Radosław Rola

Glutamate and its receptors in cancer.

Abstract Glutamate, a nonessential amino acid, is a major bioenergetic substrate for proliferating normal and neoplastic cells on one hand and an excitatory neurotransmitter that is actively involved in biosynthetic, bioenergetic, metabolic, and oncogenic signaling pathways on the other. It exerts its action through a family of receptors consisting of metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs), both of which have been implicated previously in a broad spectrum of acute and chronic neurodegenerative diseases. In this review, we discuss existing data on the role of glutamate as a growth factor for neoplastic cells, the expression of glutamate receptors in various types of benign and malignant neoplasms, and the potential roles that GluRs play in cancer development and progression along with their clinical significance. We conclude that glutamate-related receptors and their signaling pathways may provide novel therapeutic opportunities for a variety of malignant human diseases.

Chemical exchange saturation transfer for Predicting response to stereotactic radiosurgery in human brain metastasis

The purpose of this work was to determine the predictive value of chemical exchange saturation transfer (CEST) metrics in brain metastases treated with stereotactic radiosurgery (SRS).

Prolonged Subdural Infusion of Kynurenic Acid Is Associated with Dose-Dependent Myelin Damage in the Rat Spinal Cord.

Background Kynurenic acid (KYNA) is the end stage metabolite of tryptophan produced mainly by astrocytes in the central nervous system (CNS). It has neuroprotective activities but can be elevated in the neuropsychiatric disorders. Toxic effects of KYNA in the CNS are unknown. The aim of this study was to assess the effect of the subdural KYNA infusion on the spinal cord in adult rats. Methods A total of 42 healthy adult rats were randomly assigned into six groups and were infused for 7 days with PBS (control) or 0.0002 pmol/min, 0.01 nmol/min, 0.1 nmol/min, 1 nmol/min, and 10 nmol/min of KYNA per 7 days. The effect of KYNA on spinal cord was determined using histological and electron microscopy examination. Myelin oligodendrocyte glycoprotein (MOG) was measured in the blood serum to assess a degree of myelin damage. Result In all rats continuous long-lasting subdural KYNA infusion was associated with myelin damage and myelin loss that was increasingly widespread in a dose-depended fashion in peripheral, sub-pial areas. Damage to myelin sheaths was uniquely related to the separation of lamellae at the intraperiod line. The damaged myelin sheaths and areas with complete loss of myelin were associated with limited loss of scattered axons while vast majority of axons in affected areas were morphologically intact. The myelin loss-causing effect of KYNA occurred with no necrosis of oligodendrocytes, with locally severe astrogliosis and no cellular inflammatory response. Additionally, subdural KYNA infusion increased blood MOG concentration. Moreover, the rats infused with the highest doses of KYNA (1 and 10 nmol/min) demonstrated adverse neurological signs including weakness and quadriplegia. Conclusions We suggest, that subdural infusion of high dose of KYNA can be used as an experimental tool for the study of mechanisms of myelin damage and regeneration. On the other hand, the administration of low, physiologically relevant doses of KYNA may help to discover the role of KYNA in control of physiological myelination process.

An in vivo model of anti-inflammatory activity of subdural dexamethasone following the spinal cord injury

Current therapies to limit the neural tissue destruction following the spinal cord injury are not effective. Our recent studies indicate that the injury to the white matter of the spinal cord results in a severe inflammatory response where macrophages phagocytize damaged myelin and the fluid-filled cavity of injury extends in size with concurrent and irreversible destruction of the surrounding neural tissue over several months. We previously established that a high dose of 4mg/rat of dexamethasone administered for 1 week via subdural infusion remarkably lowers the numbers of infiltrating macrophages leaving large amounts of un-phagocytized myelin debris and therefore inhibits the severity of inflammation and related tissue destruction. But this dose was potently toxic to the rats. In the present study the lower doses of dexamethasone, 0.125-2.0mg, were administered via the subdural infusion for 2 weeks after an epidural balloon crush of the mid-thoracic spinal cord. The spinal cord cross-sections were analyzed histologically. Levels of dexamethasone used in the current study had no systemic toxic effect and limited phagocytosis of myelin debris by macrophages in the lesion cavity. The subdural infusion with 0.125-2.0mg dexamethasone over 2 week period did not eliminate the inflammatory process indicating the need for a longer period of infusion to do so. However, this treatment has probably lead to inhibition of the tissue destruction by the severe, prolonged inflammatory process.

