Glucose Influences the Response of Glioblastoma Cells to Temozolomide and Dexamethasone.

OBJECTIVE: Current research indicates that weakness of glucose metabolism plays an important role in silencing of invasiveness and growth of hypoxic tumors such as GBM. Moreover, there are indications that DXM, frequently used in treatment, may support GBM energy metabolism and provoke its recurrence. METHODS: We carried out in vitro experiments on the commercial T98G cell line and two primary GBM lines (HROG02, HROG17) treated with TMZ and/or DXM in physiological oxygen conditions for GBM (2.5% oxygen) and for comparison, in standard laboratory conditions (20% oxygen). The influence of different glucose levels on selected malignancy features of GBM cells-cellular viability and division, dynamic of cell culture changes, colony formation and concentration of InsR have been elevated. RESULTS: Under 2.5% oxygen and high glucose concentration, an attenuated cytotoxic effect of TMZ and intensification of malignancy features in all glioblastoma cell lines exposed to DXM was seen. Furthermore, preliminary retrospective analysis to assess the correlation between serum glucose levels and Ki-67 expression in surgical specimens derived from patients with GBM (IV) treated with radio-chemotherapy and prophylactic DXM therapy was performed. CONCLUSION: The data suggest a link between the in vitro study results and clinical data. High glucose can influence on GBM progression through the promotion of the following parameters: cell viability, dispersal, InsR expression and cell proliferation (Ki-67). However, this problem needs more studies and explain the mechanism of action studied drugs.

Microcrystalline paclitaxel-coated balloon for revascularization of femoropopliteal artery disease: Three-year outcomes of the randomized BIOPAC trial.

The aim of the BIOPAC trial was to determine long-term safety and efficacy of a novel microcrystalline paclitaxel-coated balloon (mcPCB) with a biocompatible polymer as an excipient in the treatment of occlusive femoropopliteal lesions. In this first-in-human prospective controlled randomized trial, 66 patients with femoropopliteal, symptomatic (Rutherford stages 2B to 5) occlusive arterial disease were randomized to either mcPCB (study group) or POBA (plain old balloon angioplasty) (control group) on a 1:1 basis. Late lumen loss (LLL) at 6 months was the primary endpoint of the study and serious adverse events (SAE: death, amputation, repeated revascularization) were considered a composite secondary endpoint. Routine angiography was scheduled for all study subjects at 6-month follow-up; outpatient appointments were scheduled at 12 and 36 months after intervention. At 6 months, the LLL was 63% lower in the mcPCB group compared to the POBA group (0.52 ± 1.2 vs 1.39 ± 1.1 mm; psup < 0.01). Binary restenosis occurred in 23% vs 52% of patients (p = 0.02). At 3 years, the prevalence of SAE was significantly lower in the mcPCB group (33.3 vs 63.3%; p = 0.02), which mainly resulted from a twofold reduction in target vessel revascularization rate (28.6 vs 59.3%; p = 0.02). The difference in mortality was nonsignificant (7.4 vs 14.3%; p = 0.42). Patients with mcPCB were less symptomatic and less likely to adhere to secondary prevention measures. In this pivotal trial, a novel mcPCB proved superior to POBA concerning LLL at 6-month follow-up, and SAE at 12 months. This result was sustained up to 3 years. There was no difference between groups regarding mortality. ClinicalTrials.gov Identifier: NCT02145065.

Imipramine and Venlafaxine Differentially Affect Primary Glial Cultures of Prenatally Stressed Rats.

Here, we examine the effects of prenatal administration of two antidepressants-imipramine (IMI) and venlafaxine (VEN)-on morphology and activity of a primary glial culture. Microglia are targeted by antidepressants used for antenatal depression and are important regulators of central nervous system development. In this study, female Wistar rats were assigned to one of four groups: a control group that received water ad libitum (1), and groups that received additionally once daily either water (2), IMI (10 mg/kg) (3), or VEN (20 mg/kg) (4) by oral gavage from gestation day 7 to 22. Oral gavage administration induced prenatal stress. Cell cultures were obtained from the brains of 1-day-old pups. Prenatal stress caused a disturbance of sensorimotor function in pups. Prenatal stress also produced alterations in the glial cultures, specifically, an increased percentage of microglia in the mixed glial cultures and an increased percentage of dead cells. Moreover, increased levels of IL1-ß, TNF-α, NO, and an increased expression of CX3CR1 mRNA were found in microglia. However, the ratio of Bax/Bcl2 mRNA was reduced. Prenatal stress increased the vulnerability of microglia to lipopolysaccharide (LPS). The mixed glial culture derived from pups exposed to IMI showed greater morphological changes and the highest percentage of microglia. Microglia were characterized by the largest increase in the production of pro-inflammatory cytokines and NO, and the greatest reduction in the expression of CX3CR1 mRNA. Exposure to IMI reduced the effects of LPS on IL-1ß production and Bax/Bcl2 mRNA, and exacerbated the effects of LPS on CX3CR1 mRNA expression. Prenatal administration of VEN induced protective effects on microglia, as measured by all studied parameters. Taken together, our data suggest that, by disturbing microglia function, exposure to even mild forms of chronic prenatal stress may predispose individuals to psychiatric or neurodevelopmental disorders. These data also indicate that chronic mild stress sensitizes microglia to immune challenges, which may lead to enhanced neuronal damage in the embryonic brain. The observed detrimental effects of IMI on microglial activity under conditions of prenatal stress may help to explain the teratogenic effects of IMI reported in the literature.

