Androgen receptor moonlighting in the prostate cancer microenvironment.

Androgen receptor (AR) signaling is vital for the normal development of the prostate and is critically involved in prostate cancer (PCa). AR is not only found in epithelial prostate cells but is also expressed in various cells in the PCa-associated stroma, which constitute the tumor microenvironment (TME). In the TME, AR is expressed in fibroblasts, macrophages, lymphocytes and neutrophils. AR expression in the TME was shown to be decreased in higher-grade and metastatic PCa, suggesting that stromal AR plays a protective role against PCa progression. With that, the functionality of AR in stromal cells appears to deviate from the receptor's classical function as described in PCa cells. However, the biological action of AR in these cells and its effect on cancer progression remains to be fully understood. Here, we systematically review the pathological, genomic and biological literature on AR actions in various subsets of prostate stromal cells and aim to better understand the consequences of AR signaling in the TME in relation to PCa development and progression.

Fish oil has beneficial effects on behavior impairment and oxidative stress in rats subjected to a hepatic encephalopathy model.

Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of liver failure, in which there is injury to brain cells, particularly neurons and glia. Brain cells and their function are greatly influenced by omega-3 polyunsaturated fatty acids, essential components of cell membrane phospholipids in the brain that are crucial to normal function. This study assessed the effect of chronic fish oil (FO) supplementation (rich in omega-3 polyunsaturated fatty acids) on behavior and oxidative stress of Wistar rats subjected to HE due to a liver failure caused by thioacetamide (TAA) intoxication. The FO supplementation started in an early phase of brain development, that is, at the 21st day of life, and extended to the 122th day of life. The results indicated that cognitive function, specifically spatial memory, was markedly affected in the group that received TAA. Most notably, the ill effects caused by TAA administration were counteracted by FO supplementation. In addition to behavioral improvements, FO also promoted reduction in levels of thiobarbituric acid-reactive substances and superoxide dismutase activity in hippocampus and cerebral cortex. In summary, FO protected against spatial memory deficits and oxidative stress caused by HE in rats subjected to liver lesion due to TAA intoxication. Further studies are necessary to understand the mechanism underlying FO behaviors in rats subjected to encephalopathy.

Results by motor cortex stimulation in treatment of focal dystonia, Parkinson's disease and post-ictal spasticity. The experience of the Italian Study Group of the Italian Neurosurgical Society.

Extradural motor cortex stimulation has been employed in cases of Parkinson's disease (PD), fixed dystonia (FD) and spastic hemiparesis (SH) following cerebral stroke. Symptoms of PD are improved by EMCS: results were evaluated on the basis of the UPDRS and statistically analysed. In PD EMCS is less efficacious than bilateral subthalamic nucleus (STN) stimulation, but it may be safely employed in patients not eligible for deep brain stimulation (DBS). The most rewarding effect is the improvement, in severely affected patients, of posture and gait. FD, unresponsive to bilateral pallidal stimulation, has been relieved by EDMS. In SH reduction of spasticiy by EMCS allows improvement of the motor function.

Neurophysiological aspects of chronic motor cortex stimulation.

Chronic motor cortex stimulation is a treatment option for neuropathic drug-resistant pain and possibly associated movement disorders. Preliminary studies suggest the possibility to treat symptoms of Parkinson disease in selected patients. Recently, MCS has been suggested to enhance motor recovery in patients with poststroke hemiparesis. One or more electrodes are placed extradurally over the motor cortex through a burr hole or a small craniotomy, and then connected to a totally implantable neurostimulator. The accurate positioning of the stimulating electrodes over the motor cortex is the key point of the surgical procedure. Motor cortex identification results from the integration of anatomical, neuroradiological, functional, and neurophysiological data, taking into account the huge population variability. Intraoperative neurophysiological mapping of the motor cortex is of paramount importance, in spite of very sophisticated neuroradiological mathematical reconstructions of the motor area. We discuss and compare the different techniques that are utilized by different authors. Moreover, clinical neurophysiology is also helpful in evaluating the results of this neuromodulation procedure and in hypothesizing the mechanisms that are put in play by MCS.

