Optimizing the selection of the endoscopically assisted supracerebellar transtentorial approach to the medial temporo-occipital region: Clinical application of one novel grid coordinate system.

The endoscopically assisted supracerebellar transtentorial (eSCTT) approach is advocated for managing pathologies of the medial temporo-occipital region, but quantitative analysis is currently lacking. The aims of this study were to establish a grid coordinate system on the tentorium to model the anatomical relationship between medial temporo-occipital region pathology and the slope of the tentorium, and then to compare the paramedian eSCTT and extreme-lateral eSCTT approaches quantitatively. Bilateral paramedian and extreme-lateral eSCTT approaches were used to dissect three adult cadaveric heads anatomically. A grid coordinate system was established on the tentorium, and the angles of attack and depth of the surgical corridor of each coordinate point were obtained so that the two eSCTT approaches could be compared statistically. The measurements were then analyzed to determine the condition for selecting each eSCTT approach, and its clinical feasibility was assessed in three patients with large tumors in the medial temporo-occipital region. For coordinate points where the X-coordinate on the grid coordinate system was 1 cm outside the apex of the tentorium, the paramedian eSCTT approach had a significantly wider angle of attack and shorter depth of surgical corridor than the extreme-lateral eSCTT approach. In contrast, the extreme-lateral eSCTT approach was better for coordinate points where the Y-coordinate on the grid coordinate system was 1 cm in front of the apex of the tentorium. The long axis of each patient's tumor was projected on to the tentorium and its corresponding coordinate points were used to match the more appropriate eSCTT approach. Preliminary results for three patients treated with the eSCTT approach for large tumors in the medial temporo-occipital region were encouraging. When the eSCTT approach is applied to manage a large tumor of the medial temporo-occipital region, assessment of the long axis of the tumor and knowledge of the selective condition for each eSCTT approach can help in clinical decision-making.

Regulation of glycolysis-derived L-lactate production in astrocytes rescues the memory deficits and Aß burden in early Alzheimer's disease models.

Aberrant energy metabolism in the brain is a common pathological feature in the preclinical Alzheimer's Disease (AD). Recent studies have reported the early elevations of glycolysis-involved enzymes in AD brain and cerebrospinal fluid according to a large-scale proteomic analysis. It's well-known that astrocytes exhibit strong glycolytic metabolic ability and play a key role in the regulation of brain homeostasis. However, its relationship with glycolytic changes and cognitive deficits in early AD patients is unclear. Here, we investigated the mechanisms by which astrocyte glycolysis is involved in early AD and its potential as a therapeutic target. Our results suggest that Aß-activated microglia can induce glycolytic-enhanced astrocytes in vitro, and that these processes are dependent on the activation of the AKT-mTOR-HIF-1α pathway. In early AD models, the increase in L-lactate produced by enhanced glycolysis of astrocytes leads to spatial cognitive impairment by disrupting synaptic plasticity and accelerating Aß aggregation. Furthermore, we find rapamycin, the mTOR inhibitor, can rescue the impaired spatial memory and Aß burden by inhibiting the glycolysis-derived L-lactate in the early AD models. In conclusion, we highlight that astrocytic glycolysis plays a critical role in the early onset of AD and that the modulation of glycolysis-derived L-lactate by rapamycin provides a new strategy for the treatment of AD.

Serotonergic Regulation of Synaptic Dopamine Levels Mitigates L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson's Disease.

