ABSTRACT
BACKGROUND: Satellite glial cells (SGCs) in the dorsal root ganglia (DRG) play a pivotal role in the formation of neuropathic pain (NP). Sciatic nerve stimulation (SNS) neuromodulation was reported to alleviate NP and reduce neuroinflammation. However, the mechanisms underlying SNS in the DRG remain unclear. This study aimed to elucidate the mechanism of electric stimulation in reducing NP, focusing on the DRG. METHODS: L5 nerve root ligation (NRL) NP rat model was studied. Ipsilateral SNS performed 1 day after NRL. Behavioral tests were performed to assess pain phenotypes. NanoString Ncounter technology was used to explore the differentially expressed genes and cellular pathways. Activated SGCs were characterized in vivo and in vitro. The histochemical alterations of SGCs, macrophages, and neurons in DRG were examined in vivo on post-injury day 8. RESULTS: NRL induced NP behaviors including decreased pain threshold and latency on von Frey and Hargreaves tests. We found that following nerve injury, SGCs were hyperactivated, neurotoxic and had increased expression of NP-related ion channels including TRPA1, Cx43, and SGC-neuron gap junctions. Mechanistically, nerve injury induced reciprocal activation of SGCs and M1 macrophages via cytokines including IL-6, CCL3, and TNF-α mediated by the HIF-1α-NF-κB pathways. SNS suppressed SGC hyperactivation, reduced the expression of NP-related ion channels, and induced M2 macrophage polarization, thereby alleviating NP and associated neuroinflammation in the DRG. CONCLUSIONS: NRL induced hyperactivation of SGCs, which had increased expression of NP-related ion channels. Reciprocal activation of SGCs and M1 macrophages surrounding the primary sensory neurons was mediated by the HIF-1α and NF-κB pathways. SNS suppressed SGC hyperactivation and skewed M1 macrophage towards M2. Our findings establish SGC activation as a crucial pathomechanism in the gliopathic alterations in NP, which can be modulated by SNS neuromodulation.
Subject(s)
Disease Models, Animal , Ganglia, Spinal , Neuralgia , Neuroinflammatory Diseases , Rats, Sprague-Dawley , Sciatic Nerve , Animals , Ganglia, Spinal/metabolism , Neuralgia/therapy , Neuralgia/metabolism , Male , Neuroinflammatory Diseases/metabolism , Sciatic Nerve/pathology , Macrophages/metabolism , Neuroglia/metabolism , Rats , Behavior, AnimalABSTRACT
OBJECTIVE: Hereditary amyloid transthyretin (ATTRv) amyloidosis with polyneuropathy, a rare autosomal-dominant disease, has gained attention in recent years owing to treatment improvements. However, epidemiological real-world mega database of nationwide natural history and survival rates, especially with the specific mutation of Ala97Ser, are limited. METHODS: Taiwan National Health Insurance Research Database contains data from over 23 million individuals; Among them, 175 ATTRv amyloidosis patients validated by rare disease registry were enrolled. Multivariable Cox proportional hazard analyses were applied to investigate the association between baseline characteristics and all-cause mortality. FINDINGS: From 2008 to 2020, the annual incidence and prevalence rates of specific mutations (Ala97Ser) leading to ATTRv amyloidosis with polyneuropathy were 0.04-1.14 and 0.04-4.79 per million in Taiwan, respectively. In Taiwan, these patients exhibited male predominance with a mean age at validation of 62.75 years. At the 5th year after validation, patients exhibited a survival rate of approximately 50%, with higher mortality in male patients (hazard ratio [HR]: 2.22, 95% confidence interval [CI]: 1.15-4.31) and patients older at validation (HR: 1.10, 95% CI: 1.06-1.15). The two most common departments in outpatient were neurology and family medicine, and neurology and cardiology in inpatient. The three most common causes of death registered were unspecified amyloidosis (30.6%), organ-limited amyloidosis (20.9%), and neuropathic heredofamilial amyloidosis (9.7%). INTERPRETATION: The annual prevalence rate of specific mutation (Ala97Ser)-dominant ATTRv amyloidosis with polyneuropathy in Taiwan is comparable to the mid- to high-prevalence country level of the research by Schmidt et al. The extraordinarily high mortality, especially among patients older at validation, may reflect the inadequate awareness and the necessity of early intervention with novel disease-modifying regimens.
