Chemokines and their receptors play important roles in the development of hepatocellular carcinoma

The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their new roles in hepatocellular carcinoma(HCC). The chemokines and their receptors in the microenvironment influence the development of HCCby several aspects including:inflammation,effects on immune cells,angiogenesis,and direct effects on HCC cells. Regarding these aspects,pre-clinical research by targeting the chemokine system has yielded promising data,and these findings bring us new clues in the chemokine-based therapies for HCC.

Effect of Retinoic Acid on Apoptosis and Expression of Fas Proteins in Mouse Blastocysts Cultured In Vitro

Mouse blastocysts were exposed to doses of 0, 1 and 10 μmol/L retinoic acid （RA） for 24 h and the cytotoxic effect of RA on the mouse blastocysts in vitro was observed. FITC-labeled terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling （TUNEL-FITC） assay was employed to stain apoptotic cells and immunohistochemical S-P staining method was used to detect the expression of Fas protein in mouse blastocysts in vitro. The results showed that RA could induce apoptosis and increase the expression of Fas proteins of trophectoderm （TE） and inner cell mass （ICM） cells in blastocysts. Compared with the findings for the control blastocysts, exposure to RA （10 μmol/L） resulted in a more significant apoptosis and higher expression level of Fas proteins （P〈0.01）. It was concluded that RA could induce apoptosis, which may result in a significant reduction in the average number of total cells and the trophectoderm/inner cell mass in blastocysts and an increased expression of Fas protein, suggesting that RA had a cytotoxic effect on the growth and development of early embryos in mice.

Neurotrophic and metabotrophic potential of nerve growth factor and brain-derived neurotrophic factor: Linking cardiometabolic and neuropsychiatric diseases

One of biggest recent achievements of neurobiology is the study on neurotrophic factors. The neurotrophins are exciting examples of these factors. They belong to a family of proteins consisting of nerve growth fac-tor （NGF）, brain-derived neurotrophic factor （BDNF）, neurotrophin-3 （NT-3）, NT-4/5, NT-6, and NT-7. Today, NGF and BDNF are well recognized to mediate a diz-zying number of trophobiological effects, ranging from neurotrophic through immunotrophic and epitheliotro-phic to metabotrophic effects. These are implicated in the pathogenesis of various diseases. In the same vein, recent studies in adipobiology reveal that this tissue is the body’s largest endocrine and paracrine organ producing multiple signaling proteins collectively termed adipokines, with NGF and BDNF being also produced from adipose tissue. Altogether, neurobio-logy and adipobiology contribute to the improvement of our knowledge on diseases beyond obesity such as cardiometabolic （atherosclerosis, type 2 diabetes, and metabolic syndrome） and neuropsychiatric （e.g. , Alzheimer’s disease and depression） diseases. The present review updates evidence for （1） neurotrophic and metabotrophic potentials of NGF and BDNF linking the pathogenesis of these diseases, and （2） NGF- and BDNF-mediated effects in ampakines, NMDA receptor antagonists, antidepressants, selective deacetylase inhibitors, statins, peroxisome proliferator-activated receptor gamma agonists, and purinergic P2X3 recep-tor up-regulation. This may help to construct a novel paradigm in the feld of translational pharmacology of neuro-metabotrophins, particularly NGF and BDNF.

Anti-inflammatory and antipyretic potential of Arbutus andrachne L.methanolic leaf extract in rats

Objective:To explore the anti-inflammatory and antipyretic effects of methanolic leaf extract from Arbutus andrachne and its mechanism of action.Methods:Paw edema was induced by intraplantar(i.pl.)injection ofλ-carrageenan(1%w/v,100μL/paw)while pyrexia was evoked by intraperitoneal(i.p.)injection of 20% baker’s yeast(20 mL/kg body wt)in male Wistar rats.The anti-inflammatory and antipyretic effects of Arbutus andrachne methanolic leaf extract were explored by injecting rats with different doses of the plant extract(150,300,and 600 mg/kg body wt,i.p.).Selective antagonists for transient receptor potential vanilloid-1(TRPV1),cannabinoid receptor 1(CB1),and alpha-2 adrenergic receptor(α2-AR)were used to unravel the extracts’mechanism of action.Blood samples were collected from the heart of rats to measure the levels of interleukin-6(IL-6)and prostaglandin E2(PGE2)by enzyme-linked immunosorbent assay.Results:The extract exhibited potent anti-inflammatory activity by decreasing paw thickness and IL-6 levels.In addition,yeast-evoked pyrexia was attenuated by the extract treatment via TRPV1 and CB1 receptors and a reduction in PGE2 levels.No significant effects were found for α2-AR.Moreover,the rats that received the plant extract demonstrated similar responses to the positive control group.Conclusions:Arbutus andrachne can be a good candidate for treating inflammation and pyrexia and should be further investigated.

