Methods for Improving Brain-Computer Interface: Using A Brain-Directed Adjuvant and A Second-Generation Artificial Intelligence System to Enhance Information Streaming and Effectiveness of Stimuli

Background: The brain-computer interface (BCI) is gaining much attention to treat neurological disorders and improve brain-dependent functions. Significant achievements over the last decade have focused on engineering and computation technology to enhance the recording of signals and the generation of output stimuli. Nevertheless, many challenges remain for the translation of BCIs to clinical applications. Methods: We review the relevant data on the four significant gaps in enhancing BCI's clinical implementation and effectiveness. Results: The paper describes three methods to bridge the current gaps in the clinical application of BCI. The first is using a brain-directed adjuvant with a high safety profile, which can improve the accuracy of brain signaling, summing of information, and production of stimuli. The second is implementing a second-generation artificial intelligence system that is outcome-oriented for improving data streaming, recording individualized brain-variability patterns into the algorithm, and improving closed-loop learning at the level of the brain and with the target organ. The system overcomes the compensatory mechanisms that underlie the loss of stimuli' effectiveness for ensuring sustainable effects. Finally, we use inherent brain parameters relevant to consciousness and brain function to bridge some of the described gaps. Conclusions: Combined with the currently developed techniques for enhancing effectiveness and ensuring a sustainable response, these methods can potentially improve the clinical outcome of BCI techniques.

Clinical characteristics and prognostic risk factors of patients with colchicine poisoning / 中华急诊医学杂志

Objective:To explore the clinical characteristics of patients with colchicine poisoning, and analyze the risk factors affecting the prognosis of colchicine poisoning and its value in the prognostic assessment.Methods:Patients with colchicine poisoning admitted to the Emergency Intensive Care Unit of the First Affiliated Hospital of Wenzhou Medical University from December 2017 to October 2022 were retrospectively included and divided into the survival group and death group according to the 14-d outcome. The general conditions of the two groups of patients were compared, and the clinical characteristics of patients with colchicine poisoning were analyzed. The differences of laboratory indexes, electrocardiogram, cardiac ultrasound and other clinical indexes during the first admission of patients between the two groups were compared, and their value in the prognosis evaluation of patients with colchicine poisoning was explored.Results:There were 41 patients with colchicine poisoning, aged 15-85 years, including 35 males and 6 females. There were 27 patients (65.9%) in the survival group and 14 patients (34.1%) in the death group, including accumulative poisoning (58.7%) and suicide poisoning (41.3%). The main clinical manifestations of patients with colchicine poisoning were gastrointestinal symptoms (82.93%), multiple organ dysfunction (78.05%), infectious fever (73.17%), myocardial damage (48.78%), coagulation dysfunction (46.34%), and bone marrow suppression (41.46%). Intestinal obstruction (19.51%) and rhabdomyolysis (2.44%) occurred in some patients. Multivariate Logistic regression analysis showed that the increase in absolute value of QTc interval ( OR=1.028, 95% CI: 1.000~1.056, P<0.05), lactic acid ( OR=1.599, 95% CI: 1.088~2.350, P<0.05), prothrombin time ( OR=1.205, 95% CI: 1.002~1.450, P<0.05), D-dimer ( OR=1.242, 95% CI: 1.089~1.417, P<0.05), and alkaline phosphatase ( OR=1.013, 95% CI: 1.002~1.024, P<0.05) were the risk factors for the prognosis of patients with colchicine poisoning. The decrease in the absolute value of ADL score ( OR=0.947, 95% CI: 0.909~0.988, P<0.05) and indirect bilirubin ( OR=0.756, 95% CI: 0.572~0.999, P<0.05) were the protective factors for the prognosis of patients with colchicine poisoning. D-dimer (AUC=0.913), lactic acid (AUC= 0.875) and alkaline phosphatase (AUC=0.770) had predictive value for the prognosis of patients with colchicine poisoning, and their cut-off values were 8.965 mg/L, 4.05 mmol/L and 230.5 U/L, respectively. Conclusions:The patients with colchicine poisoning have multiple organ dysfunction on admission, and are in a critical condition. The early levels of D-dimer, lactic acid and alkaline phosphatase could effectively predict the prognosis of patients with colchicine poisoning.

Efficacy and safety of Ixekizumab vs. low-dose IL-2 vs. Colchicine vs. standard of care in the treatment of patients hospitalized with moderate-to-critical COVID-19: A pilot randomized clinical trial (STRUCK: Survival Trial Using Cytokine Inhibitors)

ABSTRACT Background: Cases of coronavirus disease 2019 (COVID-19) requiring hospitalization continue to appear in vulnerable populations, highlighting the importance of novel treatments. The hyperinflammatory response underlies the severity of the disease, and targeting this pathway may be useful. Herein, we tested whether immunomodulation focusing on interleukin (IL)-6, IL-17, and IL-2, could improve the clinical outcomes of patients admitted with COVID-19. Methods: This multicenter, open-label, prospective, randomized controlled trial was conducted in Brazil. Sixty hospitalized patients with moderate-to-critical COVID-19 received in addition to standard of care (SOC): IL-17 inhibitor (ixekizumab 80 mg SC/week) 1 dose every 4 weeks; low-dose IL-2 (1.5 million IU per day) for 7 days or until discharge; or indirect IL-6 inhibitor (colchicine) orally (0.5 mg) every 8 hours for 3 days, followed by 4 weeks at 0.5 mg 2x/day; or SOC alone. The primary outcome was accessed in the "per protocol" population as the proportion of patients with clinical improvement, defined as a decrease greater or equal to two points on the World Health Organization's (WHO) seven-category ordinal scale by day 28. Results: All treatments were safe, and the efficacy outcomes did not differ significantly from those of SOC. Interestingly, in the colchicine group, all participants had an improvement of greater or equal to two points on the WHO seven-category ordinal scale and no deaths or patient deterioration were observed. Conclusions: Ixekizumab, colchicine, and IL-2 were demonstrated to be safe but ineffective for COVID-19 treatment. These results must be interpreted cautiously because of the limited sample size.