Subject(s)
Amyloid Neuropathies, Familial , Amyloidosis, Familial , Polyneuropathies , Humans , Male , Middle Aged , Female , Survival Rate , Amyloid Neuropathies, Familial/epidemiology , Amyloid Neuropathies, Familial/genetics , Polyneuropathies/epidemiology , Polyneuropathies/genetics , MutationABSTRACT
BACKGROUND: Neuropathic pain (NP) is characterized by abnormal activation of pain conducting pathways and manifests as mechanical allodynia and thermal hypersensitivity. Peripheral nerve stimulation is used for treatment of medically refractory chronic NP and has been shown to reduce neuroinflammation. However, whether sciatic nerve stimulation (SNS) is of therapeutic benefit to NP remains unclear. Moreover, the optimal frequency for SNS is unknown. To address this research gap, we investigated the effect of SNS in an acute NP rodent model. METHODS: Rats with right L5 nerve root ligation (NRL) or Sham surgery were used. Ipsilateral SNS was performed at 2 Hz, 20 Hz, and 60 Hz frequencies. Behavioral tests were performed to assess pain and thermal hypersensitivity before and after NRL and SNS. Expression of inflammatory proteins in the L5 spinal cord and the immunohistochemical alterations of spinal cord astrocytes and microglia were examined on post-injury day 7 (PID7) following NRL and SNS. The involvement of the descending pain modulatory pathway was also investigated. RESULTS: Following NRL, the rats showed a decreased pain threshold and latency on the von Frey and Hargreaves tests. The immunofluorescence results indicated hyperactivation of superficial spinal cord dorsal horn (SCDH) neurons. Both 2-Hz and 20-Hz SNS alleviated pain behavior and hyperactivation of SCDH neurons. On PID7, NRL resulted in elevated expression of spinal cord inflammatory proteins including NF-κB, TNF-α, IL-1ß, and IL-6, which was mitigated by 2-Hz and 20-Hz SNS. Furthermore, 2-Hz and 20-Hz SNS suppressed the activation of spinal cord astrocytes and microglia following NRL on PID7. Activity of the descending serotoninergic pain modulation pathway showed an increase early on PID1 following 2-Hz and 20-Hz SNS. CONCLUSIONS: Our results support that both 2-Hz and 20-Hz SNS can alleviate NP behaviors and hyperactivation of pain conducting pathways. We showed that SNS regulates neuroinflammation and reduces inflammatory protein expression, astrocytic gliosis, and microglia activation. During the early post-injury period, SNS also facilitates the descending pain modulatory pathway. Taken together, these findings support the therapeutic potential of SNS for acute NP.
Subject(s)
Neuralgia , Rodentia , Animals , Hyperalgesia/metabolism , Hyperalgesia/therapy , Neuralgia/metabolism , Neuralgia/therapy , Neuroinflammatory Diseases , Rats , Sciatic Nerve/metabolism , Spinal Cord/metabolismABSTRACT
BACKGROUND AND OBJECTIVES: The GGC repeat expansion in the 5' untranslated region of NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease (NIID), which may manifest with peripheral neuropathy. The aim of this study is to investigate its contribution to inherited neuropathy. METHODS: This cohort study screened patients with molecularly undiagnosed Charcot-Marie-Tooth disease (CMT) and healthy controls for the GGC repeat expansion in NOTCH2NLC using repeat-primed PCR and fragment analysis. The clinical and electrophysiologic features of the patients harboring the GGC repeat expansion were scrutinized. Skin biopsy with immunohistochemistry staining and electric microscopic imaging were performed. RESULTS: One hundred twenty-seven unrelated patients with CMT, including 66 cases with axonal CMT (CMT2), and 200 healthy controls were included. Among them, 7 patients with CMT carried a variant NOTCH2NLC allele with GGC repeat expansion, but it was absent in controls. The sizes of the expanded GGC repeats ranged from 80 to 104 repeats. All 7 patients developed sensory predominant neuropathy with an average age at disease onset of 37.1 years (range 21-55 years). Electrophysiologic studies revealed mild axonal sensorimotor polyneuropathy. Leukoencephalopathy was absent in the 5 patients who received a brain MRI. Skin biopsy from 2 patients showed eosinophilic, ubiquitin- and p62-positive intranuclear inclusions in the sweat gland cells and dermal fibroblasts. Two of the 7 patients had a family history of NIID. DISCUSSION: The NOTCH2NLC GGC repeat expansions are an underdiagnosed and important cause of inherited neuropathy. The expansion accounts for 10.6% (7 of 66) of molecularly unassigned CMT2 cases in the Taiwanese CMT cohort. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in Taiwanese patients with genetically undiagnosed CMT, 10.6% of the CMT2 cases have the GGC repeat expansion in NOTCH2NLC.
