Causal Effect of Chondroitin, Glucosamine, Vitamin, and Mineral Intake on Kidney Function: A Mendelian Randomization Study.

The causal effects of chondroitin, glucosamine, and vitamin/mineral supplement intake on kidney function remain unknown, despite being commonly used. We conducted a two-sample summary-level Mendelian randomization (MR) analysis to test for causal associations between regular dietary supplement intake and kidney function. Genetic instruments for chondroitin, glucosamine, and vitamin/mineral supplement intake were obtained from a genome-wide association study of European ancestry. Summary statistics for the log-transformed estimated glomerular filtration rate (log-eGFR) were provided by the CKDGen consortium. The multiplicative random-effects inverse-variance weighted method showed that genetically predicted chondroitin and glucosamine intake was causally associated with a lower eGFR (chondroitin, eGFR change beta = -0.113%, standard error (SE) = 0.03%, p-value = 2 × 10-4; glucosamine, eGFR change beta = -0.240%, SE = 0.035%, p-value = 6 × 10-12). However, a genetically predicted vitamin/mineral supplement intake was associated with a higher eGFR (eGFR change beta = 1.426%, SE = 0.136%, p-value = 1 × 10-25). Validation analyses and pleiotropy-robust MR results for chondroitin and vitamin/mineral supplement intake supported the main results. Our MR study suggests a potential causal effect of chondroitin and glucosamine intake on kidney function. Therefore, clinicians should carefully monitor their long-term effects.

PLM-101 is a novel and potent FLT3/RET inhibitor with less adverse effects in the treatment of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a prevalent form of leukemia in adults. As its survival rate is low, there is an urgent need for new therapeutic options. In AML, FMS-like tyrosine kinase 3 (FLT3) mutations are common and have negative outcomes. However, current FLT3-targeting agents, Midostaurin and Gilteritinib, face two significant issues, specifically the emergence of acquired resistance and drug-related adverse events leading to treatment failure. Rearranged during transfection (RET), meanwhile, is a proto-oncogene linked to various types of cancer, but its role in AML has been limited. A previous study showed that activation of RET kinase enhances FLT3 protein stability, leading to the promotion of AML cell proliferation. However, no drugs are currently available that target both FLT3 and RET. This study introduces PLM-101, a new therapeutic option derived from the traditional Chinese medicine indigo naturalis with potent in vitro and in vivo anti-leukemic activities. PLM-101 potently inhibits FLT3 kinase and induces its autophagic degradation via RET inhibition, providing a superior mechanism to that of FLT3 single-targeting agents. Single- and repeated-dose toxicity tests conducted in the present study showed no significant drug-related adverse effects. This study is the first to present a new FLT3/RET dual-targeting inhibitor, PLM-101, that shows potent anti-leukemic activity and fewer adverse effects. PLM-101, therefore, should be considered for use as a potential therapeutic agent for AML.

Genetically Predicted Body Selenium Concentration and estimated GFR: A Mendelian Randomization Study.

Introduction: Selenium is a trace mineral that is commonly included in micronutrient supplements. The effect of selenium on kidney function remains unclear. A genetically predicted micronutrient and its association with estimated glomerular filtration rate (eGFR) can be used to assess the causal estimates by Mendelian randomization (MR). Methods: In this MR study, we instrumented 11 genetic variants associated with blood or total selenium levels from a previous genome-wide association study (GWAS). The association between genetically predicted selenium concentration and eGFR was first assessed by summary-level MR in the chronic kidney disease(CKDGen) GWAS meta-analysis summary statistics, including 567,460 European samples. Inverse-variance weighted and pleiotropy-robust MR analyses were performed, in addition to multivariable MR adjusted for the effects of type 2 diabetes mellitus. Replication analysis was performed with individual-level UK Biobank data, including 337,318 White individuals of British ancestry. Results: Summary-level MR analysis indicated that a genetically predicted 1 SD increase in selenium concentration was significantly associated with lower eGFR (-1.05 [-1.28, -0.82] %). The results were similarly reproduced by pleiotropy-robust MR analysis, including MR-Egger and weighted-median methods, and consistent even in the multivariable MR adjusted for diabetes. In the UK Biobank data, genetically predicted higher selenium concentration was also significantly associated with lower eGFR (- 0.36 [-0.52, -0.20] %), and the results were similar when body mass index, waist circumference, hypertension, and diabetes mellitus covariates were adjusted (-0.33 [-0.50, -0.17] %). Conclusion: This MR study supports the hypothesis that higher genetically predicted body selenium is causally associated with lower eGFR.

Synthesis and Structure-Activity Relationship Studies of Benzimidazole-4,7-dione-Based P2X3 Receptor Antagonists as Novel Anti-Nociceptive Agents.