Intentional and unintentional impacts of anaesthesia： insights from experiments in pain and injury

The study of brain function in the presence of pain and injury is a rapidly expanding field of experimental research.Clinically,the presence of pain and injury is often accompanied by reports of behavioural change and altered cognition.Even in a highly controlled environment such as the surgical operating theatre postoperative behavioural changes including posttraumatic stress disorder,depression,chronic fatigue,

Loss of the ubiquitin-conjugating enzyme Rad6B disturbs mitochondrial function and cellular homeostasis in mouse skin

Various factors can induce cell degeneration by altering the phenotype and metabolism of cells.Mitochondria play an essential role in cellular homeostasis and function,rendering aging processes highly associated with mitochondrial function and status.Herein,we describe an aging-prone phenotype of murine skin cells caused by depletion of Rad6B(Ube2b),an E2 ubiquitin-conjugating enzyme.In this study,using Masson’s trichrome,we showed that loss of Rad6B causes physiological structure changes in mouse skin with age.In addition,a combination of western blotting experiments,transmission electron microscopy and employment of immunofluorescence staining revealed that depletion of Rad6B was characterized by an abnormal mitochondrial metabolic profile,including decreased mitochondrial biosynthesis and mitochondrial complex activities,increased ROS production and suppressed mitophagy resulting in metabolic disorders.Taken together,these results highlight an important relationship between Rad6B and skin senescence,suggesting that Rad6B plays an indispensable role in maintaining a healthy mitochondrial network and intracellular homeostasis.

CONSTRUCTION AND IDENTIFICATION OF EUKARYOTIC VECTOR EXPRESSING SIRNA SPECIFIC FOR BACE

Objective To generate eukaryotic expression vector of siRNA specific for β-site APP cleaving enzyme(BACE),and detect the interfering effect to the expression of BACE. Methods To clone the BACE targeting siRNA gene by PCR, the PCR products was inserted into the pUC19/EGFP-U6 plasmid. Then it was sub-cloned into the vector named pLXSN. The resultant plasmid was named pLXSN/EGFP-U6-siBACE, it was packaged into AmphoPack-293 cells by calcium phosphate transfection and collected the virus supernatant. The neuroblastoma cells SK-N-SH was infected with the pLXSN/EGFP-U6-siBACE retroviral vector, immunohistochemistry method was used to detect whether the pLXSN/EGFP-U6-siBACE infection can inhibit the expression of BACE of the neuroblastoma cells. Results The pLXSN/EGFP-U6-siBACE retroviral vector was constructed successfully and the siBACE can inhibit the BACE of the neuroblastma effectively. Conclusion The siRNA can inhibit the expression of the BACE gene, the endogenous production of BACE protein was decreased. It will lay the important foundation for using RNA technology to prevent the Alzheimer's disease.

Variations in the bifurcation level of the abdominal aorta, formation level of the inferior vena cava, and insertion level of the left renal vein into the inferior vena cava and their clinical importance in laparoscopic surgery