Subject(s)
Intercellular Signaling Peptides and Proteins , Nerve Tissue Proteins , Neurodegenerative Diseases , Peripheral Nervous System Diseases , Adult , Case-Control Studies , Cohort Studies , Humans , Intercellular Signaling Peptides and Proteins/genetics , Intranuclear Inclusion Bodies/pathology , Middle Aged , Nerve Tissue Proteins/genetics , Neurodegenerative Diseases/pathology , Peripheral Nervous System Diseases/pathology , Trinucleotide Repeat Expansion , Young AdultABSTRACT
BACKGROUND AND OBJECTIVES: The mechanisms of particulate matter (PM) toxicity involve the generation of ROS and upregulation of proinflammatory molecules. Nrf2 is a multifunctional cytoprotective transcription factor that regulates the expression of various antioxidant, anti-inflammatory, and detoxifying molecules, such as HO-1. As surfactin has potential to induce Nrf2 activation and HO-1 expression, this study aimed to investigate the anti-inflammatory effects of surfactin on PM-exposed human gingival fibroblasts (HGFs) and signaling pathways engaged by surfactin. MATERIALS AND METHODS: Human gingival fibroblasts were challenged by PM with or without surfactin pretreatment. The expression of Nrf2, HO-1, VCAM-1, and other molecules was determined by western blot, real-time PCR, or ELISA. Human monocytic THP-1 cells labeled with fluorescent reagent were added to HGFs, and the cell adhesion was assessed. ROS generation and NADPH oxidase activity were also measured. The involvement of Nrf2/HO-1 and ROS signaling pathways was investigated by treating HGFs with specific pathway interventions, genetically or pharmacologically. One dose of surfactin was given to mice before PM treatment to explore its in vivo effect on VCAM-1 expression in gingival tissues. RESULTS: Particulate matter led to VCAM-1-dependent monocyte adhesion in HGFs, which was regulated by PKCα/NADPH oxidase/ROS/STAT1/IL-6 pathway. Surfactin could attenuate monocyte adhesion by disrupting this VCAM-1-dependent pathway. Additionally, surfactin promoted Nrf2-dependent HO-1 expression in HGFs, mitigating VCAM-1 expression. PM-treated mice exhibited the lower expression of IL-6 and VCAM-1 in gingival tissues if they previously received surfactin. CONCLUSION: Surfactin exerts anti-inflammatory effects against PM-induced inflammatory responses in HGFs by inhibiting VCAM-1-dependent pathway and inducing Nrf2/HO-1 axis.