Clinical efficacy of etocoxib combined with low dose colchicine in the treatment of acute gouty arthritis in 37 patients / 中国基层医药

Objective:To investigate the clinical efficacy of etocoxib combined with low-dose colchicine in the treatment of acute gouty arthritis in 37 patients.Methods:A total of 74 patients with acute gouty arthritis who received treatment in The Second People's Hospital of Liaocheng from October 2019 to October 2021 were included in this study. They were randomly assigned to undergo treatment with etocoxib alone (control group, n = 37) or etocoxib combined with low-dose colchicine (observation group, n = 37). All patients were treated for 1 week. Clinical efficacy, Visual Analogue Scale score, laboratory indicators, incidence of adverse reactions, and Quality of Life Comprehensive Assessment Questionnaire-74 score were compared between the two groups. Results:The total response rate in the observation group was significantly higher than that in the control group [95% (35/37) vs. 65% (24/37)]. At 1, 3, and 6 days after treatment, the Visual Analogue Scale score in the observation group was significantly lower than that in the control group ( t = 19.77, 15.43, 29.01, all P < 0.001). After treatment, blood uric acid, C-reactive protein, and erythrocyte sedimentation rate in the observation group was (432.26 ± 31.26) μmol/L, (16.25 ± 1.62) mg/L, (31.26 ± 1.25) mm/h, respectively, which was significantly lower than (485.26 ± 39.62) μmol/L, (45.26 ± 3.88) mg/L, (46.52 ± 2.82) mm/h in the control group ( t = 6.39, 41.97, 30.09, all P < 0.001). Quality of Life Comprehensive Assessment Questionnaire-74 score in the observation group was significantly higher than that in the control group ( t = 13.41, 17.73, 16.09, 11.77, all P < 0.001). There was no significant difference in the incidence of adverse reactions between the two groups ( P > 0.05). Conclusion:Etocoxib combined with low-dose colchicine can effectively reduce pain and inflammatory reactions in patients with acute gouty arthritis and improve quality of life, with a low incidence of adverse reactions.

In vitro and in vivo anticancer potential and molecular targets of the new colchicine analog IIIM-067 / 中西医结合学报

OBJECTIVE@#The current study evaluated various new colchicine analogs for their anticancer activity and to study the primary mechanism of apoptosis and in vivo antitumor activity of the analogs with selective anticancer properties and minimal toxicity to normal cells.@*METHODS@#Sulforhodamine B (SRB) assay was used to screen various colchicine analogs for their in vitro cytotoxicity. The effect of N-[(7S)-1,2,3-trimethoxy-9-oxo-10-(pyrrolidine-1-yl)5,6,7,9-tetrahydrobenzo[a] heptalene-7-yl] acetamide (IIIM-067) on clonogenicity, apoptotic induction, and invasiveness of A549 cells was determined using a clonogenic assay, scratch assay, and staining with 4',6-diamidino-2-phenylindole (DAPI) and annexin V/propidium iodide. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels were observed using fluorescence microscopy. Western blot analysis was used to quantify expression of proteins involved in apoptosis, cell cycle, and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling. Pharmacokinetic and in vivo efficacy studies against Ehrlich ascites carcinoma (EAC) and Ehrlich solid tumor models were conducted using Swiss albino mice.@*RESULTS@#IIIM-067 showed potent cytotoxicity and better selectivity than all other colchicine analogs screened in this study. The selective activity of IIIM-067 toward A549 cells was higher among other cancer cell lines, with a selectivity index (SI) value of 2.28. IIIM-067 demonstrated concentration- and time-dependent cytotoxicity against A549 cells with half-maximal inhibitory concentration values of 0.207, 0.150 and 0.106 μmol/L at 24, 48 and 72 h, respectively. It also had reduced toxicity to normal cells (SI > 1) than the parent compound colchicine (SI = 1). IIIM-067 reduced the clonogenic ability of A549 cells in a dose-dependent manner. IIIM-067 enhanced ROS production from 24.6% at 0.05 μmol/L to 82.1% at 0.4 μmol/L and substantially decreased the MMP (100% in control to 5.6% at 0.4 μmol/L). The annexin V-FITC assay demonstrated 78% apoptosis at 0.4 μmol/L. IIIM-067 significantly (P < 0.5) induced the expression of various intrinsic apoptotic pathway proteins, and it differentially regulated the PI3K/AKT/mTOR signaling pathway. Furthermore, IIIM-067 exhibited remarkable in vivo anticancer activity against the murine EAC model, with tumor growth inhibition (TGI) of 67.0% at a dose of 6 mg/kg (i.p.) and a reduced mortality compared to colchicine. IIIM-067 also effectively inhibited the tumor growth in the murine solid tumor model with TGI rates of 48.10%, 55.68% and 44.00% at doses of 5 mg/kg (i.p.), 6 mg/kg (i.p.) and 7 mg/kg (p.o.), respectively.@*CONCLUSION@#IIIM-067 exhibited significant anticancer activity with reduced toxicity both in vitro and in vivo and is a promising anticancer candidate. However, further studies are required in clinical settings to fully understand its potential.