Objective: It is important to minimize the risk of major vascular injury during pneumoperitoneumestablishment in laparoscopic surgeries for patients with unusual variations in the levels of theabdominal aorta, the inferior vena cava (IVC), and the left renal vein, which will decrease the morbidityand mortality. The study aims to assess the variations regarding the bifurcation level of the abdominalaorta, formation level of the IVC, and insertion level of the left renal vein into the IVC.Methods: This retrospective study was conducted on 100 patients (50 males and 50 females) referred tothe Department of Radiology, Jordan University Hospital for abdomino-pelvic CT with intra-venouscontrast from January 2018 to December 2019. The three vessels were determined on the axial plane,the coronal plane, and the midsagittal plane. The central vertebral body height as well as the distance ofthe level of the point of interest to the upper end plate of the vertebrae were measured. Afterwards, theresults were classified into the following categories, upper end plate, lower end plate, intervertebral disc,upper half, and lower half of the vertebra.Results: The aortic bifurcation was mainly found at the level of the L4 vertebral body (65, 65%). In theremaining cases, the bifurcation was found to be variably located spanning from L3 in 11 (11%) cases to3 (3%) cases at L5. As for the iliocaval junction, the most common site was also at the level of L4 with41 (41%) cases followed by 39 (39%) cases at the level of L5, and 20 (20%) cases at the intervertebral discof L4/L5. The left renal vein most commonly joined the IVC at the level of L1 with 62 (62%) cases followedby 20 (20%) cases at the intervertebral disc T12/L1. There was wide variation in its entry to the IVCspanning from 4 (4%) cases at T12/L1 to 1 (1%) case at L4.Conclusion: The anatomical variation of the major vessels can be found in the normal population.Therefore, sufficient investigation of the anatomical position of these vessels is essential for patientsbefore laparoscopic surgery.

Immunohistochemical Localization of Some Neurotrophic Factors and Their Receptors in the Rat Carotid Body

The carotid body (CB) is a small neural crest-derived organ that registers oxygen and glucose levels in blood and regulates ventilation. The most abundant cell type in the CB glomeruli is glomus or type I cells, which is enveloped by processes of sustentacular or type II cells. Growth and neurotrophic factors have been established as signaling molecules played an important role in the development of the CB. To gain insight whether these signaling molecules are present in the adult rat CB, we examined the expression and cellular localization of some neurotrophic factors and their corresponding receptors in this organ by immunohistochemistry. The results showed the presence of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) as well as p75NTR, tyrosine kinase A receptor (TrkA), tyrosine kinase B receptor (TrkB) and GDNF family receptor alpha1 (GFRα1) in the adult CB. At the light-microscopical level, the immunoreactivity for NGF and both its low-affinity (p75) and high-affinity (TrkA) receptors was detected in the majority of glomus cells and also in a subset of sustentacular cells. BDNF and its receptors, p75 and TrkB, were observed in the glomus cells, too. Remarkably, the immunohistochemical analysis revealed that the neuron-like glomus cells, but not the glial-like sustentacular cells, expressed GDNF and GFRα1. Taken together with prior results, it can be inferred that neurotrophins may be involved in the CB cell differentiation and survival in adulthood, and may exert a potent glomic protective action as well. It is also presumable that GDNF production by glomus cells plays a pivotal role in permitting long-term viability of CB grafts, which permits their potential applicability in cell therapy as a promising tool in neurodegenerative disorders.

Construction and identification of eukaryotic eukaryotic expression plasmid pcdna3.1-bace and its transient expression in cells

Objective： To generate eukaryotic expression vector of pcDNA3.1-BACE and obtain its transient expression in COS-7 cells and high expression in the neuroblastoma SK-N-SH cells. Methods： A 1503 bp cDNA fragment was amplified from the total RNA of human neuroblastoma by RT-PCR method and cloned into plasmid pcDNA3.1. The vector was identified by digestion with restriction enzymes BamHI and XhoI and sequenced by Sanger-dideoxy：mediated chain termination. The expression of BACE gene was detected by immunocytochemistry method. Results： The results showed that the cDNA fragment included 1503 bp total coding region. The recombinant eukaryotic cell expression vector of pcDNA3.1-BACE was constructed successfully, and the sequence of insert was identical to the published sequence. The COS-7 cells and the neuroblastoma SK-N-SH cells transfected with the pcDNA3.1-BACE plasmid expressed high level of BACE protein in cytoplasm. Conclusion： The recombinant plasmid pcDNA3.1-BACE can provide very useful tool for researching the mason of Alzheimer＇s disease and lays the important foundation for preventing the AD laterly.