Tricyclic Antidepressants Modulate Stressed Mitochondria in Glioblastoma Multiforme Cells.

A common feature of solid tumors, including glioblastoma multiforme (GBM), is mitochondrial dysfunction. However, it is reported that the current standard of anti-GBM therapies may potentiate mitochondrial damage and, in effect, support the aggressive character of cancer. As mitochondria are implicated in the modulation of cellular drug sensitivity and chemoresistance mechanisms, activation-stressed mitochondria in GBM cells may represent a new target for anti-GBM therapy that is nontoxic for normal cells. METHODS: As mitochondria are possible targets for antidepressant drugs used as adjuvant therapy in patients with GBM, we examined their influence on mitochondrial volume and activity, reactive oxygen species level, extracellular lactate concentration, and p65 NF-κB gene expression in GBM cells. RESULTS: Our investigation showed, for the first time, that tricyclic antidepressants, imipramine and amitriptyline, partially reverse GBM abnormalities. CONCLUSION: In the light of reported studies, the mitochondrial disturbance observed in glioma cells is a dynamic process that can be reversed or silenced. Moreover, imipramine and amitriptyline are attractive cellular metabolic modulators and can potentially be used to restoring a proper function of mitochondria in GBM cells.

Reversing glioma malignancy: a new look at the role of antidepressant drugs as adjuvant therapy for glioblastoma multiforme.

PURPOSE: The role of glioma stem cells (GSCs) in cancer progression is currently debated; however, it is hypothesised that this subpopulation is partially responsible for therapeutic resistance observed in glioblastoma multiforme (GBM). Recent studies have shown that the current treatments not only fail to eliminate the GSC population but even promote GSCs through reprogramming of glioma non-stem cells to stem cells. Since the standard GBM treatment often requires supplementation with adjuvant drugs such as antidepressants, their role in the regulation of the heterogeneous nature of GSCs needs evaluation. METHODS: We examined the effects of imipramine, amitriptyline, fluoxetine, mirtazapine, agomelatine, escitalopram, and temozolomide on the phenotypic signature (CD44, Ki67, Nestin, Sox1, and Sox2 expression) of GSCs isolated from a human T98G cell line. These drugs were examined in several models of hypoxia (1% oxygen, 2.5% oxygen, and a hypoxia-reoxygenation model) as compared to the standard laboratory conditions (20% oxygen). RESULTS: We report that antidepressant drugs, particularly imipramine and amitriptyline, modulate plasticity, silence the GSC profile, and partially reverse the malignant phenotype of GBM. Moreover, we observed that, in contrast to temozolomide, these tricyclic antidepressants stimulated viability and mitochondrial activity in normal human astrocytes. CONCLUSION: The ability of phenotype switching from GSC to non-GSC as stimulated by antidepressants (primarily imipramine and amitriptyline) sheds new light on the heterogeneous nature of GSC, as well as the role of antidepressants in adjuvant GBM therapy.

Efficacy and safety of cutting balloons for the treatment of obstructive lesions in the internal jugular veins.

BACKGROUND: In this technical note we present the results of endovascular treatment for chronic cerebrospinal venous insufficiency with the use of cutting balloons, with focus on feasibility and safety of these endovascular devices. METHODS: We used cutting balloons during 70 procedures in 65 multiple sclerosis patients presenting with strictures of the internal jugular veins, primarily at the level of jugular valves. These devices were used only in selected cases, following unsuccessful standard balloon angioplasty, and on condition that commercially available devices could be applied (currently they are maximally 8 mm in diameter). RESULTS: In all cases the perioperative course was uneventful, with no serious adverse events. Immediate technical success rate was 94.3%. In four cases (5.7%) cutting-balloon angioplasty alone was unsuccessful and stents were implanted. Primary, assisted primary and secondary patency rates after 6 months were: 94%, 98.5%, and 98.5%, respectively. Follow-up has revealed that out of the remaining 66 angioplasties four procedures failed (failure rate: 6.1%): in two patients stents were implanted, in one patient successful redo cutting-balloon angioplasty was performed, while in another case the treated segment of jugular vein totally occluded and was not feasible to reopen endovascularly. CONCLUSIONS: Cutting balloons can be safely used for the management of stenosed internal jugular veins. These devices can replace stents in the majority of cases, especially if standard balloon angioplasty is insufficient to restore proper outflow. However, the use of cutting balloons in this particular venous territory is limited by the fact that currently only small diameter devices are available.