Colchicina, perspectivas de un viejo amigo para la reumatología en la COVID-19: una revisión exploratoria / no

Introducción: La colchicina es ampliamente utilizada en enfermedades inflamatorias como la gota y la fiebre mediterránea familiar. Debido a su capacidad inmunomoduladora, podría tener un papel importante en el tratamiento de la COVID-19. Objetivo: Explorar la evidencia médica publicada hasta el 28 de diciembre del 2020, acerca de la eficacia y la seguridad de la colchicina en el tratamiento de pacientes con infección confirmada por SARS-CoV-2. Material y métodos: Revisión exploratoria de la literatura que incluyó PubMed y Scopus. Se tuvieron en cuenta registros de ensayos clínicos y publicaciones con datos empíricos (estudios observacionales y experimentales) en inglés y español. Resultados: Se encontraron 33 ensayos clínicos y 6 publicaciones empíricas: estudios de cohorte prospectivos (n = 2) y retrospectiva (n = 2), ensayo clínico aleatorizado (n = 1) y estudio casos y controles (n = 1). La suma de los participantes en los ensayos es de 46.324 individuos, el 73% (24/33) de los estudios recluta a la población de estudio y el 51% (17/33) son fase 3. Conclusiones: Un ensayo clínico respalda la disminución en marcadores inflamatorios pronósticos y el tiempo de estancia hospitalaria en la infección por SARS-CoV-2. Los ensayos clínicos en desarrollo ayudarán a esclarecer la eficacia y la seguridad de la colchicina para el manejo de pacientes con COVID-19.

Introduction: Colchicine is widely used to treat inflammatory diseases such as gout and Mediterranean fever. Due to its immunomodulatory capacity, it could play an important role in the treatment of COVID-19. Objective: To explore the current available medical evidence, published until 28 December 2020, regarding the efficacy and safety of colchicine in the treatment of patients with confirmed SARS-CoV-2 infection. Material and methods: Scoping review of the literature that included PubMed and Scopus. Records of clinical trials and publications with empirical data (observational and experimental studies) in English and Spanish were included. Results: A total of 33 clinical trials and 6 publications were found: prospective (n = 2) and retrospective (n = 2) cohort studies, randomised clinical trials (n = 1) and case-control studies (n = 1). The total number of participants in the trials is 46,324 individuals, 73% (24/33) of the studies are recruiting participants and 51% (17/33) are phase 3 studies. Conclusions: One clinical trial reports a decrease in prognostic inflammatory markers and length of hospital stay in SARS-CoV-2 infection. The ongoing clinical trials will clarify the efficacy and safety of colchicine for the management of patients with COVID-19.

Colchicine for pericarditis due to COVID-19: a case report

The pericardium is a fibroelastic sac made up of visceral and parietal layers separated by a (potential) space, the pericardial cavity.The most troublesome complication of acute pericarditis is the development of recurrent episodes of pericardial inflammation, occurring in 15% to 32% of cases. Therapeutic modalities are nonspecific and include non-steroidal anti-inflammatory drugs(NSAIDs) and corticosteroids. Here we present a case of a patient presenting with pericarditis due to COVID-19. He was successfully treated with colchicine. To our knowledge acute pericarditis due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)might be an under diagnosed condition in this pandemic. We want to share our findings, given the urgent need for different diagnostic and therapeutic strategies in order to better manage COVID-19 patients, and diminish the SARS-CoV-2 complications.

Predictive factors of recurrence after pediatric acute pericarditis

Abstract Objective The predisposing factors for pericarditis recurrence in the pediatric population have not yet been established. This study aimed to define the risk factors for the unfavorable prognosis of pediatric acute pericarditis. Methods This was a retrospective study that included all patients with acute pericarditis treated from 2011 to 2019 at a tertiary referent pediatric center. Results The study included 72 children. Recurrence was observed in 22.2% patients. Independent risk factors for recurrence were: erythrocyte sedimentation rate ≥ 50 mm/h (p = 0.003, OR 186.3), absence of myocarditis (p = 0.05, OR 15.2), C-reactive protein ≥ 125 mg/L (p = 0.04, OR 1.5), and non-idiopathic etiology pericarditis (p = 0.003, OR 1.3). Corticosteroid treatment in acute pericarditis was associated with a higher recurrence rate than treatment with non-steroid anti-inflammatory therapy (p = 0.04). Furthermore, patients treated with colchicine in the primary recurrence had lower recurrence rate and median number of repeated infections than those treated without colchicine (p = 0.04; p = 0.007, respectively). Conclusion Independent risk factors for recurrence are absence of myocarditis, non-idiopathic etiology pericarditis, C-reactive protein ≥ 125 mg/L, and erythrocyte sedimentation rate ≥ 50 mm/h. Acute pericarditis should be treated with non-steroid anti-inflammatory therapy. A combination of colchicine and non-steroid anti-inflammatory drugs could be recommended as the treatment of choice in recurrent pericarditis.