Differences in iron and manganese concentration may confound the measurement of myelin from R1 and R2 relaxation rates in studies of dysmyelination

A model of dysmyelination, the Long Evans Shaker (les) rat, was used to study the contribution of myelin to MR tissue properties in white matter. A large region of white matter was identified in the deep cerebellum and was used for measurements of the MR relaxation rate constants, R1 = 1/T1 and R2 = 1/T2, at 7 T. In this study, R1 of the les deep cerebellar white matter was found to be 0.55 ± 0.08 s –1 and R2 was found to be 15 ± 1 s–1, revealing significantly lower R1 and R2 in les white matter relative to wild‐type (wt: R1 = 0.69 ± 0.05 s–1 and R2 = 18 ± 1 s–1). These deviated from the expected ΔR1 and ΔR2 values, given a complete lack of myelin in the les white matter, derived from the literature using values of myelin relaxivity, and we suspect that metals could play a significant role. The absolute concentrations of the paramagnetic transition metals iron (Fe) and manganese (Mn) were measured by a micro‐synchrotron radiation X‐ray fluorescence (μSRXRF) technique, with significantly greater Fe and Mn in les white matter than in wt (in units of μg [metal]/g [wet weight tissue]: les: Fe concentration,19 ± 1; Mn concentration, 0.71 ± 0.04; wt: Fe concentration,10 ± 1; Mn concentration, 0.47 ± 0.04). These changes in Fe and Mn could explain the deviations in R1 and R2 from the expected values in white matter. Although it was found that the influence of myelin still dominates R1 and R2 in wt rats, there were non‐negligible changes in the contribution of the metals to relaxation. Although there are already problems with the estimation of myelin from R1 and R2 changes in disease models with pathology that also affects the relaxation rate constants, this study points to a specific pitfall in the estimation of changes in myelin in diseases or models with disrupted concentrations of paramagnetic transition metals. Copyright

Langerhans cell histiocytosis of the parietal bone with epidural and extracranial expansion – case report and a review of the literature

Langerhans cell histiocytosis is a rare neoplasm that belongs to the histiocytic and dendritic cell neoplasm group according to the 2008 WHO classification. It has been defined as neoplastic proliferation of Langerhans cells that express CD1a and S-100 proteins and have Birbeck granules on the ultrastructural examination. Clinical presentation and behaviour are heterogeneous and can range from a solitary lytic bone lesion with a favourable course to a fatal disseminated leukaemia-like form, with a wide spectrum of intermediate clinical presentations between these two extremes. Here, we present a case report of a solitary calvarial lesion in an adolescent boy along with a review of the literature. Presenting features, initial diagnostic evaluation and treatment protocol of a unifocal monosystemic calvarial location of LCH are presented.

Size and location correlations with higher rupture risk of intracranial aneurysms

AIM The purpose of this study was to investigate the impact of size and location of the intracranial aneurysm on rupture probability. MATERIAL AND METHODS 265 patients with diagnosis of intracranial aneurysms were admitted to the department from January 2012 to December 2013. The characteristic of aneurysm, such as median size, location, single and multiple aneurysms and presentation were retrospectively reviewed using cerebral angiography reports. RESULTS There were 265 patients admitted with the diagnosis of intracranial aneurysms, 193 with single and 72 with multiple aneurysms. Among them there were 197 women (74,3%) and 68 men (25,7%). The total number of aneurysms harbored by the patients with multiple aneurysms were 184. Among all patients 96 had ruptured aneurysm, most of them located at the AComA and the minority of ruptured aneurysms were located at the ICA and MCA, In most cases the size of ruptured aneurysm was smaller than 10 mm. CONCLUSION The location of an aneurysm is an important factor allowing to predict the rupture probability and to plan proper treatment. The size of the aneurysm is also very useful predictor especially correlated with the location but the impact on rupture probability still needs further examination.