Motor cortex stimulation for chronic non-malignant pain: current state and future prospects.

Motor cortex stimulation (MCS) was proposed by Tsubokawa in 1991 for the treatment of post-stroke thalamic pain. Since that time, the indications have been increased and included trigeminal neuropathic pain and later other types of central and peripheral deafferentation pain. The results reported in the literature are quite good; the mean long-term success rate is 80% in facial pain and 53% in non-facial pain. Our own results are less impressive: 4 of 14 patients (28%) experienced a greater than 40% pain relief, but in 2 of them the effect faded with time. Only few minor complications have been reported. The accurate placement of the epidural electrode over the motor cortex that somatotopically corresponds to the painful area is believed to be essential for pain relief. Predictive factors included the response to pharmacological tests, the relative sparing from the disease process of the cortico-spinal tract and the sensory system, and the analgesic response achieved during the test period of MCS. A possible predictive factor might be a test of repetitive transcranial magnetic stimulation (rTMS) of the motor cortex. MCS may act by rebalancing the control of non-nociceptive sensory inputs over nociceptive afferents at cortical, thalamic, brainstem and spinal level. In addition, it may interfere with the emotional component of nociceptive perception. Biochemical processes involving endorphins and GABA may also be implicated in the mechanism of MCS. It is time for a large multicenter prospective randomized double blind study evaluating not only the effect of MCS on pain (based on the available guidelines for assessment of neuropathic pain), but also the optimal electrode placement and stimulation parameters, and the possible relationship with the response to rTMS. New electrode design and a new generation of stimulators may help in improving the results.

Motor cortex stimulation for Parkinson's disease.

In 2000, Canavero and Paolotti reported the improvement of symptoms in a case of advanced Parkinson disease (PD), following chronic epidural motor cortex stimulation (MCS). In 2002, the same group reported the results obtained in 2 patients with PD. Unilateral MCS proved to be beneficial bilaterally. They concluded that MCS may represent a cost-effective alternative to deep brain stimulation. In 2003, Pagni promoted an Italian Multicenter Study and in June 2005 the results in the first 29 cases were reported. Any symptom of PD could be modulated by MCS, but improvement of different symptoms was variable and unpredictable, with some patients being unresponsive. L-Dopa induced dyskinesias, painful dystonia and motor fluctuations were satisfactorily controlled. In the author's series, 2 patients were unresponsive and 5 patients showed a clinical improvement, particularly evident in the off-medication state; UPDRS-III mean improvement was 30% at 3 months and 22% at 12 months. Quality of life (QOL) also improved. Assessment by the Parkinon's disease quality of life (PDQL) scale showed a mean decrease by 26% at 12 months. No complication or adverse events were observed. These preliminary data indicated the possibility to modulate PD symptoms by MCS. Several unsettled issues remain such as the optimal electrode position, the best stimulation parameters, the usefulness of unilateral versus bilateral stimulation, the prognostic factors for best selection of patients, and the optimal assessment of clinical effects. The mechanisms of MCS may be only the subject of hypothesis.

Extradural motor cortex stimulation (EMCS) for Parkinson's disease. History and first results by the study group of the Italian neurosurgical society.

The preliminary results obtained by the Study Group for Treatment of Involuntary Movements by Extradural Motor Cortex Stimulation (EMCS) of the Italian Neurosurgical Society, are reported. The series includes 16 cases of very advanced Parkinson's Disease (PD), aged 46-81; 15 of them were not eligible for Deep Brain Stimulation. Ten cases have been evaluated at 3-30 months after implantation. Unilateral, sub-threshold extradural motor cortex stimulation (2 8 Volt, 100-400 microsec., 20-120 Hz) by chronically implanted electrodes, relieves, at least partially, but sometime dramatically, the whole spectrum of symptoms of advanced PD. Tremor and rigor bilaterally in all limbs and akinesia are reduced. Standing, gait, motor performance, speech and swallowing are improved. Benefit is marked as far as axial symptoms is concerned. Also the symptoms of Long Term Dopa Syndrome -dyskinesias, motor fluctuations - and other secondary effect of levodopa administration psychiatric symptoms - are improved. Levodopa dosage may be reduced by 50%. The effect seems persistent and does not fade away with time. Improvement ranged, on the basis of the UPDRS scale, from <25% to 75%. There was only one case of complete failure. Quality of life is markedly improved in patients who were absolutely incapable of walking and unable arise out of chair. After stimulation they could walk, even if assistance was necessary. Improvement was observed also in those with disabling motor fluctuation and dyskinesias which could be abolished.