Estudio de utilización de fármacos antigotosos en población colombiana, 2016 / Patterns of anti-gout drug use in a Colombian population: 2016

RESUMEN Objetivo: Identificar las características clínicas de los pacientes con gota y la forma de utilización de los medicamentos antigotosos en Colombia. Métodos: Estudio de corte transversal en el que se analizaron 310 historias clínicas de pacientes atendidos en el último trimestre del 2016 y que recibieron un medicamento antigotoso. Se identificaron variables sociodemográficas, clínicas, farmacológicas, comorbilidades y paraclínicas. Para cada medicamento antigotoso se determinó si el uso fue según las recomendaciones aprobadas por la Federal Drug Administration (FDA). Se realizaron análisis descriptivos, bivariados y multivariados. Resultados: Se evaluaron pacientes de 14 diferentes ciudades de Colombia, con un predominio masculino del 70,3% (n = 218) y una mediana de edad de 64 arios (RIC: 26-94 arios). El antigotoso más frecuentemente utilizado fue alopurinol (n = 255; 82,3%), seguido de colchicina (n = 54; 17,4%). Los diagnósticos hallados como indicación fueron: hiperuricemia (n = 181; 58,4%), gota (n = 34; 11%), artritis gotosa (n = 28; 9%). El 74,5% (n = 231) de las prescripciones tenía un uso aprobado según la FDA, especialmente alopurinol en el manejo de gota e hiperuricemias, mientras que colchicina se encontró siendo utilizada en indicaciones no aprobadas (n = 44; 81,4%). Las comorbilidades más frecuentes fueron hipertensión (68,4%) y dislipidemia (55,8%). Conclusiones: Los pacientes con gota en tratamiento farmacológico tienen una elevada frecuencia de comorbilidades cardiovasculares, y están siendo tratados con alopurinol para la prevención a largo plazo, mientras que una menor proporción recibe colchicina que comúnmente es utilizada para indicaciones no aprobadas por las agencias reguladoras.

ABSTRACT Objective: To identify the clinical characteristics of patients with gout, and the prescription patterns of anti-gout medications in Colombia. Methods: Cross-sectional study, that analysed the data from 310 medical records of patients treated in the last quarter of 2016, and who received an anti-gout medication. Sociodemographic, clinical, pharmacological, comorbidities, and paraclinical variables were identified. For each anti-gout drug used, it was determined whether the use was in accordance with Federal Drug Administration (FDA) approved recommendations. Descriptive, bivariate and multivariate analyses were performed. Results: Patients from 14 different cities in Colombia were evaluated, with a male predominance of 70.3% (n = 218) and a median age of 64 years (RIC: 26-94 years). The most frequently used anti-gout medication was allopurinol (n = 255; 82.3%), followed by colchicine (n = 54; 17.4%). The main diagnoses found as an indication were: hyperuricaemia (n=181, 58.4%), gout (n = 34; 11.0%), and gouty arthritis (n = 28; 9.0%). Almost three-quarters (74.5%; n = 231) of the prescriptions had an approved use according to the FDA, especially allopurinol in the management of gout and hyperuricaemia, while colchicine was found to be used in unapproved indications (n = 44, 81.4%). The most frequent comorbidities were hypertension (68.4%) and dyslipidaemia (55.8%). Conclusions: Patients with gout who are under pharmacological treatment have a high frequency of cardiovascular comorbidities. They were being treated with allopurinol for long-term prevention, while a smaller proportion received colchicine, which is often used for indications not approved by regulatory agencies.

¿La colchicina puede prevenir el infarto agudo de miocardio? Revisión sistemática y metaanálisis / Can colchicine prevent acute myocardial infarction? Systematic review and meta-analysis

RESUMEN Introducción y objetivos: La asociación entre el uso de colchicina y la incidencia de infarto agudo de miocardio (IAM) es heterogénea. El objetivo principal del presente estudio fue evaluar el efecto de la colchicina sobre la incidencia de IAM. La evaluación de la incidencia de accidente cerebrovascular (ACV) y la mortalidad cardiovascular fueron los objetivos secundarios. Material y métodos: Se realizó un metaanálisis de estudios aleatorizados que evaluaron el uso de colchicina en pacientes con enfermedad aterosclerótica y que reportaron los eventos cardiovasculares, luego de una búsqueda en las bases de datos PubMed/MEDLINE, Embase, Scielo y Cochrane Controlled Trials. Se utilizó un modelo de efectos fijos o aleatorios según la heterogeneidad observada. Resultados: Se seleccionaron para el análisis del punto final primario 7 estudios (con un total de 5966 sujetos en la rama colchicina y 5948 pacientes en la rama control). Este metaanálisis demostró que la terapia con colchicina se asoció a un menor riesgo de IAM (OR: 0,76, IC 95%: 0,62-0,92; I2=15%). Asimismo, se observó una reducción significativa en la incidencia de ACV, sin un efecto significativo en la mortalidad cardiovascular, con la intervención farmacológica. Conclusión: El uso de colchicina en pacientes con enfermedad cardiovascular aterosclerótica se asoció a una reducción significativa en la incidencia de IAM. La incorporación de la colchicina dentro del arsenal terapéutico de la enfermedad cardiovascular deberá ser considerada por las futuras guías de práctica clínica.