Subject(s)
NF-E2-Related Factor 2 , Particulate Matter , Animals , Fibroblasts , Heme Oxygenase-1/genetics , Humans , Mice , Monocytes , Particulate Matter/toxicity , Vascular Cell Adhesion Molecule-1ABSTRACT
BACKGROUND: Previous studies have assessed note quality and the use of electronic medical record (EMR) as a part of medical training. However, a generalized and user-friendly note quality assessment tool is required for quick clinical assessment. We held a medical record writing competition and developed a checklist for assessing the note quality of participants' medical records. Using the checklist, this study aims to explore note quality between residents of different specialties and offer pedagogical implications. METHODS: The authors created an inpatient checklist that examined fundamental EMR requirements through six note types and twenty items. A total of 149 records created by residents from 32 departments/stations were randomly selected. Seven senior physicians rated the EMRs using a checklist. Medical records were grouped as general medicine, surgery, paediatric, obstetrics and gynaecology, and other departments. The overall and group performances were analysed using analysis of variance (ANOVA). RESULTS: Overall performance was rated as fair to good. Regarding the six note types, discharge notes (0.81) gained the highest scores, followed by admission notes (0.79), problem list (0.73), overall performance (0.73), progress notes (0.71), and weekly summaries (0.66). Among the five groups, other departments (80.20) had the highest total score, followed by obstetrics and gynaecology (78.02), paediatrics (77.47), general medicine (75.58), and surgery (73.92). CONCLUSIONS: This study suggested that duplication in medical notes and the documentation abilities of residents affect the quality of medical records in different departments. Further research is required to apply the insights obtained in this study to improve the quality of notes and, thereby, the effectiveness of resident training.
Subject(s)
Internship and Residency , Physicians , Child , Documentation , Electronic Health Records , Humans , Medical Records , WritingABSTRACT
Rationale: Oxaliplatin-induced peripheral neuropathy (OIPN) is a common adverse effect that causes delayed treatment and poor prognosis among colorectal cancer (CRC) patients. However, its mechanism remains elusive, and no effective treatment is available. Methods: We employed a prospective cohort study of adult patients with pathologically confirmed stage III CRC receiving adjuvant chemotherapy with an oxaliplatin-based regimen for investigating OIPN. To further validate the clinical manifestations and identify a potential therapeutic strategy, animal models, and in vitro studies on the mechanism of OIPN were applied. Results: Our work found that (1) consistent with clinical findings, OIPN was observed in animal models. Targeting the enzymatic activity of cathepsin S (CTSS) by pharmacological blockade and gene deficiency strategy alleviates the manifestations of OIPN. (2) Oxaliplatin treatment increases CTSS expression by enhancing cytosol translocation of interferon response factor 1 (IRF1), which then facilitates STIM-dependent store-operated Ca2+ entry homeostasis. (3) The cytokine array demonstrated an increase in anti-inflammatory cytokines and suppression of proinflammatory cytokines in mice treated with RJW-58. (4) Mechanistically, inhibiting CTSS facilitated olfactory receptors transcription factor 1 release from P300/CBP binding, which enhanced binding to the interleukin-10 (IL-10) promoter region, driving IL-10 downstream signaling pathway. (5) Serum CTSS expression is increased in CRC patients with oxaliplatin-induced neurotoxicity. Conclusions: We highlighted the critical role of CTSS in OIPN, which provides a therapeutic strategy for the common adverse side effects of oxaliplatin.
Subject(s)
Cathepsins/genetics , Neurons/metabolism , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cathepsins/antagonists & inhibitors , Cathepsins/drug effects , Chemotherapy, Adjuvant , Cohort Studies , Colorectal Neoplasms/drug therapy , Cytokines/metabolism , Disease Models, Animal , Enzyme Inhibitors , Female , Fluorouracil/therapeutic use , Ganglia, Spinal , Humans , In Vitro Techniques , Leucovorin/therapeutic use , Male , Mice , Mice, Knockout , Microglia/drug effects , Microglia/metabolism , Molecular Targeted Therapy , Neural Conduction , Neurons/drug effects , Organoplatinum Compounds/therapeutic use , Oxaliplatin/adverse effects , Oxaliplatin/pharmacology , Peripheral Nervous System Diseases/chemically induced , Prospective StudiesABSTRACT
Background and Objective. The main purpose of this study was to develop a simple automatic diagnostic classification scheme for chemotherapy-induced peripheral neuropathy. METHODS: This was a prospective cohort study that enrolled patients with colorectal or gynecologic cancer post chemotherapy for more than 1 year. The patients underwent laboratory examinations (nerve conduction studies and quantitative sensory tests), and a questionnaire about the quality of life. An unsupervised classification algorithm was used to classify the patients into groups using a small number of variables derived from the laboratory tests. A panel of five neurologists also diagnosed the types of neuropathies according to the laboratory tests. The results by the unsupervised classification algorithm and the neurologists were compared. RESULTS: The neurologists' diagnoses showed much higher rates of entrapment syndromes (66.1%) and radiculopathies (55.1%) than polyneuropathy (motor/sensory: 33.1%/29.7%). A multivariate analysis showed that the questionnaire was not significantly correlated with the results of quantitative sensory tests (r = 0.27) or the neurologists' diagnoses (r = 0.27) or the neurologists' diagnoses (. CONCLUSION: The results of our unsupervised classification algorithm based on three variables of laboratory tests correlated well with the neurologists' diagnoses.