Acrylic polymeric nanospheres for the release and recognition of molecules of clinical interest.

Cross-linked poly(methylmethacrylate-co-methacrylic acid) nanospheres were imprinted with theophylline through template radical polymerisation in diluted acetonitrile solution. This study will focus on the effect of functional monomer nature used (methylmethacrylate and/or methacrylic acid) in the recognition and in the release of template in order to develop a material with combined properties of drug delivery and rebinding for clinical applications. After template extraction the nanospheres showed satisfactory recognition properties (up to 1mg template/g of polymer). Moreover polymers prepared selectively removed theophylline with a theophylline rebinding of 5.1 times higher than that of caffeine, a compound of similar structure. Drug release properties were also satisfactory (up to 95% of loaded theophylline in 7 days).

Comparison of descending volleys evoked by transcranial and epidural motor cortex stimulation in a conscious patient with bulbar pain.

OBJECTIVE: To compare the pattern of activation of motor cortex produced by transcranial magnetic stimulation and epidural electrical stimulation. METHODS: The spinal volleys evoked by transcranial magnetic stimulation and epidural electrical stimulation over the cerebral motor cortex were recorded from an electrode inserted into the cervical epidural space of one conscious subject who also had a cortical epidural electrode over the motor area. The volleys were termed D- and I-waves according to their latency. Magnetic stimulation was performed with a figure-of-eight coil and the induced current flowed either in a postero-anterior (PA) or in latero-medial (LM) direction. RESULTS: At active motor threshold intensity LM magnetic stimulation evoked a D wave whereas PA stimulation evoked an I(1) wave with later I waves being recruited at increasing stimulus intensities. Electrical epidural stimulation evoked both a D wave and I waves. However, the D wave evoked by electrical epidural stimulation had a longer latency than the LM D wave, suggesting either a more proximal site of activation of the pyramidal axon or activation of slightly faster conducting set of corticospinal fibres by LM stimulation. The I3 wave evoked by electrical epidural stimulation also had a longer latency than the PA I3-wave CONCLUSIONS: Epidural stimulation of the motor cortex can produce repetitive excitation of corticospinal neurones. The order of recruitment of the volleys, and the latency of the D and I3 waves may be slightly different to that seen after transcranial magnetic stimulation. SIGNIFICANCE: Our findings suggest that there may be subtle differences in the populations of neurones activated by the two forms of stimulation.

Direct recording of the output of the motor cortex produced by transcranial magnetic stimulation in a patient with cerebral cortex atrophy.

OBJECTIVE: To examine the descending motor activity evoked by transcranial magnetic stimulation (TMS) in a chronic alcoholic patient with a slight atrophy of the peri-central cortex and compare with that observed in neurologically intact subjects. METHODS: EMGs from the first dorsal interosseous (FDI) muscle, and descending activity from an electrode implanted in the high cervical epidural space for relief of pain were recorded after TMS of the hand area of motor cortex. A figure-of-8 coil was used to induce either a posterior-anterior (PA) or a latero-medial (LM) flow across the central sulcus. RESULTS: In intact subjects, LM stimulation evoked the earliest volley, which we termed a D wave. This was followed by later, presumed I waves at intervals of about 1.5 ms. At a stimulus intensity of 120% resting threshold (RMT), up to 5 I waves were seen. PA stimulation rarely evoked D waves at intensities up to 120% RMT, but 3 or 4 I waves were visible in all subjects. The patient had an increased resting threshold, and the descending volleys were dominated by a D wave. I waves were unclear, with two possible small peaks at 5.5 and 7.2 ms. CONCLUSIONS: The lack of I waves in the patient was probably due to an impairment of interneuronal circuitry in the context of the brain damage related to chronic alcohol abuse, and is consistent with a trans-synaptic origin of the I waves in humans. The intact D wave is consistent with the assumption that the D wave represents direct stimulation of the axons of intact corticospinal neurones in the subcortical white matter. The patient's increased RMT reflects the fact that usually multiple descending volleys are needed to discharge resting spinal motoneurones.