SUMMARY Introduction and objectives: The association between the use of colchicine and the incidence of acute myocardial infarction (AMI) is inconsistent. The main objective of this study was to evaluate the effect of colchicine on the incidence of AMI. Assessment of the incidence of stroke and cardiovascular mortality were secondary endpoints. Methods: A meta-analysis of randomized studies that evaluated the use of colchicine in patients with atherosclerotic disease and reported cardiovascular events was performed, after searching the PubMed/MEDLINE, Embase, Scielo and Cochrane Controlled Trials databases. A fixed or random effects model were used depending on the heterogeneity observed. Results: Seven studies were selected for the analysis of the primary end point (5966 subjects in the colchicine arm and 5948 patients in the control arm). This meta-analysis demonstrated that colchicine therapy was associated with a lower risk of AMI (OR: 0.76, 95% CI: 0.62-0.92; I2 = 15%). Likewise, a significant reduction in the incidence of stroke was observed without a significant effect on cardiovascular mortality with pharmacological intervention. Conclusion: The use of colchicine in patients with atherosclerotic cardiovascular disease was associated with a significant reduction in the incidence of AMI. The incorporation of colchicine into the therapeutic arsenal of cardiovascular disease should be considered by future clinical practice guidelines.

A case report of colchicine-induced myopathy in a patient with chronic kidney disease / 北京大学学报(医学版)

Colchicine plays an important role in the treatment of gout and some other diseases. Besides gastrointestinal symptoms, myopathy has been reported as a rare side effect of colchicine in some patients. We report a case of myopathy in a patient with chronic kidney disease caused by high-dose colchicine, and then review literature on colchicine-induced myopathy, so as to provide some experience for the clinical diagnosis, treatment and medication safety. A 51-year-old male patient with 10 years of gout and 5 years of chronic kidney disease history and irregular treatment was admitted to the hospital with complaint of recurrent left wrist arthralgia and emerging lower extremities myalgia after intake of 40-50 mg colchicine in total within 20 days. Laboratory examinations showed significantly increased creatine kinase (CK) and then colchicine-induced myopathy was diagnosed preliminarily. After withdrawl of colchicine and implementation of hydration, alkalization and intramuscular injection of compound betamethasone, the symptoms of arthralgia and myalgia were relieved within 3 days and CK decreased to normal range gradually. According to literature reports, colchicine related myopathy was mostly characterized by proximal myasthenia and myalgia, accompanied by elevated CK level, which usually occurred days to weeks after initial administration of colchicine at the usual dosage in patients with renal impairment or a change in the underlying disease state in those receiving long-term therapy, and the features might remit within three to four weeks after the drug was discontinued. Electromyography of proximal muscles showed myopathy marked by abnormal spontaneous activity and muscle pathology waa marked by accumulation of lysosomes and autophagic vacuoles. Chronic kidney disease, liver cirrhosis, higher colchicine dose and concomitant cytochrome P450 3A4 (CYP3A4) inhibitors were associated with increased risk of myo-pathy. Based on the similar efficacy and lower adverse reaction rate compared with larger dosage, small dose of colchicine was recommended by many important current guidelines and recommendations in the treatment of gout. In consideration of potential risks, colchicine should be used with caution in patients with kidney or liver impairment, and in those taking CYP3A4 or P-glycoprotein inhibitors. For those patients, the drug dose should be adjusted and the latent adverse reactions should be monitored carefully.

Initiation of Urate Lowering Therapy (ULT)

@#Mr Tan, 60, a smoker with diabetes mellitus (DM), hypertension and chronic kidney disease (CKD) Stage 3, and recurrent gout flares last five weeks of increasing intensity and duration. He assumes it is due to frequent travel and lack of exercise. He comes today for routine review of his chronic diseases. Current laboratory results are creatinine 106, eGFR 56, uric acid 490, HbA1c 7.3%, random hypocount 8.5 mmol/L. He is on glipizide 5mg bd, Metformin 250mg BD, Amlodipine 5mg OM. He complains of severe gout pain. He had always been reluctant to start definitive treatment which you had previously mentioned. What will you do next?

De novo transcriptome assembly and mining of EST-SSR markers in Gloriosa superba

Gloriosa superba is an economical source of pharmaceutical colchicine, which is a mitotic poison used to treat gout, cancer and inflammatory diseases. It is important to study the genetic variations in this plant, but the progress is impeded due to limited number of molecular markers. In this study, we developed the expressed sequence tag-derived simple sequence repeat (EST-SSR) markers from the transcriptome sequence of the leaf samples of three different ecotypes of G. superba. De novo assembly was performed on these sequencing data to generate a total of 65,579 unigenes and 38,200 coding sequences (CDSs). These CDSs were annotated using NCBI Nr protein database, gene ontology terms and KEGG pathways. Differential gene expression was studied to yield differences in these ecotypes at the molecular level. Finally, a total of 14,672 potential EST-SSRs were identified from these unigenes, among which the dinucleotide (5754, 39.22%) and trinucleotide (5421, 36.95%) repeats were most abundant types followed by mononucleotides (3213, 21.83%). The most frequent motifs were CT/GA (1392, 9.48%), AG/TC (1219, 8.31%), and GA/CT (1146, 7.82%) among the dinucleotide repeats and CCG/ CGG (1487, 10.13%), AGG/CCT (1421, 9.68%), AGC/CTG (697, 4.75%) and AAG/CTT (621, 4.23%) among the trinucleotide repeats. Polymorphism study using a random set of 20 newly developed EST-SSRs revealed polymorphic information content value ranging from 0 to 0.5926 with an average of 0.4021. The large-scale ESTs developed in the current study will be useful as a genomic resource for further investigation of the genetic variations in this species