Background: The serotonin (5-HT) system can manipulate the processing of exogenous L-DOPA in the DA-denervated striatum, resulting in the modulation of L-DOPA-induced dyskinesia (LID). Objective: To characterize the effects of the serotonin precursor 5-hydroxy-tryptophan (5-HTP) or the serotonin transporter (SERT) inhibitor, Citalopram on L-DOPA-induced behavior, neurochemical signals, and underlying protein expressions in an animal model of Parkinson's disease. Methods: MitoPark (MP) mice at 20 weeks of age, subjected to a 14-day administration of L-DOPA/Carbidopa, displayed dyskinesia, referred to as LID. Subsequent investigations explored the effects of 5-HT-modifying agents, such as 5-HTP and Citalopram, on abnormal involuntary movements (AIMs), locomotor activity, neurochemical signals, serotonin transporter activity, and protein expression in the DA-denervated striatum of LID MP mice. Results: 5-HTP exhibited duration-dependent suppressive effects on developing and established LID, especially related to abnormal limb movements observed in L-DOPA-primed MP mice. However, Citalopram, predominantly suppressed abnormal axial movement induced by L-DOPA in LID MP mice. We demonstrated that 5-HTP could decrease L-DOPA-upregulation of DA turnover rates while concurrently upregulating 5-HT metabolism. Additionally, 5-HTP was shown to reduce the expressions of p-ERK and p-DARPP-32 in the striatum of LID MP mice. The effect of Citalopram in alleviating LID development may be attributed to downregulation of SERT activity in the dorsal striatum of LID MP mice. Conclusions: While both single injection of 5-HTP and Citalopram effectively mitigated the development of LID, the difference in mitigation of AIM subtypes may be linked to the unique effects of these two serotonergic agents on L-DOPA-derived DA and 5-HT metabolism.

Yangonin, one of the kavalactones isolated from Piper methysticum G. Forst, acts through cannabinoid 1 (CB1) receptors to induce an intrathecal anti-hyperalgesia.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper methysticum G. Forst (Piperaceae) is traditionally consumed in Polynesian culture. The roots are used to produce an entheogenic drink and traditional medicine with sedative and anxiolytic properties. There is also evidence that it functions as a pain reliever. Kavalactones, its main active ingredients, exhibit psychoactive effects on the central nervous system. However, the active ingredients and pharmacological mechanisms underlying the analgesic effect of kavalactones are unclear. AIM OF THE STUDY: This study investigated the effects of kavain and yangonin on nociception, inflammatory hyperalgesia, and neuropathic mechanical allodynia at the spinal level. MATERIALS AND METHODS: Male Sprague-Dawley rats were administered kavain and yangonin (27.14 and 19.36 nmol/rat) via intrathecal injection. Tail-flick tests were performed to evaluate the anti-nociceptive properties. The efficacy of kavain and yangonin on inflammatory hyperalgesia was examined using a plantar test in rats with carrageenan-induced paw inflammation. The von Frey test was used to assess mechanical allodynia induced by partial sciatic nerve ligation. RESULTS: Intrathecal injection of yangonin demonstrated a relatively potent anti-nociceptive effect and attenuated carrageenan-induced hyperalgesia. These effects were completely reversed by the co-administration of PF 514273, a cannabinoid 1 (CB1) receptor antagonist. However, yangonin did not affect mechanical allodynia at the spinal level. Kavain, another abundant kavalactone, did not affect nociception, hyperalgesia, or mechanical allodynia at the spinal level. CONCLUSIONS: Overall, our study demonstrated that yangonin exerts anti-nociception and anti-inflammatory hyperalgesia effects via CB1 receptors at the spinal level. We identified a single kavalactone, yangonin, extracted from kava as a promising treatment for pain.

Attenuating mitochondrial dysfunction and morphological disruption with PT320 delays dopamine degeneration in MitoPark mice.

BACKGROUND: Mitochondria are essential organelles involved in cellular energy production. Changes in mitochondrial function can lead to dysfunction and cell death in aging and age-related disorders. Recent research suggests that mitochondrial dysfunction is closely linked to neurodegenerative diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonist has gained interest as a potential treatment for Parkinson's disease (PD). However, the exact mechanisms responsible for the therapeutic effects of GLP-1R-related agonists are not yet fully understood. METHODS: In this study, we explores the effects of early treatment with PT320, a sustained release formulation of the GLP-1R agonist Exenatide, on mitochondrial functions and morphology in a progressive PD mouse model, the MitoPark (MP) mouse. RESULTS: Our findings demonstrate that administration of a clinically translatable dose of PT320 ameliorates the reduction in tyrosine hydroxylase expression, lowers reactive oxygen species (ROS) levels, and inhibits mitochondrial cytochrome c release during nigrostriatal dopaminergic denervation in MP mice. PT320 treatment significantly preserved mitochondrial function and morphology but did not influence the reduction in mitochondria numbers during PD progression in MP mice. Genetic analysis indicated that the cytoprotective effect of PT320 is attributed to a reduction in the expression of mitochondrial fission protein 1 (Fis1) and an increase in the expression of optic atrophy type 1 (Opa1), which is known to play a role in maintaining mitochondrial homeostasis and decreasing cytochrome c release through remodeling of the cristae. CONCLUSION: Our findings suggest that the early administration of PT320 shows potential as a neuroprotective treatment for PD, as it can preserve mitochondrial function. Through enhancing mitochondrial health by regulating Opa1 and Fis1, PT320 presents a new neuroprotective therapy in PD.