Descending spinal cord volleys evoked by transcranial magnetic and electrical stimulation of the motor cortex leg area in conscious humans.

1. Descending corticospinal volleys evoked after transcranial magnetic or electrical stimulation of the leg area of the motor cortex were recorded from an electrode in the spinal epidural space of six conscious patients who had electrodes implanted for treatment of chronic pain, and from one anaesthetised patient undergoing surgery for a spinal tumour. 2. At threshold, the shortest-latency volley (L1 volley) was evoked by stimulation with an anode 2 cm lateral to the vertex. Anodal stimulation at the vertex also elicited a volley at this latency in two patients, but in the other patients the first volley evoked appeared 1-1.3 ms later (L2 volley), at the same latency as the initial volley evoked by magnetic stimulation. High-intensity stimulation of any type could evoke both the L1 and L2 waves as well as later ones (L3, L4, etc.) that had a periodicity of about 1.5 ms. 3. Voluntary contraction increased the amplitude of the L2 and later volleys, but had no effect on the L1 volley. 4. Intracortical inhibition between pairs of magnetic stimuli resulted in clear suppression of the L4 and later waves. The L2 and L3 waves were unaffected. 5. In the anaesthetised patient the L1 volley occurred 1.7 ms later than the volley produced by transmastoid stimulation of the corticospinal pathways in the brainstem. 6. The L1 volley is likely to be a D wave produced by the direct activation of pyramidal axons in the subcortical white matter; the L2 and later volleys are likely to be I waves produced by the trans-synaptic activation of corticospinal neurones. The implication is that electrical stimulation with an anode at the vertex is more likely to evoke I waves preferentially than stimulation over the hand area. A more secure way to ensure D wave activation of corticospinal fibres from the leg area is to place the anode 2 cm lateral to the vertex.

Spinal cord stimulation and early experimental cerebral spasm: the "functional monitoring" and the "preventing effect".

BACKGROUND: Clinical and experimental data on cerebral blood flow (CBF) changes during spinal cord stimulation (SCS) were published since 1986. The aims of the present work are: 1. To find an experimental model of reliable, simple and in vivo monitoring of "early" basilar artery spasm after subarachnoid haemorrhage (SAH) and 2. To investigate the effects of cervical spinal cord stimulation (CSCS) on it. Vasospasm due to SAH is both "acute" and "recurrent". Early spasm occurs within minutes of the SAH. its duration is approximately 1 hour. The need of different morphological and haemodynamic methods to evaluate experimental early spasm is reported. To overcome intracranial surgical manipulations and biological effects of contrast and fixation media we designed a model that allows "in vivo" functional monitoring of basilar blood flow far away from the spasm without direct surgical and chemical interference. Subsequently we investigated the effects of CSCS on the new model of "functional monitoring" of the "early" cerebral vasospasm. METHOD: 29 adult Burgundy rabbits were studied. Group 1: under homeostatic monitoring, "on-line" carotid blood flow (carotid BF) changes produced by SAH in cisterna magna of 12 (plus 5 sham treated) animals were studied from the common carotid artery after external carotid artery occlusion before, during SAH and up to the end of the experiments. All the animals underwent digital subtraction cerebral panangiography (CPA) after SAH obtaining a significant increase of carotid BF only when basilar vasospasm was shown by CPA. Carotid BF increase during basilar vasospasm was defined "functional monitoring" of early spasm. Group 2: Twelve animals wearing a cervical epidural electrode underwent carotid BF "functional monitoring" of early basilar spasm before and during CSCS. FINDINGS: Carotid BF changes during CSCS occurred in 10 animals. No carotid BF changes (i.e. no basilar vasospasm) occurred after SAH up to the end of the experiments in all the stimulated animals. INTERPRETATION: CSCS is able to prevent "early spasm" due to SAH in all the animals studied with the new model of "functional monitoring" described, independently from the occurence and the sign for stimulation-induced carotid BF variations. The role and the limits of reversible functional sympathectomy in mediating the effect of CSCS on early vasospam are discussed.