Histological Characteristics of the Skin and Cuticle of the Wool Fibers in Dubska Pramenka and the Use in Industry

Microscopic analysis of the skin and cuticle of wool fibers in Dubska pramenka show different qualitative parameters. The research study included different parts of the body and the samples of the wool fibers from different regions of the body. Histological description shows difference in the basic structurers of the skin in Dubska pramenka. A very pronounced thin epidermis, while dermis and hypodermis are more developed on the samples from the shoulder. Cornified flakes-cuticle of the root of the tail was of a fine structure, and comified flakes from the rump showed the features of the rough wool fibers. ＂Transitional form of cuticle＂ was dominant on the shoulder. The qualitative parameters have a significant influence on the overall quality of wool in general, and the research contributes to a greater usability value of the wool and development of livestock farming in areas in a broader sense.

Varicocele and infertility: Role of pressure flow dynamics

Varicocele is prevalent in infertile individuals as well as in normal adolescents and adults.It has an increasing trend with growing age.Infertile individuals with varicocele,develop varying degrees of sperm abnormalities that range from mild to severe semen abnormalities,even azoospermia may develop.The main proposed features of these abnormalities are incompetence of one-way valves of the draining veins of testes,that allow backflow of blood into testes.This backflow produces abnormally high intra-testicular pressure and temperature,that has been confirmed by thermography and pressure estimation in various studies.Microsurgical varicocelectomy may reverse the pathologic effects on spermatogenesis in most patients,which points towards the cause and effect relationship of varicocele with testicular damage.We propose that the prolonged effect of gravity might or may not be the initiating factor for varicocele,as in our experience,around 1/4th of hypogonadotropic hypogonadism patients who had no varicocele before treatment,developed varicocele within 3 to 6 mo of treatment with gonadotropins.Occasionally varicocele is produced by"Nutcrackerphenomenon",which is compression of left renal vein between the abdominal aorta and superior mesenteric artery.The deleterious effects of varicocele may develop slowly,causing delayed secondary infertility or rapidly,leading to azoospermia or individual may be spared of damage due to unknown factors that need further research.

The Role of HER2/Neu and BRCA1 Genes in the Diagnosis of Breast Cancer among Sudanese Women

Background: Knowledge of HER2/Neu and BRCA1 Genes might be helpful for development of strategies for decreasing the burden of risk of breast cancer. Therefore, the aim of this study to detect the role of HER2/Neu and BRCA1 Genes expression in diagnosis of breast cancer in Sudanese women. Methodology: A total of 100 tissue samples obtained from patients with breast cancer in addition to 50 tissue samples obtained from patients with benign breast lesions, were detected the expression of HER2/Neu and BRCA1 Genes by Polymerase Chain Reaction (PCR). Results: The prevalence of HER2/Neu and BRCA1 Genes, among cases was 6%, and 10% respectively. Conclusion: HER2/Neu and BRCA1 Genes have a considerable contribution to etiology of breast cancer in Sudan that requires further consideration.

Based on necroptosis identifying the immunological features and prognostic signatures of lung adenocarcinoma

Background:Lung adenocarcinoma is one of the most common pathological types of lung malignant tumor with high morbidity and mortality.Long non-coding RNAs are gradually recognized to play crucial roles in tumor occurrence and development.Necroptosis is a newly established way for cell programmed death,undertaking essential roles in anti-tumor.Therefore,identifying necroptosis-related l ong non-coding RNAs and based on them to evaluate the signatures of l ung adenocarcinoma is essential for patients’survival prediction and therapy.Methods:We collected data from the public database and performed the least absolute shrinkage to construct a 13-lncRNAs prognostic model.Based on the Consensus Clustering,ESTIMATE,CIRERSORT,and weighted gene co-expression network analysis to identify the immune signatures.Results:This study identified a 13-lncRNAs prognostic model.The model’s prediction accuracy was evaluated by receiver operating characteristic and independent-prognosis analysis;besides,a Gene Expression Omnibus dataset was applied for external validation.Furthermore,we analyzed the immune features of subgroups in multiple dimensions.A consensus clustering analysis based on the 41 genes was implemented to separate lung adenocarcinoma patients into two subgroups.We compared the features of subgroups in multiple dimensions,including survival,immune microenvironment,immune cells infiltration and gene co-expression network analysis.Conclusion:W e established a prognosis necroptosis-related risk model to predict lung adenocarcinoma patients’prognosis and systematically understood the correlation between immune and necroptosis.This study can applicate in clinical to predict the prognosis of lung adenocarcinoma patients and provide new insight into lung adenocarcinoma immune therapy.