Intrathecal injections of angiotensin IV and oxytocin conjugates induce antihyperalgesia and antiallodynia in both sexes of rats.

Our previous studies have established that intrathecal oxytocin (OT) and angiotensin IV (Ang IV) injections induce antihyperalgesia and antiallodynia in rodents. Ang IV, a renin-angiotensin system hexapeptide, acts as an endogenous inhibitor that inhibits the oxytocin-degrading enzyme insulin-regulated aminopeptidase (IRAP). The pain inhibitory effects by Ang IV were found to be through its inhibition on IRAP to potentiate the effect of OT. However, these effects were found to be with a significant sex difference, which could be partially due to the higher expression of IRAP at the spinal cords of female. Therefore, we synthesized Ang IV and OT conjugates connected with a peptide bond and tested for their effects on hyperalgesia and allodynia. Carrageenan-induced hyperalgesia and partial sciatic nerve ligation (PSNL) were performed using rat models. Conjugates Ang IV-OT (Ang IV at the N-terminal) and OT-Ang IV (OT at the N-terminal) were synthesized and intrathecally injected into male and female rats. Our results showed that Ang IV-OT exhibited prominent antihyperalgesia in male rats, particularly during hyperalgesia recovery, whereas OT-Ang IV was more effective during development stage. Ang IV-OT showed clear antihyperalgesia in female rats, but OT-Ang IV had no significant effect. Notably, both conjugates alleviated neuropathic allodynia in male rats; however, OT-Ang IV had no effect in female rats, whereas Ang IV-OT induced significant antiallodynia. In conclusion, Ang IV-OT has greater therapeutic potential for treating hyperalgesia and allodynia than OT-Ang IV. Its effects were not affected by sex, unlike those of OT and OT-Ang IV, extending its possible clinical applications.

Endoscopic transorbital decompression for traumatic superior orbital fissure syndrome: from cadaveric study to clinical application.

PURPOSE: The endoscopic endonasal approach (EEA) is a minimally invasive and promising modality for treating traumatic superior orbital fissure (SOF) syndrome (tSOFS). Recently, the endoscopic transorbital approach (ETOA) has been considered an alternative method for reaching the anterolateral skull base. This study accessed the practicality of using the ETOA to treat SOF decompression using both cadaveric dissection and clinical application. METHODS: Bilateral anatomic dissections were performed on four adult cadaveric heads using the ETOA and EEA to address SOF decompression. The ETOA procedure for SOF decompression is described, and the extent of SOF decompression was compared between the ETOA and EEA. The clinical feasibility of the ETOA for treating SOF decompression was performed in two patients diagnosed with tSOFS. RESULTS: ETOA allowed for decompression over the lateral aspect of the SOF, from the meningo-orbital band superolaterally to the maxillary strut inferomedially. By contrast, the EEA allowed for decompression over the medial aspect of the SOF, from the lateral opticocarotid recess superiorly to the maxillary strut inferiorly. In both patients treated using the ETOA and SOF decompression, the severity of ophthalmoplegia got obvious improvement. CONCLUSIONS: Based on the cadaveric findings, ETOA provided a feasible access pathway for SOF decompression with reliable outcomes, and our patients confirmed the clinical efficacy of the ETOA for managing tSOFS.

Transorbital transposition of the temporoparietal fascia flap to reconstruct the skull base defects: A preclinical study with comparison to the transpterygoid transposition.