Spinal cord stimulation in patients with refractory anginal pain and normal coronary arteries.

BACKGROUND: Spinal cord stimulation (SCS) has been shown to be effective in patients with refractory angina and coronary artery disease. No previous study assessed the clinical effects of SCS in patients with refractory angina who present angiographically normal coronary arteries. METHODS: SCS was performed in 7 patients (4 men, 3 women, mean age 59.3 +/- 11 years) with refractory angina and normal coronary arteries. Clinical status was assessed 1 month after SCS device implantation and at a mean follow-up of 11 months (range 2-17 months) by: 1) an estimate of the number of anginal attacks and nitrate consumption in the 2 weeks prior to implantation and to follow-up visits; 2) a score of quality of life by a visual analogic scale; 3) a five-item questionnaire assessing effort angina and satisfaction with treatment; 4) treadmill exercise testing. RESULTS: At the last follow-up the number of anginal episodes (p < 0.001) and nitrate consumption (p < 0.004) were both reduced by SCS. Visual analogic scale score improved from 2.1 +/- 0.98 to 9.0 +/- 0.9 (p < 0.001) at 1 month and to 6.4 +/- 2.3 (p < 0.01) at the last follow-up. Questionnaire analysis showed that mild (p = 0.006) and moderate (p = 0.000) physical activity, as well as patient satisfaction with anginal status (p = 0.000) and with current treatment (p = 0.000) all improved by SCS. Finally, time to 1 mm ST segment depression, time to angina, and exercise duration were all prolonged by SCS. CONCLUSIONS: Our data point out that SCS may considerably improve anginal symptoms and exercise tolerance in a significant number of patients with refractory angina and normal coronary arteries and therefore it should be considered as a valuable treatment option in this group of patients.

Spinal cord stimulation and cerebral blood flow in stroke: personal experience.

Spinal cord stimulation (SCS) can increase cerebral blood flow (CBF) and improve stroke patients. In order to better understand the haemodynamic changes underlining the clinical improvement, we have studied with transcranial Doppler (TCD), SPECT and NIRS 18 patients harbouring a stroke. SPECT Group: An increase of regional CBF during SCS was measured far from the stroke areas in 9 patients, further decrease in CBF was found in 2, no changes in 1. TCD Group: An increase of CBF velocities during SCS was found in 4 patients, no changes in 6, a decrease in 1. NIRS Group: Data consistent with and increase in CBF were obtained during SCS in the only patient undergone such a study. In 6 patients studied with different techniques, data obtained fitted only in 2 patients. In 3 patients no changes in TCD faced with changes in SPECT. In one case an improvement in TCD was evident in the left while an improvement of SPECT was shown in the right site. SCS is a valid therapeutic tool in stroke patient even if, as matter of fact, parallelism between clinical and haemodynamic changes during SCS is not demonstrated in our patients, rising the question on the role of ischemic penumbra in mediating clinical improvement.

Direct demonstration of the effect of lorazepam on the excitability of the human motor cortex.