Subject(s)
Antineoplastic Agents/adverse effects , Colorectal Neoplasms/drug therapy , Genital Neoplasms, Female/drug therapy , Peripheral Nervous System Diseases/diagnosis , Adult , Aged , Aged, 80 and over , Algorithms , Early Diagnosis , Female , Humans , Male , Middle Aged , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/classification , Prospective Studies , Quality of Life , Severity of Illness Index , Unsupervised Machine LearningABSTRACT
OBJECTIVE: To investigate whether indicators of cortical excitability are good biomarkers of seizure controllability in temporal lobe epilepsy (TLE). MATERIALS AND METHODS: Three groups of subjects were recruited: those with poorly controlled (PC) TLE (N = 41), well-controlled (WC) TLE (N = 71), and healthy controls (N = 44). Short- and long-latency recovery curves were obtained by paired-pulse transcranial magnetic stimulation. Linear mixed effect models were used to study the effects of group, interstimulus interval (ISI), and antiepileptic drugs on long-interval intracortical inhibition (LICI) and short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). RESULTS: The mixed effect model that did not incorporate antiepileptic drugs showed that group and ISI were significant factors for LICI and SICI/ICF. LICI in the healthy control group was greater than in the two epilepsy groups, and the difference was significant at ISIs of 50, 150, and 200 msec. In contrast, SICI/ICF in the PC group was greater than in the healthy control and WC groups, and the difference was significant at an ISI of 15 msec. However, due to large variance, it was difficult to identify a cutoff value with both good sensitivity and good specificity. Incorporating the information of antiepileptic drugs to the mixed effect model did not change the overall results. CONCLUSIONS: Although LICI and SICI/ICF parameters were significantly different at the group level, they may not be suitable biomarkers for the controllability of TLE at the subject level.
Subject(s)
Cortical Excitability , Drug Resistant Epilepsy/physiopathology , Epilepsy, Temporal Lobe/physiopathology , Seizures/physiopathology , Transcranial Magnetic Stimulation/methods , Adult , Anticonvulsants/therapeutic use , Cerebral Cortex/physiopathology , Cortical Excitability/drug effects , Drug Resistant Epilepsy/drug therapy , Female , Humans , Male , Middle Aged , Seizures/prevention & control , Treatment OutcomeABSTRACT
BACKGROUND: In gastric cancer, various surveillance strategies are suggested in international guidelines. The current study is intended to evaluate the current strategies and provide more personalized proposals for personalized cancer medicine. MATERIALS AND METHODS: In the aggregate, 9191 patients with gastric cancer after gastrectomy from 1998 to 2009 were selected from the Surveillance, Epidemiology, and End Results database. Disease-specific survival was analyzed by Kaplan-Meier method and the log-rank test. Cox proportional hazards regression analyses were used to confirm the independent prognostic factors. As well, hazard ratio (HR) curves were used to compare the risk of death over time. Conditional survival (CS) was applied to dynamically assess the prognosis after each follow-up. RESULTS: Comparisons from HR curves on different stages showed that earlier stages had distinctly lower HR than advanced stages. The curve of stage IIA was flat and more likely the same as that of stage I while that of stage IIB is like that of stage III with an obvious peak. After estimating CS at intervals of three months, six months, and 12 months in different periods, stages I and IIA had high levels of CS all along, while there were visible differences among CS levels of stages IIB and III. CONCLUSIONS: The frequency of follow-up for early stages, like stages I and IIA, could be every six months or longer in the first three years and annually thereafter. And those with unfavorable conditions, such as stages IIB and III, could be followed up much more frequently and sufficiently than usual.