BACKGROUND: Transpterygoid transposition of the temporoparietal fascia flap (TPFF) is a feasible selection for ventral skull base defect (VSBD) reconstruction, but not anterior skull base defect (ASBD) reconstruction, after expanded endoscopic endonasal approach (EEEA). The goal of this study is to introduce the transorbital transposition of the TPFF for skull base defects reconstruction after EEEA, and make quantitative comparison between the transpterygoid transposition and transorbital transposition. METHODS: Cadaveric dissections were performed in five adult cadaveric heads with creating three transporting corridors bilaterally, encompassing superior transorbital corridor, inferior transorbital corridor, and transpterygoid corridor. For each transporting corridor, the minimum necessary length of the TPFF for skull base defects reconstruction was measured. RESULTS: The areas of ASBD and VSBD were 1019.63 ± 176.32 mm2 and 572.99 ± 126.21 mm2 . The length of the harvested TPFF was 149.38 ± 6.21 mm. In contrast to the transpterygoid transposition with incomplete coverage, transorbital transposition of the TPFF allowed full coverage of ASBD with a minimum necessary length of 109.75 ± 8.31 mm. For VSBD reconstruction, transorbital transposition of the TPFF needs shorter minimum necessary length (123.88 ± 4.49 mm) than transpterygoid transposition (138.00 ± 6.28 mm). CONCLUSIONS: Transorbital corridor is a novel pathway for transporting the TPFF into the sinonasal cavity for skull base defects reconstruction after EEEA. In comparison with transpterygoid transposition, transorbital transposition provides wider coverage of skull base defects with a fixed length of the TPFF.

PT320, a Sustained-Release GLP-1 Receptor Agonist, Ameliorates L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson's Disease.

To determine the efficacy of PT320 on L-DOPA-induced dyskinetic behaviors, and neurochemistry in a progressive Parkinson's disease (PD) MitoPark mouse model. To investigate the effects of PT320 on the manifestation of dyskinesia in L-DOPA-primed mice, a clinically translatable biweekly PT320 dose was administered starting at either 5 or 17-weeks-old mice. The early treatment group was given L-DOPA starting at 20 weeks of age and longitudinally evaluated up to 22 weeks. The late treatment group was given L-DOPA starting at 28 weeks of age and longitudinally observed up to 29 weeks. To explore dopaminergic transmission, fast scan cyclic voltammetry (FSCV) was utilized to measure presynaptic dopamine (DA) dynamics in striatal slices following drug treatments. Early administration of PT320 significantly mitigated the severity L-DOPA-induced abnormal involuntary movements; PT320 particularly improved excessive numbers of standing as well as abnormal paw movements, while it did not affect L-DOPA-induced locomotor hyperactivity. In contrast, late administration of PT320 did not attenuate any L-DOPA-induced dyskinesia measurements. Moreover, early treatment with PT320 was shown to not only increase tonic and phasic release of DA in striatal slices in L-DOPA-naïve MitoPark mice, but also in L-DOPA-primed animals. Early treatment with PT320 ameliorated L-DOPA-induced dyskinesia in MitoPark mice, which may be related to the progressive level of DA denervation in PD.

Endoscopically assisted presigmoid retrolabyrinthine approach to the lateral mesencephalic sulcus: a cadaveric study with comparison to the variant supracerebellar infratentorial approaches.

The supracerebellar infratentorial (SCIT) approach is commonly used to gain access to the lateral mesencephalic sulcus (LMS), which has been established as a safe entry point into the posterolateral midbrain. This study describes a lateral variant of the SCIT approach, the supreme-lateral SCIT approach, for accessing the LMS through the presigmoid retrolabyrinthine craniectomy and quantitatively compares this approach with the paramedian and extreme-lateral SCIT approaches. Anatomical dissections were performed in four cadaveric heads. In each head, the supreme-lateral SCIT approach was established on one side, following a detailed description of each step, whereas the paramedian and supreme-lateral SCIT approaches were established on the other side. Quantitative measurements of the exposed posterolateral midbrain, the angles of LMS entry, and the depth of surgical corridors were recorded and compared between the three SCIT approach variants. The supreme-lateral (67.70 ± 23.14 mm2) and extreme-lateral (70.83 ± 24.99 mm2) SCIT approaches resulted in larger areas of exposure anterior to the LMS than the paramedian SCIT approach (38.61 ± 9.84 mm2); the supreme-lateral SCIT approach resulted in a significantly smaller area of exposure posterior to the LMS (65.24 ± 6.81 mm2) than the other two variants (paramedian = 162.75 ± 31.98 mm2; extreme-lateral = 143.10 ± 23.26 mm2; both P < .001). Moreover, the supreme-lateral SCIT approach resulted in a surgical corridor with a shallower depth and a smaller angle relative to the horizontal plane than the other two variants. The supreme-lateral SCIT approach is a more lateral approach than the extreme-lateral SCIT approach, providing a subtemporal approach with direct LMS visualization. The supreme-lateral SCIT offers the benefits of both subtemporal and SCIT approaches and represents a suitable option for the management of selected midbrain pathologies.