OBJECTIVES: The present study explored the effects of lorazepam, a benzodiazepine with agonist action at the GABA(A) receptor, on human motor cortex excitability as tested using transcranial magnetic stimulation. METHODS: We recorded directly the descending volley evoked by single and paired transcranial magnetic stimulation from the spinal cord of a conscious subject with a cervical epidural electrode before and after a single oral dose of lorazepam. We evaluated the effects of lorazepam on the descending volleys evoked by a single magnetic stimulation and paired cortical stimulation using the intracortical inhibition paradigm (subthreshold conditioning stimulus) and the short latency intracortical facilitation paradigm (suprathreshold conditioning stimulus). RESULTS: Using a single magnetic stimulus lorazepam decreased the amplitude of the later I waves in the descending volley; this was accompanied by a decrease in the amplitude of the evoked EMG response. Using the intracortical inhibition paradigm lorazepam increased the amount of corticocortical inhibition, particularly at 4 and 5 ms interstimulus intervals. There was no effect on the amount of facilitation observed in the short latency intracortical facilitation paradigm. CONCLUSIONS: The present findings provide direct evidence that lorazepam increases the excitability of inhibitory circuits in the human motor cortex.

Intraoperative motor evoked potentials monitoring in spinal neurosurgery.

Neurological damage may follow even a technically accurate spinal surgery. The intraoperative monitoring of neurological functions put at risk by the operation is a method utilized to correctly identify the topography of neural structures and to avoid surgical insults. SEPs monitoring is 20 year old, and only recently direct motor tract monitoring has become possible. Transcranial electrical motor cortex stimulation with single pulses or with short trains of stimuli and recording of the evoked responses from the spinal epidural space (D-waves) and from limb muscles is a reliable and safe technique for monitoring corticospinal tract activity even under general anesthesia. The method has a solid theoretical experimental background. Its clinical application has demonstrated high sensitivity and specificity. Intraoperative MEPs monitoring is nowadays considered indispensable during spinal neurosurgery.

Inconsistent MRI findings in acute pre-Willisian brain ischemia in rabbit: a useful model?

BACKGROUND: We have investigated a model of "preterminal ischemia" in order A) to assess the MRI findings and the repeatability of the anatomical changes as showed by MRI, and B) to compare the data so obtained with the humans. METHODS: Twenty rabbits were used. Under general anesthesia, the occlusion of 1) the two common carotid arteries (from 2 hours up to 24 hours) was performed in 8 cases, and of 2) the epi-aortic vessels at the aortic arch (from 2 hours up to 4 hours) was performed in 4 cases in general anesthesia. RESULTS: In the vessels occlusion group MRI study showed inconsistent, inconstant, predominantly ill defined, linear and/or spotlike hyperintense deep cerebral alterations, variable in location, unilateral and bilateral in 8 cases. Although in carotid occlusion the damage was already evident within the first two hours, aortic arch occlusion was unable to produce global brain lesional pattern even up to 4 hours. MRI study of the sham operated animals was negative. CONCLUSIONS: The selective vulnerability of mesial deep cerebral structures to hypoxia, different in location from the human's, and the more effective pre-Willisian compensation, suggests to look for different animals when dealing with preterminal ischemic models comparable to the humans' as studied with MRI.

Cervical cord compression due to atypical primary neuroectodermal tumor (PNET): one-stage removal and combined cervical spine stabilization. Case report.

INTRODUCTION: The neuroectodermal tumor of bone constitutes a recently isolated neoplasm, which morphologically resembles the peripheral neuroepithelioma of soft tissue. The diagnosis is made by excluding readily classified small round cell neoplasms and then demonstrating the neural origin of the tumor by means of ultrastructural or immunocytochemical studies. CLINICAL CASE: We report a case of a primary neuroectodermal tumor (PNET) with atypical findings (primary cervical location, massive vertebral body infiltration and isolated neurological symptomatology). Total tumor removal was achieved by means of a one-stage three-level laminectomy (partial C5, total C6-C7), C6 somatectomy, and combined anterior and posterior cervical spinal instrumentation and fusion. CONCLUSIONS: Our case presents three peculiar features: 1) isolated myelopathic symptomatology (first case described); 2) primary isolated massive vertebral cervical involvement with intraspinal epidural extension (first case described); 3) one-stage tumor resection, fusion and instrumentation. Since radiation therapy causes tumor shrinkage but is not curative, radical removal is mandatory even with complex instrumentation procedures.