Deep Brain Stimulation of the Ventral Intermediate Nucleus of the Thalamus in Writer's Cramp: A Case Report.

Background: Globus pallidus internus (GPi) deep brain stimulation (DBS) and thalamotomy are interventions for writer's cramp (WC). Ventralis intermedius nucleus (VIM) DBS is targeted for tremor, however, many aspects of VIM DBS remained underexplored in WC. Case Report: A 62-year-old man with WC underwent DBS. Dystonic tremor improved intraoperatively with ventralis oralis anterior (VoA)/ventral oralis posterior (VoP) and with subthalamic nucleus stimulation; although greatest benefit was obtained with VIM stimulation. Sustained benefit with VIM DBS at ten months post-operative was obtained. Discussion: This case demonstrates an intraoperative approach in target selection and supports benefits of VIM DBS for WC. Highlights: This case highlights the intraoperative approach and clinical effects of VIM DBS in the treatment of medically refractory writer's cramp (WC). We contextualize our results from this case with previous reports of VoA/VoP stimulation for WC.

Predictive lifestyle markers for efficacy of cancer immune checkpoint inhibitors: a commentary.

Lifestyle factors could plausibly modulate the host immune system, the tumor microenvironment and, hence, immune checkpoint inhibitor (ICI) response. As such, these factors should be considered in ICI studies.

Discrete changes in brain volume after deep brain stimulation in patients with Parkinson's disease.

OBJECTIVES: Deep brain stimulation (DBS), targeting the subthalamic nucleus (STN) and globus pallidus interna, is a surgical therapy with class 1 evidence for Parkinson's disease (PD). Bilateral DBS electrodes may be implanted within a single operation or in separate staged surgeries with an interval of time that varies patient by patient. In this study, we used the variation in the timing of implantation from the first to the second implantation allowing for examination of potential volumetric changes of the basal ganglia in patients with PD who underwent staged STN DBS. METHODS: Thirty-two patients with a mean time interval between implantations of 141.8 (±209.1; range: 7-700) days and mean duration of unilateral stimulation of 244.7 (±227.7; range: 20-672) days were included in this study. Using volumetric analysis of whole hemisphere and subcortical structures, we observed whether implantation or stimulation affected structural volume. RESULTS: We observed that DBS implantation, but not the duration of stimulation, induced a significant reduction of volume in the caudate, pallidum, putamen and thalamus ipsilateral to the implanted hemisphere. These findings were not dependent on the trajectory of the implanted electrode nor on first surgery pneumocephalus (0.07%: %Δ for intracranial volume between first and second surgery). In addition, unique regional atrophy differences were evident in each of the structures. CONCLUSION: Our results demonstrate that DBS implantation surgery may affect hemisphere volume at the level of subcortical structures connected to the surgical target.

Striatal and Thalamic Auditory Response During Deep Brain Stimulation for Essential Tremor: Implications for Psychosis.

INTRODUCTION: The P50, a positive auditory-evoked potential occurring 50 msec after an auditory click, has been characterized extensively with electroencephalography (EEG) to detect aberrant auditory electrophysiology in disorders like schizophrenia (SZ) where 61-74% have an auditory gating deficit. The P50 response occurs in primary auditory cortex and several thalamocortical regions. In rodents, the gated P50 response has been identified in the reticular thalamic nucleus (RT)-a deep brain structure traversed during deep brain stimulation (DBS) targeting of the ventral intermediate nucleus (VIM) of the thalamus to treat essential tremor (ET) allowing for interspecies comparison. The goal was to utilize the unique opportunity provided by DBS surgery for ET to map the P50 response in multiple deep brain structures in order to determine the utility of intraoperative P50 detection for facilitating DBS targeting of auditory responsive subterritories. MATERIALS AND METHODS: We developed a method to assess P50 response intraoperatively with local field potentials (LFP) using microelectrode recording during routine clinical electrophysiologic mapping for awake DBS surgery in seven ET patients. Recording sites were mapped into a common stereotactic space. RESULTS: Forty significant P50 responses of 155 recordings mapped to the ventral thalamus, RT and CN head/body interface at similar rates of 22.7-26.7%. P50 response exhibited anatomic specificity based on distinct positions of centroids of positive and negative responses within brain regions and the fact that P50 response was not identified in the recordings from either the internal capsule or the dorsal thalamus. CONCLUSIONS: Detection of P50 response intraoperatively may guide DBS targeting RT and subterritories within CN head/body interface-DBS targets with the potential to treat psychosis and shown to modulate schizophrenia-like aberrancies in mouse models.