Augmenting hematoma-scavenging capacity of innate immune cells by CDNF reduces brain injury and promotes functional recovery after intracerebral hemorrhage.

During intracerebral hemorrhage (ICH), hematoma formation at the site of blood vessel damage results in local mechanical injury. Subsequently, erythrocytes lyse to release hemoglobin and heme, which act as neurotoxins and induce inflammation and secondary brain injury, resulting in severe neurological deficits. Accelerating hematoma resorption and mitigating hematoma-induced brain edema by modulating immune cells has potential as a novel therapeutic strategy for functional recovery after ICH. Here, we show that intracerebroventricular administration of recombinant human cerebral dopamine neurotrophic factor (rhCDNF) accelerates hemorrhagic lesion resolution, reduces peri-focal edema, and improves neurological outcomes in an animal model of collagenase-induced ICH. We demonstrate that CDNF acts on microglia/macrophages in the hemorrhagic striatum by promoting scavenger receptor expression, enhancing erythrophagocytosis and increasing anti-inflammatory mediators while suppressing the production of pro-inflammatory cytokines. Administration of rhCDNF results in upregulation of the Nrf2-HO-1 pathway, but alleviation of oxidative stress and unfolded protein responses in the perihematomal area. Finally, we demonstrate that intravenous delivery of rhCDNF has beneficial effects in an animal model of ICH and that systemic application promotes scavenging by the brain's myeloid cells for the treatment of ICH.

Effects of Dextromethorphan on Nicotine-Induced Reward, Behavioral Sensitization, Withdrawal Signs, and Drug Seeking-Related Behavior in Rats.

INTRODUCTION: Tobacco products are addictive, with nicotine serving as the major addictive ingredient. Chronic tobacco use or chronic administration of nicotine alone results in both physiological and psychological dependence. Our previous studies indicated that dextromethorphan (DM) could effectively attenuate the dependence of morphine and methamphetamine. Thus, we further investigated the possible effects of DM on nicotine dependence. AIMS AND METHODS: Conditioned place preference (CPP) test was used to examine nicotine-induced rewarding effects as well as the drug-seeking-related behavior in rats. Nicotine dependence was induced by continuous subcutaneous infusion of nicotine via an osmotic minipump for 7 days and abstinence was initiated by removal of the pump. Withdrawal signs were observed and quantified. Locomotor activity was measured to determine the behavioral sensitization induced by nicotine. To investigate the activity of mesolimbic dopaminergic neuronal activity in correlation with the effects of nicotine, the animals were sacrificed and the nucleus accumbens (NAc), dorsal striatum (DS), and medial prefrontal cortex (mPFC) were dissected and used to determine the contents of dopamine (DA) and its metabolites using high-performance liquid chromatography (HPLC). RESULTS: Our results showed that DM could suppress nicotine-induced rewarding effect and drug-seeking-related behavior. In addition, co-administration and post-treatment of DM could both attenuate nicotine withdrawal signs. Moreover, DM could suppress nicotine-induced behavioral sensitization. Neurochemical experiments show that co-administration and post-treatment of DM abolished nicotine-induced increase of the DA turnover rate in the mPFC, but not in the NAc and DS. CONCLUSIONS: The results suggest that DM has a great therapeutic potential in the treatment of nicotine dependence. IMPLICATIONS: Our results showed that DM could suppress nicotine-induced rewarding effect and drug-seeking-related behavior. In addition, co-administration and post-treatment of DM could both attenuate nicotine withdrawal signs. Moreover, DM could suppress nicotine-induced behavioral sensitization. Neurochemical experiments show that co-administration and post-treatment of DM abolished nicotine-induced increase of the DA turnover rate in the mPFC, but not in the NAc and DS. These results suggest that DM has a great therapeutic potential in the treatment of nicotine dependence.