Transcatheter closure of patent foramen ovale using the internal jugular venous approach.

Transcatheter closure of patent foramen ovale is routinely performed using the transfemoral approach, which is safe and technically easy. Our case represents the rare situation where the procedure needs to be performed using the right internal jugular venous approach. According to our best knowledge this is the first report of a patent foramen ovale closure procedure with access through the internal jugular with necessity to advance the guide wire and transseptal sheath into the left ventricle. Developing alternative techniques of transcatheter patent foramen ovale closure seems to be especially important in rare cases where transfemoral access is unavailable.

Catheter venography for the assessment of internal jugular veins and azygous vein: position statement by expert panel of the International Society for Neurovascular Disease.

This document by an expert panel of the International Society for Neurovascular Disease is aimed at presenting current technique and interpretation of catheter venography of the internal jugular veins, azygous vein and other veins draining the central nervous system. Although interventionalists agree on general rules, significant differences exist in terms of details of venographic technique and interpretations of angiographic pictures. It is also suggested that debatable findings should be investigated using multimodal diagnostics. Finally, the authors recommend that any publication on chronic cerebrospinal venous insufficiency should include detailed description of venographic technique used, to facilitate a comparison of published results in this area.

Chronic cerebrospinal venous insufficiency is unlikely to be a direct trigger of multiple sclerosis.

BACKGROUND: Chronic cerebrospinal venous insufficiency, a vascular pathology affecting the veins draining the central nervous system can accompany multiple sclerosis and is suspected to be involved in its pathogenesis. OBJECTIVE: This study was aimed at exploring a potential role for chronic cerebrospinal venous insufficiency in triggering multiple sclerosis. If it were venous abnormalities responsible for neurological pathology, one should expect negative correlation, i.e. more severe vascular lesions in the patients with early onset of multiple sclerosis. METHODS: Localization and degree of venous blockages in 350 multiple sclerosis patients were assessed using catheter venography. Statistical analysis comprised evaluation of the correlations between severity of venous lesions and patients' age at onset of the disease. RESULTS: We found weak, yet statistically significant positive correlations between patients' age at onset of multiple sclerosis and accumulated and maximal scores of venous lesions. The patients, also those with duration of multiple sclerosis not longer than 5 years, who had their first attack of the disease at younger age, presented with less severe vascular lesions. CONCLUSION: Positive correlation suggests that venous lesions are not directly triggering multiple sclerosis. There should be another factor that initiates pathological processes in the central nervous system.

Multiple sclerosis, an unlikely cause of chronic cerebrospinal venous insufficiency: retrospective analysis of catheter venography.

OBJECTIVES: It is unknown if a relationship exists between multiple sclerosis and chronic cerebrospinal venous insufficiency and if this venous pathology is a causal factor for multiple sclerosis or is a product of a neurological disease. Even so, one should expect that if multiple sclerosis were the cause for venous lesions, then patients with an extended history of the disease would present with a more severe venous pathology. DESIGN: Retrospective analysis of catheter venography of the azygous and internal jugular veins, and duration of clinical history of the disease in multiple sclerosis patients. SETTING: Mono-profile specialist hospital. PARTICIPANTS: 353 multiple sclerosis patients, with duration of the disease: 0.5-41 years (median: 10 years). MAIN OUTCOME MEASURES: We performed statistical analysis of the correlations between the duration of multiple sclerosis and the degree and number of venous lesions revealed using catheter venography. RESULTS: We observed weak, statistically insignificant correlations between the severity of chronic cerebrospinal venous insufficiency and the duration of multiple sclerosis. For the cumulated scores of venous lesions, Spearman and Kendall's tau correlation coefficients were 0.03 and 0.02, respectively; for maximal scores of venous lesions, coefficients were 0.06 and 0.05, while for the number of diseased veins they were 0.007 and 0.006, respectively. Consequently, this analysis did not yield any data supporting the idea that MS is the cause of venous lesions. CONCLUSION: The results of our survey indicated that venous malformations are most likely congenital, and multiple sclerosis had no significant impact on the development of venous pathology.