Uterine receptivity and the plasma membrane transformation

This review begins with a brief commentary on the diversity of placentation mechanisms, and then goes on to examine the extensive alterations which occur in the plasma membrane of uterine epithelial cells during early pregnancy across species. Ultrastructural, biochemical and more general morphological data reveal that strikingly common phenomena occur in this plasma membrane during early pregnancy despite the diversity of placental types-from epitheliochorial to hemochorial, which ultimately form in different species. To encapsulate the concept that common morphological and molecular alterations occur across species, that they are found basolaterally as well as apically, and that moreover they are an ongoing process during much of early pregnancy, not just an event at the time attachment, the term 'plasma membrane transformation' is suggested which also emphasises that alterations in this plasma membrane during early pregnancy are key to uterine receptivity.

Effects of acupuncture stimulation on brain activation induced by cue-elicited alcohol craving

Acupuncture has been shown to be effective on alcohol use disorder.However,the underlying mechanism remains poorly understood.To investigate the effects of Shenmen(HT7)acupoint on brain activation induced by cue-elicited alcohol craving,30 right-handed healthy light to moderate alcohol drinkers were recruited from the community.They were randomly assigned to undergo acupuncture either at HT7(experimental acupoint,n=15)or Jingqu(LU8,control acupoint,n=15)acupoints.This randomized controlled study was performed in Daegu Haany University and Daegu-Gyeongbuk Medical Innovation Foundation,Republic of Korea.Recruitment and data collection were conducted from December 2018 to May 2019.The results showed that after acupuncture at HT7 acupoint,the activation of orbitofrontal cortex and dorsolateral prefrontal cortex was greatly increased,while the activation of dorsolateral prefrontal cortex was obviously reduced,and subject's craving for alcohol was reduced when he/she seeing alcohol-related video clips involving various alcohols(beer,wine,or soju)or drinking scenarios.Acupuncture at HT7 more greatly reduced subject's alcohol cravings than acupuncture at LU8 acupoint.These findings suggest that acupuncture can improve the self-control of mild to moderate social drinkers through the activation of the orbitofrontal cortex and dorsolateral prefrontal cortex,thereby reducing the craving for alcohol.The study protocol was approved by the Institutional Review Board of Daegu Haany University Korean Medicine Hospital,Republic of Korea(approval No.DHUMC-D-18026-PRO-02)on November 30,2018.

Renaldopaminergic system:Pathophysiological implications andclinical perspectives

Fluid homeostasis, blood pressure and redox balance in the kidney are regulated by an intricate interaction between local and systemic anti-natriuretic and natriuretic systems. Intrarenal dopamine plays a central role on this interactive network. By activating specifc receptors, dopamine promotes sodium excretion and stimulates anti-oxidant and anti-inflammatory pathways. Different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome, hypertension and renal infammation, can be associated with impaired action of renal dopamine including alteration in biosynthesis, dopamine receptor expression and signal transduction. Given its properties on the regulation of renal blood fow and sodium excretion, exogenous dopamine has been postulated as a potential therapeutic strategy to preventrenal failure in critically ill patients. The aim of this review is to update and discuss on the most recent findings about renal dopaminergic system and its role in several diseases involving the kidneys and the potential use of dopamine as a nephroprotective agent.

Prodigious therapeutic effects of combining mesenchymal stem cells with magnetic nanoparticles

Mesenchymal stem cells(MSCs)have gained wide-ranging reputation in the medical research community due to their promising regenerative abilities.MSCs can be isolated from various resources mostly bone marrow,Adipose tissues and Umbilical cord.Huge advances have been achieved in comprehending the possible mechanisms underlying the therapeutic functions of MSCs.Despite the proven role of MSCs in repairing and healing of many disease modalities,many hurdles hinder the transferring of these cells in the clinical settings.Among the most reported problems encountering MSCs therapy in vivo are loss of tracking signal post-transplantation,insufficient migration,homing and engraftment postinfusion,and undesirable differentiation at the site of injury.Magnetic nanoparticles(MNPs)have been used widely for various biomedical applications.MNPs have a metallic core stabilized by an outer coating material and their magnetic properties can be modulated by an external magnetic field.These magnetic properties of MNPs were found to enhance the quality of diagnostic imaging procedures and can be used to create a carrying system for targeted delivery of therapeutic substances mainly drug,genes and stem cells.Several studies highlighted the advantageous outcomes of combining MSCs with MNPs in potentiating their tracking,monitoring,homing,engraftment and differentiation.In this review,we will discuss the role of MNPs in promoting the therapeutic profile of MSCs which may improve the success rate of MSCs transplantation and solve many challenges that delay their clinical applicability.