Endoscope-assisted Manipulation of Chronic Subdural Hematomas Provides a Novel Solution for Eliminating the Septum and Inner Membrane Leading to Reduced Recurrence.

BACKGROUND/AIM: Canonical burr-hole craniostomy (BHC) with drainage is the primary treatment for chronic subdural hematomas. However, complicated situations such as organized clots or compartmentation may result in recurrent chronic subdural hematoma (CSDH). Herein, we introduce a novel technique by applying an endoscope for tearing the inner membrane and septum, in addition to evacuating the hematoma in the subdural space where in-line visualization is not possible. PATIENTS AND METHODS: Two hundred and twenty-nine cases of CSDH were enrolled in this study. Of these, 13 patients were treated endoscopically. The 0-degree and 30-degree, 2.7 mm endoscope was applied after a BHC. The arachnoid knife for microsurgery was used to tear the inner membrane to open the compartments. RESULTS: Non-endoscope-assisted operated (non-Endo group) and endoscope-assisted membranectomy patients (Endo group) demonstrated no differences in sex, age, body mass index, trauma, other diseases, or use of anticoagulation agents. Although the surgery time spent for the Endo patients was longer (128.53±49.56 min) than that for the non-Endo group (65.18±32.89 min), no recurrence was found among the Endo group, whereas a higher rate was observed in the non-Endo group. CONCLUSION: Novel endoscope-assisted membranectomy is a powerful technique capable of reducing recurrence and improving surgical outcomes.

Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat Model.

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta, which leads to the motor control deficits. Recently, cell transplantation is a cutting-edge technique for the therapy of PD. Nevertheless, one key bottleneck to realizing such potential is allogenic immune reaction of tissue grafts by recipients. Cerebral dopamine neurotrophic factor (CDNF) was shown to possess immune-modulatory properties that benefit neurodegenerative diseases. We hypothesized that co-administration of CDNF with fetal ventral mesencephalic (VM) tissue can improve the success of VM replacement therapies by attenuating immune responses. Hemiparkinsonian rats were generated by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle of Sprague Dawley (SD) rats. The rats were then intrastriatally transplanted with VM tissue from rats, with/without CDNF administration. Recovery of dopaminergic function and survival of the grafts were evaluated using the apomorphine-induced rotation test and small-animal positron emission tomography (PET) coupled with [18F] DOPA or [18F] FE-PE2I, respectively. In addition, transplantation-related inflammatory response was determined by uptake of [18F] FEPPA in the grafted side of striatum. Immunohistochemistry (IHC) examination was used to determine the survival of the grated dopaminergic neurons in the striatum and to investigate immune-modulatory effects of CDNF. The modulation of inflammatory responses caused by CDNF might involve enhancing M2 subset polarization and increasing fractal dimensions of 6-OHDA-treated BV2 microglial cell line. Analysis of CDNF-induced changes to gene expressions of 6-OHDA-stimulated BV2 cells implies that these alternations of the biomarkers and microglial morphology are implicated in the upregulation of protein kinase B signaling as well as regulation of catalytic, transferase, and protein serine/threonine kinase activity. The effects of CDNF on 6-OHDA-induced alternation of the canonical pathway in BV2 microglial cells is highly associated with PI3K-mediated phagosome formation. Our results are the first to show that CDNF administration enhances the survival of the grafted dopaminergic neurons and improves functional recovery in PD animal model. Modulation of the polarization, morphological characteristics, and transcriptional profiles of 6-OHDA-stimualted microglia by CDNF may possess these properties in transplantation-based regenerative therapies.

Tetrabenazine Mitigates Aberrant Release and Clearance of Dopamine in the Nigrostriatal System, and Alleviates L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson's Disease.