Inflammation in Cardiovascular Disease: From Basic Concepts to Clinical Application

Abstract Although low-density lipoprotein cholesterol is central to the development and progression of atherosclerosis, the role of inflammation in the atherosclerotic process is becoming better understood and appreciated. Chronic inflammatory conditions such as rheumatoid arthritis, lupus, psoriasis, HIV infection, and inflammatory bowel disease have all been shown to be associated with an increased blood levels of inflammatory biomarkers and increased risk of cardiovascular events. Evidence from observational studies suggests that anti-inflammatory therapy decreases this risk in these conditions. Clinical trials of anti-inflammatory drugs in patients with coronary disease have yielded mixed results. Drugs that have failed in recent trials include the P38 MAP kinase inhibitor losmapimod, the phospholipase A2 inhibitors darapladib and varespladib, and methotrexate. Canakinumab, an interleukin-1β inhibitor, reduced cardiovascular events in patients with coronary disease in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS). Canakinumab increased the rate of fatal infections in CANTOS and is very expensive; it is thus unlikely to be widely used for risk reduction in cardiology. On the other hand, colchicine is a safe and inexpensive anti-inflammatory drug. In the Colchicine Cardiovascular Outcomes Trial (COLCOT), where patients within 30 days of a myocardial infarction were randomized to low-dose colchicine or placebo and followed for a median of almost 2 years, colchicine treatment was associated with a 23% reduction (p=0.02) in cardiovascular events. Newer studies with anti-inflammatory drugs have the potential to improve outcomes of patients with atherosclerosis, just as low-density lipoprotein cholesterol-lowering drugs have done over the past two decades.

Synthesis, Characterization, In Silico And In Vitro Studies Of Transition Metal Complexes With Biologically Active Ligand As Antigout Agent Colchicine

Colchicine is essentially useful in the treatment of gout. In the present work Colchicine Complexes has been prepared with transition metals viz; Copper(II) [Cu(II)], Zinc (II) [Zn(II)], Cobalt (II) [Co(II)], Nickel (II) [Ni(II)] and those checked for molecular docking, it has been observed that Zn(II) and Ni(II) complex has revealed good binding energy than the parent ligand, the increased binding energy of colchicine metal complexes indicates that, the tubulin polymerization inhibitor tendency is enhanced, consequently antigout property is also increased. As transition metals have antimicrobial activity in themselves, complexes are also characterized for the antimicrobial activity which is enhanced for Cu(II) and Co(II) metals.

Assessment of effectiveness of anakinra and canakinumab in patients with colchicine-resistant/unresponsive familial Mediterranean fever

Abstract İntroduction: Familial Mediterranean fever (FMF) is a hereditary auto-inflammatory disease characterized by recurrent fever and serosal inflammation. Anti-interleukin-1 (Anti-IL-1) treatments are recommended in colchicine resistant and/or intolerant FMF patients. This study aims to evaluate the efficacy of anakinra and canakinumab in FMF patients that are resistant/intolareted to colchicine or complicated with amyloidosis. Methods: Between January 2014 and March 2019, 65 patients following-up at Sivas Cumhuriyet University (Medical Faculty Rheumatology-Internal Medicine Department) who were diagnosed with FMF according to the criteria of Tel-Hashomer were included in the study. The laboratory values and clinical features of patients and disease activities were recorded at least every 3 months, and these data were analyzed. Results: Forty-one (63.1%) patients used anakinra (100 mg/day) and 24 (36.9%) patients used canakinumab (150 mg/8 week). The median duration of anti-IL-1 agents use was 7 months (range, 3-30). Fifteen (23.1%) cases were complicated with amyloidosis. Seven (10.8%) patients had renal transplantation. Overall, the FMF 50 score response was 96.9%. In the group that had a glomerular filtration rate (GFR) ≥ 60 ml/min/m2, the median proteinuria decreased from 2390 mg/day (range, 1400-7200) to 890 mg/day (range, 120-2750) (p = 0.008). No serious infections were detected, except in one patient. Conclusions: Anti-IL-1 agents are effective and safe in the treatment of FMF patients. These agents are particularly effective at reducing proteinuria in patients with GFR ≥ 60 ml/min/m2, but less effective in cases with FMF associated with arthritis and sacroiliitis. Large and long follow-up studies are now needed to establish the long-term effects of these treatments.