[Percutaneous angioplasty of the left renal artery in a patient with acute infarction of the left kidney with persistent occlusion of the right renal artery treated with angiotensin converting enzyme inhibitor]. / Przezskórna angioplastyka lewej tetnicynerkowej w przebiegu zawalu lewej nerkiu chorej z przewlekla okluzja prawej tetnicynerkowej w trakcie terapii inhibitoremkonwertazy angiotensyny.

A case of a 67 year-old woman with acute renal syndrome during treatment of angiotensin converting enzyme is presented. In angiography was affirmed acute occlusion left renal artery (LRA) with chronic occlusion right renal artery. Percutaneous angioplasty with implantation stent of the LRA were performed with optimal effect. In this article, the clinical management of patients with angiographically documented acute occlusion renal artery is discussed.

Magnetic Resonance Venography of chronic cerebrospinal venous insufficiency in patients with associated multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic disease with not well understood etiology. Recently, a possible association of MS with compromised venous outflow from the brain and spinal cord has been studied (chronic cerebrospinal venous insufficiency - CCSVI). Angioplasties of internal jugular veins (IJV) and azygous vein (AV) have given promising results, with improvements in patients' clinical status. MATERIAL/METHODS: 830 patients with clinically defined MS were scanned from the level of sigmoid sinuses to the junction with brachiocephalic veins, as well as at the level of AV. T2-weighted, 2D TOF and FIESTA sequences were used. RESULTS: The examination revealed a slower blood flow in IJVs, in 98% of patients: on the right side - in 6%, on the left side - in 15%, on both sides with right-side predominance - in 22%, on both sides with left-side predominance - in 34%, bilaterally with no side predominance - in 19%. In 2%, there was a slower blood flow in IJVs, vertebral veins and subclavian veins and also in the left brachiocephalic vein. Moreover, in 5% of patients there was a decreased blood flow in the azygous vein. CONCLUSIONS: Abnormal flow pattern in IJVs is more common on the left side. Less often it can be found in azygous vein and in brachiocephalic veins. Further research is needed to investigate the significance of CCSVI in MS patients. The protocol we described can be used for most of modern magnetic resonance units.

Ankle-brachial pressure index estimated by laser Doppler in patients suffering from peripheral arterial obstructive disease.

Ankle-brachial index (ABI) measurements are widely used for evaluating the functional state of circulation in the lower limbs. However, there is some evidence that the value of ABI does not accurately reflect the degree of walking impairment in symptomatic patients with peripheral arterial obstructive disease (PAOD). We investigated the diagnostic value of ABI estimated by means of laser Doppler flowmetry (IT) for evaluating limb ischemia. We wanted to know whether laser Doppler could be more sensitive than the Doppler method in predicting walking capacity in patients with stable intermittent claudication. We analyzed a group of 30 patients with intermittent claudication (Fontain II, II/III) who were admitted for reconstructive treatment. There were 21 men and 9 women, aged 46-74 (mean 61) years. All patients underwent the treadmill test, and pain-free walking distances were measured. In each patient, we measured ABI using the two different methods: Doppler ultrasound device (ABI-Doppler) and laser Doppler (ABI-laser Doppler). The claudication distances were 25-200 m (mean 73 +/- 50.2 m). ABI-Doppler was 0.2-0.7 (0.582 +/- 0.195). ABI-laser Doppler measurements were 0.581 (+/-0.218). A correlation was found between ABI-Doppler and claudication distance (r = 0.46, P = 0.009). Also, ABI-laser Doppler values significantly correlated with claudication distances (r = 0.536, P = 0.002). The ABI evaluated by laser Doppler correlated well with claudication distances in patients with PAOD. Comparison of Doppler and laser Doppler measurements used for determining ABI showed that both methods have similar predictive power for walking capacity; however, higher correlation was observed between claudication distances and ABI measured by laser Doppler flowmetry. ABI-laser Doppler measurements are easier, are quicker, and seem to be better suited for noncompliant patients. Further investigation should be undertaken to determine whether laser Doppler is superior to the Doppler method in advanced occlusive arterial disease.

[Aorto-caval fistula as a results of abdominal aortic aneurysm rupture imitating acute renal insufficiency]. / Pekniecie tetniaka aorty brzusznej do zyly glównej dolnej imitujace ostra niewydolnosc nerek.

Aorto-caval fistula (ACF) is a rare complication of abdominal aortic aneurysm. It occurs in 1-6% of cases. The classic diagnostic signs of an ACF (pulsatile abdominal mass with bruit and right ventricular failure) are present only in a half of the patients. The most common diagnostic imaging procedures like ultrasound and computed tomography often are not sufficient enough. This leads to the delay in diagnosis, which has a great impact on the results of operation. We report a case of a patient, who was treated before admission to the Clinic because of azotemia and oliguria suggesting renal failure.