Modular auditory decision-making behavioral task designed for intraoperative use in humans.

BACKGROUND: Neurosurgical interventions that require active patient feedback, such as deep brain stimulation surgery, create an opportunity to conduct cognitive or behavioral experiments during the acquisition of invasive neurophysiology. Optimal design and implementation of intraoperative behavioral experiments require consideration of stimulus presentation, time and surgical constraints. We describe the use of a modular, inexpensive system that implements a decision-making paradigm, designed to overcome challenges associated with the operative environment. NEW METHOD: We have created an auditory, two-alternative forced choice (2AFC) task for intraoperative use. Behavioral responses were acquired using an Arduino based single-hand held joystick controller equipped with a 3-axis accelerometer, and two button presses, capable of sampling at 2 kHz. We include designs for all task relevant code, 3D printed components, and Arduino pin-out diagram. RESULTS: We demonstrate feasibility both in and out of the operating room with behavioral results represented by three healthy control subjects and two Parkinson's disease subjects undergoing deep brain stimulator implantation. Psychometric assessment of performance indicated that the subjects could detect, interpret and respond accurately to the task stimuli using the joystick controller. We also demonstrate, using intraoperative neurophysiology recorded during the task, that the behavioral system described here allows us to examine neural correlates of human behavior. COMPARISON WITH EXISTING METHODS: For low cost and minimal effort, any clinical neural recording system can be adapted for intraoperative behavioral testing with our experimental setup. CONCLUSION: Our system will enable clinicians and basic scientists to conduct intraoperative awake and behaving electrophysiologic studies in humans.

Procyanidin B2 3,3(″)-di-O-gallate, a biologically active constituent of grape seed extract, induces apoptosis in human prostate cancer cells via targeting NF-κB, Stat3, and AP1 transcription factors.

Recently, we identified procyanidin B2 3,3(″)-di-O-gallate (B2G2) as most active constituent of grape seed extract (GSE) for efficacy against prostate cancer (PCa). Isolating large quantities of B2G2 from total GSE is labor intensive and expensive, thereby limiting both efficacy and mechanistic studies with this novel anticancer agent. Accordingly, here we synthesized gram-scale quantities of B2G2, compared it with B2G2 isolated from GSE for possible equivalent biological activity and conducted mechanistic studies. Both B2G2 preparations inhibited cell growth, decreased clonogenicity, and induced cell cycle arrest and apoptotic death, comparable to each other, in various human PCa cell lines. Mechanistic studies focusing on transcription factors involved in apoptotic and survival pathways revealed that B2G2 significantly inhibits NF-κB and activator protein1 (AP1) transcriptional activity and nuclear translocation of signal transducer and activator of transcription3 (Stat3) in PCa cell lines, irrespective of their functional androgen receptor status. B2G2 also decreased survivin expression which is regulated by NF-κB, AP1, and Stat3 and increased cleaved PARP level. In summary, we report B2G2 chemical synthesis at gram-quantity with equivalent biological efficacy against human PCa cell lines and same molecular targeting profiles at key transcription factors level. The synthetic B2G2 will stimulate more research on prostate and possibly other malignancies in preclinical models and clinical translation.

Glucuronidation and methylation of procyanidin dimers b2 and 3,3″-di-o-galloyl-b2 and corresponding monomers epicatechin and 3-o-galloyl-epicatechin in mouse liver.