Glia maturation factor-gamma inhibits the proliferation of human colorectal cancer LoVo cells and affects the cytoskeletal motion of human umbilical vein endothelial cells / 中国组织工程研究

BACKGROUND: Glial maturation factor-gamma (GMFG) is one of the members of the ADF/cofilin superfamily protein in the process of cytoskeleton remodeling. It can regulate the cell movement by regulating actin-mediated cytoskeleton reorganization. The authors previously found that the high expression of GMFG is associated with the clinicopathological features of colorectal cancer patients, but the specific upstream and downstream mechanisms need to be explored. OBJECTIVE: To study the effects of GMFG on cytoskeleton and LoVo cell proliferation. METHODS: (1) Human umbilical vein endothelial cells were inoculated in a laser confocal dish. After the cells grew stably, the correlation between the expression of GMFG and the expression of cytoskeletal protein F-actin was observed by immunofluorescence staining. Colchicine inhibited mitosis. The cells were divided into control group, 0.5 mg/L colchicine group and 1.0 mg/L colchicine group. The cell cycle was observed by flow cytometry and GMFG protein expression was observed by western blot assay. (2) Human colorectal cancer LoVo cells were inoculated in a laser confocal dish. After the cells grew stably, the correlation between GMFG expression and cell cycle was observed by immunofluorescence staining. Afterwards, siRNA was used to interfere the expression of GMFG in LoVo cells. The LoVo cells were divided into blank control group, empty transfer group and siRNA-GMFG group. The cell proliferation rate was detected by Edu assay. RESULTS AND CONCLUSION: (1) In human umbilical vein endothelial cells, the expression of GMFG was associated with the cytoskeletal motion of human umbilical vein endothelial cells, and the expression of GMFG increased when the cytoskeleton retracted. After colchicine inhibited the mitosis of human umbilical vein endothelial cells, the proportion of cells in G2/M phase increased and the expression of GMFG protein decreased with the increase of colchicine dosage. (2) In LoVo cells, the expression intensity of GMFG was associated with mitosis, and the expression of GMFG was enhanced in the middle and late stages of cell mitosis. (3) After siRNA interference with GMFG in LoVo cells, the cell proliferation rate was decreased. (4) Results verify that interference with GMFG can inhibit the proliferation rate of LoVo cells of human colorectal cancer, and there is a certain correlation between cytoskeletal motion and GMFG expression.

Efficacy of Modified Guiling Ganluyin Combined with Colchicine in Treatment of Gouty Arthritis with Damp-heat Accumulation / 中国实验方剂学杂志

Objective:To explore the clinical efficacy of modified Guiling Ganluyin combined with colchicine in treatment of gouty arthritis(GA) damp-heat accumulation. Method:A total of 210 cases of GA were randomly divided into traditional Chinese medicine(TCM) group(70 cases), western medicine group (70 cases), and integrated traditional Chinese and western medicine group(70 cases) according to the digital table method. The patients in TCM group were treated with modified Guiling Ganluyin, the patients in western medicine group were treated with colchicine, and the patients in integrated traditional Chinese and western medicine group received modified Guiling Ganluyin + colchicine, with a treatment course of 30 d in all groups. The clinical symptoms before and after the treatment [joint pain visual analogue scale(VAS), patient global appraise(PGA), number rating scale for pain(NRS)], inflammatory cytokines in serum and joint fluid [tumor necrosis factor-alpha(TNF-α), interleukin-1β(IL-1β), uric acid(UA)], hemorheology index [whole blood high cut viscosity(HCV), whole blood low cut viscosity(LCV), whole blood reductive viscosity(RV)]in 3 groups were observed. The total effective rate and the adverse reactions were compared. Result:Six cases fell off during the study period. The total effective rate in integrated traditional Chinese and western medicine group was 97.1%（67/69）, which higher than 80.8%(55/68) in TCM group (χ2=8.153, P<0.05) and 79.1%(53/67) in western medicine group (χ2=8.735, P<0.05）. Compared with TCM group and western medicine group, the clinical symptoms VAS and NRS scores in integrated traditional Chinese and western medicine group were significantly lower(P<0.05), while the PGA scores were significantly higher(P<0.05). TNF-α, IL-1β and UA in serum and articular fluid in integrated traditional Chinese and western medicine group were significantly decreased(P<0.05). HCV, LCV and RV were significantly decreased in integrated traditional Chinese and western medicine group(P<0.05). Compared with the traditional Chinese and western medicine group, the incidence of adverse reactions was higher in the western medicine group (χ2=5.538,P<0.05) and lower in the Chinese medicine group (χ2=6.273，P<0.05). Conclusion:Modified Guiling Ganluyin combined with colchicine has the effects in enhancing effect and reducing toxicity, and could improve the clinical symptoms of GA patients with damp-heat accumulation, with a low incidence of adverse reactions.

Clinical Efficacy of Modified Bixie Shengshitang on Acute Gouty Arthritis Due to Hot and Humid Syndrome / 中国实验方剂学杂志

Objective:To observe the clinical efficacy of modified Bixie Shengshitang on acute gouty arthritis due to hot and humid syndrome. Method:According to the random number table method， 130 cases were randomly divided into control group and observation group， with 65 cases in each group. All of the cases were given the basic non-drug therapy. The control group was given colchicine， while observation group was given modified Bixie Shengshitang + colchicine for 14 d. Before treatment and at 3， 7 and 14 d after treatment， total symptom score （TSS） and traditional Chinese medicine （TCM） syndrome were observed between the two groups， respectively. Blood uric acid （BUA）， urinary uric acid （UUA）， erythrocyte sedimentation rate （ESR）， proinflammatory factors ［tumor necrosis factor-α （TNF-α）， interleukin-1 （IL-1）， interleukin-8 （IL-8）］ and anti-inflammatory factors ［interforon gamma receptor （IFN-γ）， interleukin-4 （IL-4）， interleukin-18（IL-18）］ in serum and joint fluid were detected before and after treatment. The clinical efficacy and safety of the two groups were compared. Result:The total effective rate was 96.9% （62/64） in observation group， which was higher than 80.6% （50/62） in control group （χ2=5.713， P<0.05）. Compared with control group at 3， 7 and 14 d after treatment， TSS and TCM syndrome scores in observation group were significantly reduced （P<0.05）. Compared with control group after treatment， BUA， ESR， TNF-α， IL-1β， IL-8 and UUA， IFN-γ， IL-4 and IL-18 were significantly decreased in observation group （P<0.05）. There was no serious adverse event during the study period. The incidence of adverse reactions was 54.7% （35/64） in observation group， which was lower than 82.3% （51/62） in control group （χ2=9.326， P<0.05）. Conclusion:Modified Bixie Shengshitang can significantly alleviate the clinical symptoms of patients with acute gouty arthritis due to hot and humid syndrome， and adjust levels of uric acid and inflammatory cytokines， with a low recurrence rate.