ABSTRACT
Vascular endothelial growth factor receptor 2 (VEGFR2) and cMet are tyrosine kinases, which are involved in the tumorigenesis of various types of cancer. Previous studies have demonstrated that the elevated activation of cMet is associated with the drug resistance of VEGFR2 inhibitors. Therefore, dual cMet and VEGFR2 kinase inhibitors are expected to overcome VEGFR2 inhibitor resistance and subsequently lead to a superior therapeutic outcome to regular VEGFR2 inhibitors. In the present study, it was found that chrysoeriol, which can be extracted from several natural plants, was a potential dual cMet and VEGFR2 kinase inhibitor. The results of docking experiments revealed that chrysoeriol was able to efficiently bind in the active site cavity of cMet and VEGFR2. The results of enzymatic assays showed relatively high binding affinities of chrysoeriol to cMet (Kd=12 µM) and VEGFR2 (Kd=11 µM). The structure activity relationships (SARs) of chrysoeriol and its analogs were investigated using pharmacological and molecular docking experiments. To the best of our best knowledge, the present study is the first to report a natural product with both cMet and VEGFR2 inhibitory profiles, and provides insights into future dual cMet and VEGFR2 kinase inhibitor development.
Subject(s)
Flavones/chemistry , Flavones/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , High-Throughput Screening Assays , Humans , Protein Conformation , Structure-Activity RelationshipABSTRACT
BACKGROUND: The status of serosal invasion is often discordance between pathological and intraoperative evaluation. Our study sought to develop a risk-scoring system (RSS) to predict the probability of pT4a for macroscopic serosal invasion (MSI) positive patients and reevaluate the serosal invasion status. PATIENTS AND METHODS: A total of 1301 pT3/pT4a gastric cancer patients with curative surgery were reviewed. We constructed the RSS to predict the probability of pT4a and assigned MSI-positive patients into different risk groups based on the risk scores. The prognostic significance of these risk groups was also evaluated. RESULTS: Univariate and multivariate analyses identified that tumor location, Lauren type, Borrmann type, tumor size, lymphovascular invasion and pN stage were risk factors related to pT4a. Survival analyses showed that pT3 MSI-positive patients in high-risk group had similar survival with pT4a patients. We incorporated these two groups into one stage and proposed a novel revised-T stage. Two-step multivariate analyses indicated that the revised-T stage showed better prediction ability for prognosis and peritoneal recurrence assessment than original pT stage and MSI status. CONCLUSIONS: In our present study, we developed a RSS to predict the probability of pT4a for MSI-positive patients. Based on our RSS, we proposed a treatment algorithm to reevaluate the tumor invasion for MSI-positive patients in clinical practice. Future studies should include other preoperative predictors to improve the clinical utility of our model.
Subject(s)
Peritoneal Neoplasms/epidemiology , Peritoneum/pathology , Stomach Neoplasms/pathology , Blood Vessels/pathology , Chemotherapy, Adjuvant , Female , Gastrectomy , Humans , Hyperthermia, Induced , Infusions, Parenteral , Lymph Node Excision , Lymphatic Vessels/pathology , Male , Middle Aged , Multivariate Analysis , Neoplasm Invasiveness , Neoplasm Staging , Peritoneal Neoplasms/secondary , Proportional Hazards Models , Risk Assessment , Serous Membrane/pathology , Stomach Neoplasms/therapy , Tumor BurdenABSTRACT
This paper describes the identification of chlorhexidine, an agent commonly used in clinical as a novel potential allosteric inhibitor of PAK1. In cellular assays, chlorhexidine showed a good inhibitory profile, and its inhibitory profile was even better than IPA-3, a well-known allosteric inhibitor. In pharmacology experiments, chlorhexidine successfully inhibited the relief of PAK1 dimer and inhibited the activation of PAK1. Our findings offer an insight for the new drug development of PAK1 inhibitor. We also provide a possible explanation for the phenomenon that the application of the chlorhexidine in peritoneal lavage inhibited the development of tumor.