PURPOSE: The 3,3″-di-O-galloyl ester of procyanidin B2 (B2G2) is a component of grape seed extract that inhibits growth of human prostate carcinoma cell lines. In preparation for studies in mice, its hepatic metabolism was examined in vitro and compared to B2 and the corresponding monomers, epicatechin (EC) and 3-O-galloyl-epicatechin (ECG). METHODS: Compounds were incubated with liver microsomes or cytosol containing cofactors for glucuronidation, sulfation or methylation, and products analyzed by liquid chromatography-mass spectrometry (LC-MS). B2G2 was administered orally to mice and plasma analyzed by LC-MS for unmodified procyanidin and metabolites. RESULTS: Glucuronides and methyl ethers of B2 and B2G2 were formed in small amounts. In contrast, EC and ECG were largely or completely converted to glucuronides, sulfates and methyl ethers under the same incubation conditions. B2G2 given orally to mice was partially absorbed intact; no significant metabolites were detected in plasma. CONCLUSIONS: Glucuronidation and methylation of procyanidins B2 and B2G2 occurred but were minor processes in vitro. B2G2 was partially absorbed intact in mice after oral dosing and did not undergo significant metabolism. Unlike the flavanol monomers EC and ECG, therefore, B2G2 bioavailability should not be limited by metabolism. These results paved the way for ongoing pharmacokinetic and efficacy studies.

Dual pre-motor contribution to songbird syllable variation.

Many forms of learning, including songbird vocal learning, rely on the brain's ability to use pre-motor variation and sensory feedback to guide behavior toward a specific target or goal. In the vocal control system of zebra finches (Taeniopygia guttata) the pre-motor mechanisms of vocal variation are thought to be vested primarily in a neural pathway that includes the basal ganglia. A second circuit that includes avian analogues of mammalian pre-motor and motor cortex (the vocal motor pathway) generates the patterned structure of learned adult song. Here, we tested the ability of the basal ganglia pathway to generate pre-motor vocal variation within the spectral and temporal dimensions of zebra finch song structure. In adult birds, ablation of the basal ganglia pathway significantly reduced the spectral and temporal dispersion of individual song syllables, with the exception of syllable pitch, where the reduction was not statistically significant when compared against surgical controls. We found a similar pattern of results using longitudinal comparisons (juvenile vs adult) to isolate the contribution of the basal ganglia pathway to spectral dispersion in populations of developing song syllables--variation in syllable pitch was significantly smaller than in all other measured spectral features. The results indicate that pre-motor variation generated by the basal ganglia pathway may be sufficient to adjust vocal output toward highly acoustically dispersed targets of imitation, but suggest that complete acquisition of the pronounced variation in syllable pitch that characterizes adult song will necessitate a gradual developmental interaction between the basal ganglia and vocal motor pathways.

Metastatic renal cell carcinoma: current standards of care.

Surgical resection remains the cornerstone of treatment for kidney cancer. The cytokines interleukin-2 and interferon-alfa were, at one time, the only available approved systemic therapies for metastatic disease. However, the two agents are toxic when used in high doses and associated with clinical benefit for only a small subset of patients. The approval of targeted agents sunitinib, sorafenib, temsirolimus, and everolimus has offered the possibility of improved outcomes for a greater number of patients. This article reviews surgical options for metastatic renal cell carcinoma as well as clinical trial data on treatment strategies with cytokines and targeted agents.

Fractionation of high molecular weight tannins in grape seed extract and identification of procyanidin B2-3,3'-di-O-gallate as a major active constituent causing growth inhibition and apoptotic death of DU145 human prostate carcinoma cells.

Several studies have documented the anticancer and chemopreventive efficacy of grape seed extract (GSE) against various malignancies including prostate cancer (PCA). GSE is a complex mixture of polyphenols including gallic acid (GA), catechin (Cat), epicatechin (Epi) and procyanidins-oligomers of Cat and Epi, some of which are esterified with GA. Initial studies to identify the GSE components cytotoxic to human prostate carcinoma (DU145) cells demonstrated that GA and several crude chromatographic fractions containing procyanidin dimers and trimers were biologically active. The focus of the present work was to purify 14 procyanidins from the fractions and to identify those with highest activity toward growth inhibition, cell death and apoptosis in DU145 cells. The most active procyanidin was identified by mass spectrometry and enzymatic hydrolysis as the 3,3'-di-O-gallate ester of procyanidin dimer B2 (Epi-Epi). B2-digallate exhibited dose-dependent effects on DU145 cells over the range 25-100 microM, whereas GA exhibited comparable activity at lower doses but was highly lethal at 100 microM. Structure-activity studies demonstrated that all three hydroxyl groups of GA are necessary for activity, but a free carboxylic acid group is not required even though esterification reduced the activity of GA. These data, and the fact that non-esterified B2 exhibited little or no activity, suggest that the galloyl groups of B2-digallate are primarily responsible for its effects on DU145 cells. Taken together, these data identify procyanidin B2-3,3'-di-O-gallate as a novel biologically active agent in GSE that should be studied in greater detail to determine its effects against PCA.

