical studies include GABAergic drugs, no novel GABA compounds are being explored. It is suggested that filling the gap in understanding the roles played by specific GABAA receptor configurations within specific neuronal circuits could help define new therapeutic approaches. Further research into the temporal and spatial delivery of GABA modulators should also be useful. Along with GABA modulation, research into the sequencing of GABA and non-GABA treatments will be needed.

Endovascular Management of Aortic Stump Blowout by Parallel Grafting and Coil Embolization of Visceral Aorta.

Aortic graft and endograft infections remain a significant source of morbidity and mortality after abdominal aortic aneurysm repair. With graft excision and extra-anatomic bypass, an infrarenal aortic stump remains which can have suture line dehiscence and catastrophic stump blowout. Treatment of this is extremely challenging, especially for severely co-morbid patients who cannot undergo major surgery, or in patients with a hostile abdomen. We present a case study of a 74-year-old male found to have an aortoenteric fistula (AEF). This case broadens operative options for this type of patient population by demonstrating an endovascular technique for addressing aortic stump blowout by parallel grafting and coil embolization of the visceral aorta.

Diversity of thought: public perceptions of genetic testing across ethnic groups in the UK.

Genetic testing is becoming rapidly more accessible to the general populous either through or outside healthcare systems. Few large-scale studies have been carried out to gauge public opinion in this growing area. Here, we undertook the largest cross-sectional study on genetic testing in the UK. The primary purpose of this study is to identify the differences in attitudes toward genetic testing across ethnic groups. A cohort of 6500 individuals from a diverse population completed a 72-item survey in a cross-sectional study. Responses between ethnic minority and white individuals in the UK were compared using a wilcoxon rank-sum and chi-square tests. The white cohort was approximately twice as likely to have taken a genetic test and 13% more had heard about genetic testing before the survey. The ethnic minority cohort appeared more apprehensive about the impact of genetic testing on employability. This study highlights that in the UK, significant differences in opinions regarding genetic testing exist between white individuals and ethnic minority individuals. There is an urgent need to develop more inclusive strategies to equally inform individuals from all backgrounds to avoid disparities in the utilisation of genetic testing.

Effects of Tetrahydrocannabinol and Cannabidiol on Brain-Derived Neurotrophic Factor and Tropomyosin Receptor Kinase B Expression in the Adolescent Hippocampus.

Introduction: Adolescence is an important phase in brain maturation, specifically it is a time during which weak synapses are pruned and neural pathways are strengthened. Adolescence is also a time of experimentation with drugs, including cannabis, which may have detrimental effects on the developing nervous system. The cannabinoid type 1 receptor (CB1) is an important modulator of neurotransmitter release and plays a central role in neural development. Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), are also critical during development for axon guidance and synapse specification. Objective: The objective of this study was to examine the effects of the phytocannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), on the expression of BDNF, its receptor TrkB, and other synaptic markers in the adolescent mouse hippocampus. Materials and Methods: Mice of both sexes were injected daily from P28 to P49 with 3 mg/kg THC, CBD, or a combination of THC/CBD. Brains were harvested on P50, and the dorsal and ventral hippocampi were analyzed for levels of BDNF, TrkB, and several synaptic markers using quantitative polymerase chain reaction, western blotting, and image analyses. Results: THC treatment statistically significantly reduced transcript levels of BDNF in adolescent female (BDNF I) and male (BDNF I, II, IV, VI, and IX) hippocampi. These changes were prevented when CBD was co-administered with THC. CBD by itself statistically significantly increased expression of some transcripts (BDNF II, VI, and IX for females, BDNF VI for males). No statistically significant changes were observed in protein expression for BDNF, TrkB, phospho-TrkB, phospho-CREB (cAMP response element-binding protein), and the synaptic markers, vesicular GABA transporter, vesicular glutamate transporter, synaptobrevin, and postsynaptic density protein 95. However, CB1 receptors were statistically significantly reduced in the ventral hippocampus with THC treatment. Conclusions: This study found changes in BDNF mRNA expression within the hippocampus of adolescent mice exposed to THC and CBD. THC represses transcript expression for some BDNF variants, and this effect is rescued when CBD is co-administered. These effects were seen in both males and females, but sex differences were observed in specific BDNF isoforms. While a statistically significant reduction in CB1 receptor protein in the ventral dentate gyrus was seen, no other changes in protein levels were observed.

Rapid tolerance to behavioral effects of ethanol in rats: Prevention by R-(-)-ketamine.

R-(-)-ketamine has emerged as a potentially improved medication over that of the (S)-isomer (marketed as Spravato for depression). Recent data have suggested (R)-ketamine could have value in the treatment of substance use disorder. The present set of experiments was undertaken to examine whether (R)-ketamine might prevent tolerance development. Rapid ethanol (ETOH) tolerance was studied since racemic ketamine had previously been shown to block this tolerance development in rats. In the present study, male Sprague-Dawley rats were given two large doses of ETOH on Day 1 (2.3 + 1.7 g/kg) and 2.3 g/kg ETOH on Day 2. Animals were tested for effects of 2.3 g/kg ETOH on grip strength, inclined screen performance and rotarod performance on Day 1 with or without (R)-ketamine as a pretreatment. (R)-ketamine alone was tested at the highest dose studied (10 mg/kg) and did not significantly influence any dependent measure. (R)-ketamine (1-10 mg/kg) did not alter the acute effects of ETOH except for enhancing the effects of ETOH on the inclined screen test at 3 mg/kg. Between-subjects analysis documented that tolerance developed to the effects of ETOH only on the measure of grip strength. (R)-ketamine (3 mg/kg) given prior to ETOH on Day 1 exhibited a strong trend toward preventing tolerance development (p = 0.062). The present results extend prior findings on the potential value of (R)-ketamine in substance abuse disorder therapeutics and add to the literature on NMDA receptor blockade as a tolerance-regulating mechanism.

Collection of Frozen Rodent Brain Regions for Downstream Analyses.

As our understanding of neurobiology has progressed, molecular analyses are often performed on small brain areas such as the medial prefrontal cortex (mPFC) or nucleus accumbens. The challenge in this work is to dissect the correct area while preserving the microenvironment to be examined. In this paper, we describe a simple, low-cost method using resources readily available in most labs. This method preserves nucleic acid and proteins by keeping the tissue frozen throughout the process. Brains are cut into 0.5-1.0 mm sections using a brain matrix and arranged on a frozen glass plate. Landmarks within each section are compared to a reference, such as the Allen Mouse Brain Atlas, and regions are dissected using a cold scalpel or biopsy punch. Tissue is then stored at -80 °C until use. Through this process rat and mouse mPFC, nucleus accumbens, dorsal and ventral hippocampus and other regions have been successfully analyzed using qRT-PCR and Western assays. This method is limited to brain regions that can be identified by clear landmarks.