Subject(s)
Chlorhexidine/administration & dosage , Chlorhexidine/chemistry , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , p21-Activated Kinases/chemistry , p21-Activated Kinases/metabolism , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Binding Sites , Cell Line, Tumor , Humans , Molecular Docking Simulation , Molecular Targeted Therapy/methods , Neoplasms, Experimental/pathology , Protein Binding , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistryABSTRACT
Mammalian sperm motility has traditionally been analyzed to determine fertility using computer-assisted semen analysis (CASA) systems. To develop low-cost and robust male fertility diagnostics, we created a paper-based MTT assay and used it to estimate motile sperm concentration. When porcine sperm motility was inhibited using sperm enzyme inhibitors for sperm enzymes related to mitochondrial activity and glycolysis, we simultaneously recorded sperm motility and enzymatic reactivity using a portable motility analysis system (iSperm) and a paper-based MTT assay, respectively. When using our paper-based MTT-assay, we calculated the area mean value signal intensity (AMV) to evaluate enzymatic reactivity. Both sperm motility and AMV decreased following treatment with iodoacetamide (IODO) and 3-bromopyruvic acid (3BP), both of which are inhibitors of glycolytic enzymes including glyceraldehyde-3-phosphate dehydrogenase (GAPDH). We found a correlation between recorded motility using iSperm and AMV from our paper-based assay (P < 0.05), suggesting that a sperm-related enzymatic reaction is involved in sperm motility. Under this protocol, MTT reduction was coupled with catalysis of GAPDH and was promoted by electron transfer from NADH. Based on this inhibitor study, sperm motility can be estimated using our paper-based MTT-assay.
Subject(s)
Semen Analysis , Sperm Motility , Spermatozoa/physiology , Adenosine Triphosphate , Animals , Biomarkers , Dose-Response Relationship, Drug , Glyceraldehyde 3-Phosphate/metabolism , Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/metabolism , Male , Mitochondria/metabolism , Semen Analysis/methods , Sperm Motility/drug effects , Spermatozoa/drug effects , Spermatozoa/enzymology , SwineABSTRACT
RATIONALE: cetuximab, an epidermal growth factor receptor inhibitor, is a targeted therapeutic regimen of colorectal cancers. Several common adverse effects have been found, such as cutaneous or gastrointestinal toxicity. However, according to the articles had been published, upper gastrointestinal bleeding (UGIB) is considered to be rare and its mechanism remains unclear. PATIENT CONCERNS: In this report, we presented a 42-year-old male patient with advanced recto-sigmoid cancer. After palliative operation, the patient suffered from complete upper gastrointestinal (GI) obstruction, which was induced by extensive abdominal metastasis of the tumor. Considering his poor condition, we chose the targeted drug, cetuximab, as his further treatment. But after the application of cetuximab, the UGIB immediately happened twice in this patient. DIAGNOSIS: UGIB, as a rare complication of cetuximab, occured to the patient. INTERVENTIONS: We stopped the bleeding with thrombin, hemocoagulase and somatostatin and suspended the subsequent treatment plan of cetuximab. At the same time, anti-shock treatment was given immediately. OUTCOMES: He was died of respiratory and circulatory failure caused by UGIB and advanced tumor eventually. LESSONS: UGIB should be considered as a rare but severe complication of cetuximab. When cetuximab is applied for patients with advanced colon tumors, more cautions should be required if the patients are accompanied by upper gastrointestinal obstruction. In addition, for those patients who suffered from UGIB recently, cetuximab should be prohibited if the Rockall score ranged >â5 points.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents, Immunological/adverse effects , Cetuximab/adverse effects , Gastrointestinal Hemorrhage/chemically induced , Hematemesis/chemically induced , Rectal Neoplasms/drug therapy , Sigmoid Neoplasms/drug therapy , Adult , Antineoplastic Agents, Immunological/therapeutic use , Cetuximab/therapeutic use , Fatal Outcome , Gastrointestinal Hemorrhage/diagnosis , Hematemesis/diagnosis , Humans , MaleABSTRACT