BACKGROUND: L-DOPA-induced dyskinesia (LID), occurring with aberrant processing of exogenous L-DOPA in the dopamine-denervated striatum, is a main complication of levodopa treatment in Parkinson's disease. OBJECTIVE: To characterize the effects of the vesicular antagonist tetrabenazine (TBZ) on L-DOPA-induced behavior, neurochemical signals, and underlying protein expressions in an animal model of Parkinson's disease. METHODS: 20-week-old MitoPark mice were co-treated or separately administered TBZ and L-DOPA for 14 days. Abnormal involuntary movements (AIMs) and locomotor activity were analyzed. To explore dopamine (DA) transmission, fast scan cyclic voltammetry was used to assess presynaptic DA dynamics in striatal slices following treatments. PET imaging with 4-[18F]-PE2I, ADAM and immunoblotting assays were used to detect receptor protein changes in the DA-denervated striatum. Finally, nigrostriatal tissues were collected for HPLC measures of DA, serotonin and their metabolites. RESULTS: A single injection of TBZ given in the interval between the two L-DOPA/Carbidopa treatments significantly attenuated L-DOPA-induced AIMs expression and locomotor hyperactivity. TBZ was shown to reduce tonic and phasic release of DA following L-DOPA treatment in DA-denervated striatal tissue. In the DA-depleted striatum, TBZ decreased the expression of L-DOPA-enhanced D1 receptors and the serotonin reuptake transporter. Neurochemical analysis indicated that TBZ attenuated L-DOPA-induced surges of DA levels by promoting DA turnover in the nigrostriatal system. CONCLUSIONS: Our findings demonstrate that TBZ diminishes abnormal striatal DA transmission, which involves the ability of TBZ to modulate the presymptomatic dynamics of DA, and then mitigate aberrant release of exogenous L-DOPA from nerve terminals. The results support the potential of repositioning TBZ to counteract LID development.

Interstitial Control-Released Polymer Carrying a Targeting Small-Molecule Drug Reduces PD-L1 and MGMT Expression in Recurrent High-Grade Gliomas with TMZ Resistance.

In recurrent glioblastoma, Gliadel wafer implantation after surgery has been shown to result in incomplete chemical removal of residual tumor and development of brain edema. Furthermore, temozolomide (TMZ) resistance caused by O6-methylguanine-DNA-methyltransferase (MGMT) activation and programmed cell death-ligand 1 (PD-L1) expression leads to immune-cold lesions that result in poorer prognosis. Cerebraca wafer, a biodegradable polymer containing (Z)-n-butylidenephthalide (BP), is designed to eliminate residual tumor after glioma resection. An open-label, one-arm study with four dose cohorts, involving a traditional 3 + 3 dose escalation clinical trial, of the Cerebraca wafer combined with TMZ on patients with recurrent high-grade glioma, was conducted. Of the 12 patients who receive implantation of Cerebraca wafer, there were no drug-related adverse events (AEs) or serious AEs (SAEs). The median overall survival (OS) of patients receiving low-dose Cerebraca wafer was 12 months in the group with >25% wafer coverage of the resected tumor, which is longer than OS duration in previously published studies (Gliadel wafer, 6.4 months). Patients who received high-dose Cerebraca wafer treatment had not yet died at the data cut-off date; a 100% progression-free survival (PFS) rate at six month was achieved, indicating the median OS of cohort IV was more than 17.4 months. In vitro study of the primary cells collected from the patients revealed that the IC50 of BP against tumor stem cells was four times lower than that of bis-chloroethylnitrosourea (BCNU). A synergistic effect between BP and TMZ was demonstrated by a reduction in MGMT expression. Furthermore, BP inhibited PD-L1 expression, thereby activating T-cell cytotoxicity and increasing interferon-gamma (IFN-γ) secretion. The better therapeutic effect of Cerebraca wafer on recurrent high-grade glioma could occur through re-sensitization of TMZ and reduction of PD-L1.

Estrogen can abolish oxytocin-induced spinal anti-hyperalgesia.