Anticancer drug screening: standardization of in vitro wound healing assay / Triagem de drogas anticâncer: padronização do ensaio de ranhura in vitro

ABSTRACT Introduction: Gliomas are characterized by rapid proliferation and aggressive invasion into normal surrounding brain tissue. In medical laboratories, the in vitro wound healing assay stands out as a simple, easy, inexpensive and affordable method to evaluate cell migration and proliferation. Objective: To standardize the in vitro wound healing assay using antimicrotubule drugs as positive controls. Methods: U87MG glioma cells were seeded at different densities and, after 24 h, the monolayer was scratched using different micropipette tip size to create a gap with no cells. The cells were then treated with colchicine and paclitaxel in culture medium with the presence or absence of fetal bovine serum. The wound was photographed with the aid of an inverted microscope and the wound area was measured using the Image J software. Results: Better defined edges scratches and monolayer with approximately 90% confluence were obtained at 1.5 and 2 x 105 cells/well density. The width and area of the scratch were, respectively, 948 pm/2.193221 mm2; 964 pm/2.266 mm2 and 1448 pm/3.221 mm2 to 10. 200 and 1000 pl micropipette tips. Colchicine inhibited wound closure by 12.6% or 3.4%, both in the presence or absence of serum; paclitaxel 2.4 and 6.7% respectively. Conclusion: Under standardized conditions, colchicine and paclitaxel proved to be efficient positive controls into the in vitro wound healing assay.

RESUMEN Introducción: Gliomas se caracterizan por rápida proliferación e invasion agresiva del tejido cerebral normal circundante. En laboratorios médicos, el ensayo de cierre de herida - una prueba in vitro - se destaca por ser un método simple, fácil, de bajo costo y accesiblepara evaluar la migración y la proliferación celular. Objetivo: Estandarizar el ensayo de cierre de herida usando agentes anti-microtúbulos como control positivo. Métodos: Las células de glioma U87MG fueron sembradas en diferentes concentracionesy, después de 24 horas, la monocamadafue rayada con punteras de diferentes tamanos para crear una hendidura sin células. Las células fueron entonces tratadas con colchicina y paclitaxel, en medio con o sin suero fetal bovino. La ranura fue fotografiada con la ayuda de un microscopio invertido, y el área de la ranura fue medida mediante el programa Image J. Resultados: Ranuras con bordes más bien-definidos y monocamada con alrededor de 90% de confluencia se obtuvieron con 1,5 y 2 x 105 células/pozo. La anchura y el área de las ranuras obtenidas fueron, respectivamente, 948 p.m/2,193 mm2; 964p.m/2,266mm2; y 1448p.m/3,221 mm2 para las punteras de 10,200y 1000pl. La colchicina inhibió el cierre de las ranuras en 12,6% o 2,4%, tanto en presencia como en ausencia de suero; el paclitaxel, 3,4% y 6,7%, respectivamente. Conclusión: En condiciones estandarizadas, colchicina y paclitaxel pueden ser usados como control positivo en el ensayo de cierre de herida in vitro.

RESUMO Introdução: Gliomas são caracterizados por terem rápida proliferação e invasão agressiva no tecido cerebral circundante normal. Em laboratórios médicos, o ensaio de ranhura - um teste in vitro - destaca-se por ser um método simples, fácil, barato e acessível para avaliar a migração e a proliferação celular. Objetivo: Padronizar o ensaio de ranhura, utilizando drogas antimicrotúbulos como controles positivos. Métodos: As células de glioma U87MG foram semeadas em diferentes concentrações e, após 24 horas, a monocamada foi arranhada usando ponteiras de diferentes tamanhos para criar uma fenda sem células. As células foram então tratadas com colchicina e paclitaxel, com meio em ausência ou presença de soro fetal bovino. A ranhura foi fotografada com auxílio de microscópio invertido, e a área da ranhura foi medida por meio do programa Image J. Resultados: Ranhuras com bordas mais bem definidas e monocamada com aproximadamente 90% de confluência foram obtidas com 1,5 e 2 x 105 células/poço. A largura e a área das ranhuras obtidasforam, respectivamente, 948pm/2,193 mm2;964pm/2,266mm2; e 1448 pm/3,221 mm2 para as ponteiras de 10, 200 e 1000 pl. A colchicina inibiu o fechamento das ranhuras em 12,6% ou 2,4%, tanto na presença quanto na ausência de soro; o paclitaxel, em 3,4% e 6,7%, respectivamente. Conclusão: Em condições padronizadas, colchicina e paclitaxel podem ser usados como controles positivos eficientes no teste in vitro de ranhura.