Diabetes mellitus can lead to diabetic polyneuropathy (DPN) and cognitive deficits that manifest as peripheral and central neuropathy, respectively. In this study we investigated the relationship between visuospatial working memory (VSWM) capacity and DPN severity, and attempted to improve VSWM in DPN patients via the use of transcranial direct current stimulation (tDCS). Sixteen DPN patients and 16 age- and education-matched healthy control subjects received Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) and Montreal Cognitive Assessment (MOCA) for baseline cognitive assessment. A forward- and backward-recall computerized Corsi block tapping task (CBT), both with and without a concurrent motor interference task was used to measure VSWM capacity. Each DPN patient underwent a pre-treatment CBT, followed by tDCS or sham treatment, then a post-treatment CBT on two separate days. We found that although patients with severe DPN (Dyck's grade 2a or 2b) showed comparable general intelligence scores on WAIS-IV as their age- and education-matched healthy counterparts, they nonetheless showed mild cognitive impairment (MCI) on MOCA and working memory deficit on digit-span test of WAIS-IV. Furthermore, patients' peripheral nerve conduction velocity (NCV) was positively correlated with their VSWM span in the most difficult CBT condition that involved backward-recall with motor interference such that patients with worse NCV also had lower VSWM span. Most importantly, anodal tDCS over the right DLPFC was able to improve low-performing patients' VSWM span to be on par with the high-performers, thereby eliminating the correlation between NCV and VSWM. In summary, these findings suggest that (1) MCI and severe peripheral neuropathy can coexist with unequal severity in diabetic patients, (2) the positive correlation of VSWM and NCV suggests a link between peripheral and central neuropathies, and (3) anodal tDCS over the right DLPFC can improve DPN patients' VSWM, particularly for the low-performing patients.
ABSTRACT
Stimulated by retinoic acid gene homolog 6 (STRA6) and retinoic acid receptor responder 2 (RARRES2) are candidate genes involved in the pathogenesis of type 2 diabetes mellitus (T2DM). Three tag-SNPs in STRA6 and one in RARRES2 gene were selected and genotyped with TaqMan or PCR-RFLP method in 603 populations (571 patients with T2D versus 632 control subjects) in Southern Han Chinese. We estimated the interactions between T2DM risk and genetic variants in the STRA6 and RARRES2 genes using polymerase chain reaction. Rs736118 in STRA6 gene were significantly associated with T2DM occurrence in the recessive genetic model. The genotype of rs974456 was significantly associated with T2DM in the dominant genetic model correlated to sex, MBI, and triglyceride. However, the association of other SNPs with T2DM was not found. Furthermore, smoking history and other factors may be independent risk factors for the incidence of T2DM. This study suggested that a role of STRA6 polymorphism could also be of value in predicting the risk of T2DM while RARRES2 polymorphism could not predict the risk of T2DM.
Subject(s)
Chemokines/genetics , Diabetes Mellitus, Type 2/genetics , Genetic Predisposition to Disease , Intercellular Signaling Peptides and Proteins/genetics , Membrane Proteins/genetics , Aged , China , Diabetes Mellitus, Type 2/pathology , Female , Genetic Association Studies , Genotype , Humans , Male , Middle Aged , Polymorphism, Single NucleotideABSTRACT
BACKGROUND: A small group of patients with inherited neuropathy that has been shown to be caused by mutations in the BSCL2 gene. However, little information is available about the role of BSCL2 mutations in inherited neuropathies in Taiwan. METHODOLOGY AND PRINCIPAL FINDINGS: Utilizing targeted sequencing, 76 patients with molecularly unassigned Charcot-Marie-Tooth disease type 2 (CMT2) and 8 with distal hereditary motor neuropathy (dHMN), who were selected from 348 unrelated patients with inherited neuropathies, were screened for mutations in the coding regions of BSCL2. Two heterozygous BSCL2 mutations, p.S90L and p.R96H, were identified, of which the p.R96H mutation is novel. The p.S90L was identified in a pedigree with CMT2 while the p.R96H was identified in a patient with apparently sporadic dHMN. In vitro studies demonstrated that the p.R96H mutation results in a remarkably low seipin expression and reduced cell viability. CONCLUSION: BSCL2 mutations account for a small number of patients with inherited neuropathies in Taiwan. The p.R96H mutation is associated with dHMN. This study expands the molecular spectrum of BSCL2 mutations and also emphasizes the pathogenic role of BSCL2 mutations in molecularly unassigned hereditary neuropathies.