Fractionation of grape seed extract and identification of gallic acid as one of the major active constituents causing growth inhibition and apoptotic death of DU145 human prostate carcinoma cells.

The anti-cancer efficacy of grape seed extract (GSE) against prostate cancer (PCA) via its anti-proliferative, pro-apoptotic and anti-angiogenic activities in both cell culture and animal models have recently been described by us. GSE is a complex mixture containing gallic acid (GA), catechin (C), epicatechin (EC) and several oligomers (procyanidins) of C and/or EC, some of which are esterified to GA. To determine which components are most active against PCA, an ethyl acetate extract of GSE was separated by reverse-phase high-performance liquid chromatography (HPLC) into three fractions. Fraction 1 was far more effective than others in causing growth inhibition and apoptotic death of human PCA DU145 cells. Of the components in this fraction, GA showed a very strong dose- and time-dependent growth inhibition and apoptotic death of DU145 cells, but C and procyanidins B1 (EC-C dimer), B2 (EC-EC dimer) and B3 (C-C dimer) were nearly ineffective. Mechanistic studies demonstrated a strong caspase-9, caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavages by GA in DU145 cells. Procyanidin oligomers eluting in HPLC Fractions 2 and 3 were obtained in larger quantities by separating GSE into eight fractions (I-VIII) on a gel filtration column. All fractions were analyzed by HPLC-UV and negative-ion electrospray mass spectrometry. Fractions I-III contained the active compound GA and inactive components C, EC, B1 and B2. Fraction IV contained other dimers and a dimer-GA ester and was also less active than GSE in DU145 cells. Fractions V-VIII, however, caused significant growth inhibition and apoptosis with the highest activity present in the later fractions that contained procyanidin trimers and GA esters of dimers and trimers. Together, these observations identify GA as one of the major active constituents in GSE. Several procyanidins, however, and especially the gallate esters of dimers and trimers also may be efficacious against PCA and merit further investigation.

Alternatively spliced FGFR-1 isoform signaling differentially modulates endothelial cell responses to peroxynitrite.

Mounting experimental evidence has suggested that the trophic environment of cells in culture is an important determinant of their vulnerability to the cytotoxic effects of reactive oxidants such as peroxynitrite (ONOO(-)). However, acidic fibroblast growth factor (FGF-1)-induced signaling renders some cells more sensitive and others resistant to the cytotoxic effects of ONOO(-). To determine whether alternatively spliced fibroblast growth factor receptor (FGFR-1) isoforms are responsible for this differential response, we have stably transfected FGFR-negative rat brain-derived resistant vessel endothelial cells (RVEC) with human cDNA sequences encoding either FGFR-1 alpha or FGFR-1 beta. FGF-1 treatment of RVEC(R-1 alpha) transfectants enhanced ONOO(-)-mediated cell death in a manner dependent upon FGFR-1 tyrosine kinase, MEK/Erk 1/2 kinase, and p38 MAP kinase activities and independent of Src-family kinase (SFK) activity. FGF-1 treatment of RVEC(R-1 beta) transfectants inhibited the cytotoxic effects of ONOO(-) in a manner dependent upon FGFR-1 tyrosine kinase, MEK/Erk 1/2 kinase, and SFK activities and independent of p38 MAP kinase activity. FGF-1-induced preactivation of both FGFR-1 tyrosine and Erk 1/2 kinases was detected in both RVEC(R-1 alpha) and RVEC(R-1 beta) transfectants. FGF-1-induced preactivation of p38 MAPK was restricted to RVEC(R-1 alpha) transfectants, whereas, ligand-induced preactivation of SFK was limited to RVEC(R-1 beta) transfectants. Collectively, these results both reemphasize the role of extracellular trophic factors and their receptor-mediated signaling pathways during cellular responses to oxidant stress and provide a first indication that the alternatively spliced FGFR-1 isoforms induce differential signal transduction pathways.