Protective effects of components of the Chinese herb grassleaf sweetflag rhizome on PC12 cells incubated with amyloid-beta42

The major ingredients of grassleaf sweetflag rhizome are β-asarone and eugenol, which can cross the blood-brain barrier and protect neurons. This study aimed to observe the neuroprotective effects and mechanisms of β-asarone and eugenol, components of the Chinese herb grassleaf sweetflag rhizome, on PC12 cells. First, PC12 cells were cultured with different concentrations（between 1 × 10–10 M and 1 × 10–5 M） of β-asarone and eugenol. Survival rates of PC12 cells were not significantly affected. Second, PC12 cells incubated with amyloid-beta42, which reduced cell survival, were cultured under the same conditions（1 × 10–6 M β-asarone and eugenol）. The survival rates of PC12 cells significantly increased, while expression levels of the m RNAs for the pro-apoptotic protein Bax decreased, and those for the anti-apoptotic protein Bcl m RNA increased. In addition, the combination of β-asarone with eugenol achieved better results than either component alone. Our experimental findings indicate that both β-asarone and eugenol protect PC12 cells through inhibiting apoptosis, and that the combination of the two is better than either alone.

Morphological characteristics of the lumbosacral spinal cord urogenital center in Sprague Dawley rats

BACKGROUND： Studies have demonstrated that selective innervation of the sacral nerve tract to the bladder plays an important role in bladder functional reconstruction following spinal cord injury. However, there are very few studies reporting detailed morphological characteristics of urogenital center and lumbosacral nerve roots. OBJECTIVE： To analyze the spinal cord segment of the lumbosacral spinal cord urogenital center, and to observe morphological characteristics. DESIGN, TIME AND SETTING： A neuroanatomical study was performed at the Laboratory of Neuroanatomy, Peking University Health Science Center between September 2007 and March 2008. MATERIALS： Horseradish peroxidase-conjugated cholera toxin B subunit （CB-HRP） was purchased from Sigma, USA; surgical microscope was purchased from Zhenjian Zhongtian Optical Instrument, Jiangsu Province, China; BCL-420 biological and functional experimental system was purchased from Taimeng Science and Technology, Sichuan Province, China. METHODS： A total of 36 adult, Sprague Dawley rats were randomly assigned to groups A （n = 10）, B （n = 10）, C （n = 10）, and D （n = 6）. CB-HRP （3%, 10-15 μL） was injected into the bladder detrusor muscle （group A）, external urethral sphincter （group B）, and perineal muscles （group C）, respectively. Rats in group D were not given any treatments. MAIN OUTCOME MEASURES： At 72 hours after CB-HRP injection, CB-HRP-positive neurons were analyzed in lumbosacral segments using 3, 3＇, 5, 5＇-tetramethylbenzidine staining and an Olympus optic microscope, while anatomical structures in the respective spinal nerve tract were observed using a surgical microscope. RESULTS： CB-HRP-positive neurons were distributed in the L6-S1 segments of the spinal cord, and neurons primarily innervating the bladder detrusor muscle were located at the sacral parasympathetic nucleus and the intermediolateral nucleus. In addition, neurons that primarily innervate the external urethral sphincter and perineal muscles were observed in the ventrolateral portion （Onuf＇s nucleus）. The lumbar-sacral nerve roots were composed of varying nerve tracts, Le., they were typically divided into 1-2 sub-bundles, and the sub-bundles were then divided into 2-3 tiny bundles. There were extensive fibro-connections between the rootlets. CONCLUSION： The urogenital center in Sprague Dawley rats was located in the L6 -S1 segments of the spinal cord, and the rootlets were clearly observed. Therefore, this rat experimental model could be utilized for highly selective anterior/posterior rhizotomy.