Our previous study verified a sex difference of anti-hyperalgesia in rats and anti-allodynia in mice induced by intrathecal oxytocin (OT). In the model of intraplantar carrageenan-induced inflammatory hyperalgesia, intrathecal OT injection induced a substantial anti-hyperalgesia in male rats even at a low dose (0.125 nmol). In contrast, female rats only responded to an extremely high dose (1.25 nmol). This sex difference concurs with a lower expression of OT receptors and higher expression of insulin-regulated aminopeptidase (IRAP; OT degrading enzyme) in the spinal cords of female rats. In this study, we further determined the role of female hormones in this sex difference by using ovariectomized rats. Our results show that a low dose of intrathecal OT caused a significant anti-hyperalgesia effect in ovariectomized female rats, similar to that seen in male rats. Ovariectomy did not cause any change of paw edema except at the late stage of convalescence when compared with the sham-operated group. Ovariectomy-induced faster recovery from edema but did not affect the severity of hyperalgesia. Moreover, there was a similar amount of IRAP expression in ovariectomized and sham rats. When estradiol (E2) was given together with OT, OT-induced anti-hyperalgesia was abolished at the developmental stage of hyperalgesia in ovariectomized rats. These results show an inhibitory role of female hormones generated from ovaries (mainly estrogen) in the sex difference of anti-hyperalgesia induced by OT. This study suggests the feasibility of a novel OT-based remedy to treat hyperalgesia in men and in menopausal women no receiving hormonal supplements.

A controlled clinical study of a two-trocar mini-laparoscopic technique versus the standard laparoscopic technique in treatment of adult renal cysts.

INTRODUCTION: Laparoscopic renal cyst decortication is currently the best choice for the treatment of simple renal cysts and is widely used in clinical practice. AIM: To investigate the safety and clinical efficacy of two-trocar mini-laparoscopic decortication of adult renal cysts. MATERIAL AND METHODS: A total of 90 patients were enrolled in the study and randomly divided into two groups: a two-trocar mini-laparoscopic treatment group (M group) and a three-trocar standard laparoscopic treatment group (S group), with 45 patients in each group. RESULTS: The average length of hospital stay was shorter, and the demand for postoperative analgesics was less in the M group than in the S group (p < 0.05). The proportion of "very satisfied" patients in the patient physical recovery satisfaction survey was significantly higher in the M group than in the S group (p < 0.05). Of the 45 patients in the M group, 40 successfully underwent surgery. In 3 patients, the two-trocar procedure was converted to a three-trocar procedure due to difficulty in separating perirenal adhesion for visualization. Mini-laparoscopic surgery was converted to classic laparoscopic surgery in 2 patients. In the S group, 44 patients successfully underwent the renal cyst decortication procedure. One patient underwent partial renal resection due to an intraoperative diagnosis of multilocular cystic renal cell carcinoma. Postoperative urine leakage was reported in 3 patients in the M group and two in the S group. CONCLUSIONS: Two-trocar mini-laparoscopic treatment of renal cysts is as safe and effective as traditional laparoscopy but is associated with less cosmetic damage, leading to a better physical appearance.

High Resolution U-Net for Quantitatively Analyzing Early Spatial Patterning of Human Induced Pluripotent Stem Cells on Micropatterns.

Human induced pluripotent stem cells (hiPSCs) can differentiate into three germ layer cells, i.e. ectoderm, mesoderm and endoderm, on micropatterned chips in highly synchronous and reproducible manners. The cells are confined within the chip, expanding two-dimensionally as almost in the form of monolayer, thus to be ideal for serving quantitative analysis of their pluripotency. We present a new U-Net (MP-UNet) structure for cell segmentation of early spatial patterning of hiPSCs on micropattern chips using Hoechst fluorescence images. In this structure, the encoding/decoding layers can be dynamically adjusted to extract sufficient image features and be flexible to image sizes. Dice and weight loss functions are designed to identify slight difference in low signal-to-noise ratio, high boundary-to-area ratio and compacted cell images. Several sizes of Hoechst images were tested to show MP-UNet can achieve high accuracy in cell regions and number counting for various sizes of micropattern chips, thus to be excellent quantitative tool for early spatial patterning of hiPSCs.