The Prophylactic Use of Antiepileptic Drugs in Patients Scheduled for Neurosurgery

Antiepileptic drugs (AEDs) possess diverse mechanisms of action - enhancement of GABA-mediated events, inhibition of glutamate-mediated excitation, blockade of voltage-dependent sodium or calcium channels being the most frequently shared. They are not only used for the symptomatic management of epilepsy but in the treatment of psychiatric or neurologic disorders (e.g. bipolar disorder, neuropathic pain, prophylaxis of migraine). Generally, this group of drugs is also widely used in neurosurgery patients for the prevention of seizure activity and their effectiveness in this regard has been evaluated in this review. There is no controversy as to whether continue AEDs in patients with epilepsy scheduled for neurosurgery. A question arises on whether AEDs may be recommended to non-epileptic neurosurgical patients for the prevention of post-surgery early or late seizures. There are some positive examples indicating that AEDs may reduce the occurrence of preferably early seizures, some results also being positive in the case of late seizure activity. However, there are also many negative data in this regard. The existence of serious adverse effects and a possibility of pharmacokinetic interactions with the concomitant therapy may further complicate the decision on whether to start the prophylactic use of AEDs. In general, the existing evidence does not support the prophylactic use of AEDs, especially in patients who underwent craniotomy/craniectomy for the inhibition of late seizure activity.

Steerable epiduroscope in syringomyelia operations. Preliminary experience

Introduction. A cyst formed within the spinal cord is called syringomyelia or syrinx. Damage to the nerve fibers results in progressive weakness in the arms and legs, loss of sensation particularly of temperature, stiffness and pain. Even though there are known causes of the disease the exact pathological mechanism remains disputable. Management of syringomyelia is based on surgical procedures. In patients with Chiari malformation suboccipital decompression is commonly used. Drainage of the syrinx remains to be an option. When syrinx is separated into cavities by septa they need to be interrupted. This maneuver is commonly done blind with a catheter, but endoscopic vision should increases the safety and effectiveness of the procedure. Aim. The aim of this paper is evaluation of the use of steerable epiduroscope in draining syringomyelia cavities. Material and methods. Multiple cavities of syrix in three patients were connected and drained utilizing a steerable, disposable 1.4 mm diameter Prisma SRL epiduroscope to perforate the septa. Results. Epiduroscope Prisma SRL proved to be a useful instrument providing adequate vision within the syrinx cavity and an inflatable balloon an effective tool to extend the perforation of the septa. The method provided adequate vision within the syrinx cavity and an inflatable balloon was effective in extending the septa fenestration. All procedures achieved the goal. There were no early or late complications encountered. Conclusions. Disposable epiduroscope Prisma SRL of 1.4 mm diameter is a useful and safe tool enhancing the safety and effectiveness of syrinx septotomy in syrinx drainage operations.

Changes in spatial QRS-T angle and QTc interval in patients with traumatic brain injury with or without intra-abdominal hypertension

Introduction Traumatic brain injury (TBI) affects cardiac electrical function, and several extra-cerebral factors, including intra-abdominal pressure (IAP), might further modulate this brain-heart interaction. The purpose of this study was to investigate the impact of TBI, and of increased IAP during TBI, on cardiac electrical function as measured by vectorcardiographic (VCG) variables. Methods Survival, IAP and changes in VCG variables including spatial QRS-T angle and QTc interval were measured in consecutive adult patients with either isolated TBI (iTBI), or with TBI accompanied by polytrauma to the abdomen and/or limbs (pTBI). For all patients, observations were performed just after the admission to the ICU (baseline) and at 24, 48, 72 and 96 h after admission. Results 74 patients aged 45 ± 18 were studied. 44 were treated for iTBI and 30 for pTBI. In all patients, spatial QRS-T angle and QTc interval increased after TBI (p < 0.001), relatively more so in patients with pTBI. Compared to survivors, non-survivors also ultimately had greater widening of the spatial QRS-T angle (p < 0.001), most notably just before foraminal herniation. Wider spatial QRS-T angle and longer QTc interval were also noted in patients with IAP > 12 mmHg (p < 0.001), and with right compared to left hemispheric injury (p < 0.001). ST segment level at the J point decreased 24 and 48 h after TBI in leads I, II, III, aVR, aVF, V1, V2, V3 and V6, and increased in lead V1, especially in non-survivors. Conclusions Spatial QRS-T angle and QTc interval increase after TBI. If foraminal herniation complicates TBI, further widening of the spatial QRS-T angle typically precedes it, followed by notable narrowing thereafter. Increased IAP also intensifies TBI-associated increases in spatial QRS-T angle and QTc interval.