P2X3 receptors (P2X3R) are ATP-gated ion channels predominantly expressed in C- and Aδ-fiber primary afferent neurons and have been introduced as a novel therapeutic target for neurological disorders, including neuropathic pain and chronic cough. Because of its localized distribution, antagonism of P2X3R has been thoroughly considered, and the avoidance of issues related to CNS side effects has been proven in clinical trials. In this article, benzimidazole-4,7-dione-based derivatives were introduced as a new chemical entity for the development of P2X3R antagonists. Starting from the discovery of a hit compound from the screening of 8364 random library compounds in the Korea Chemical Bank, which had an IC50 value of 1030 nM, studies of structure-activity and structure-property relationships enabled further optimization toward improving the antagonistic activities as well as the drug's physicochemical properties, including metabolic stability. As for the results, the final optimized compound 14h was developed with an IC50 value of 375 nM at P2X3R with more than 23-fold selectivity versus P2X2/3R, along with properties of metabolic stability and improved solubility. In neuropathic pain animal models evoked by either nerve ligation or chemotherapeutics in male Sprague-Dawley rats, compound 14h showed anti-nociceptive effects through an increase in the mechanical withdrawal threshold as measured by von Frey filament following intravenous administration.

Deep Spinal Infection after Outpatient Epidural Injections for Pain: A Retrospective Sample Cohort Study Using a Claims Database in South Korea.

BACKGROUND: Deep spinal infection is a devastating complication after epidural injection. This study aimed to investigate the incidence of deep spinal infection primarily after outpatient single-shot epidural injection for pain. Secondarily, this study assessed the national trends of the procedure and risk factors for said infection. METHODS: Using South Korea's National Health Insurance Service sample cohort database, the 10-yr national trend of single-shot epidural injections for pain and the incidence rate of deep spinal infection after the procedure with its risk factors were determined. New-onset deep spinal infections were defined as those occurring within 90 days of the most recent outpatient single-shot epidural injection for pain, needing hospitalization for at least 1 night, and receiving at least a 4-week course of antibiotics. RESULTS: The number of outpatient single-shot epidural injections per 1,000 persons in pain practice doubled from 40.8 in 2006 to 84.4 in 2015 in South Korea. Among the 501,509 injections performed between 2007 and 2015, 52 cases of deep spinal infections were detected within 90 days postprocedurally (0.01% per injection). In multivariable analysis, age of 65 yr or more (odds ratio, 2.91; 95% CI, 1.62 to 5.5; P = 0.001), living in a rural area (odds ratio, 2.85; 95% CI, 1.57 to 5.0; P < 0.001), complicated diabetes (odds ratio, 3.18; 95% CI, 1.30 to 6.7; P = 0.005), multiple epidural injections (three times or more) within the previous 90 days (odds ratio, 2.34; 95% CI, 1.22 to 4.2; P = 0.007), and recent use of immunosuppressants (odds ratio, 2.90; 95% CI, 1.00 to 6.7; P = 0.025) were significant risk factors of the infection postprocedurally. CONCLUSIONS: The incidence of deep spinal infection after outpatient single-shot epidural injections for pain is very rare within 90 days of the procedure (0.01%). The data identify high-risk patients and procedure characteristics that may inform healthcare provider decision-making.

Discovery of Novel Pyrimidine-Based Capsid Assembly Modulators as Potent Anti-HBV Agents.

Core assembly modulators of viral capsid proteins have been developed as an effective treatment of chronic hepatitis B virus (HBV) infection. In this study, we synthesized novel potent pyrimidine derivatives as core assembly modulators, and their antiviral effects were evaluated in in vitro and in vivo biological experiments. One of the synthesized derivatives, compound 23h (R1 = MeSO2, R2 = 1-piperidin-4-amine, R3 = 3-Cl-4-F-aniline) displayed potent inhibitory effects in the in vitro assays (52% inhibition in the protein-based assay at 100 nM and an IC50 value of 181 nM in the serum HBV DNA quantification assay). Moreover, treatment with compound 23h for 5 weeks significantly decreased serum levels of HBV DNA levels (3.35 log reduction) in a human liver-chimeric uPA/SCID mouse model, and these effects were significantly increased when 23h was combined with tenofovir, a nucleotide analogue inhibitor of reverse transcriptase used for the treatment of HBV infection.

Disruption of Homeostasis Based on the Right and Left Hemisphere in Patients with Complex Regional Pain Syndrome.

OBJECTIVE: Although the clinical features and pathophysiology of complex regional pain syndrome (CRPS) have been studied in the peripheral and central nervous systems, few plausible pathological interactions are known among the metabolites in these systems. Thus, the purpose of this study was to investigate abnormal relationships and interactions between peripheral metabolites and central neurometabolites in patients with CRPS. METHODS: Various metabolites and molecules were measured in the peripheral blood, and central neurometabolites in the right and left thalamus using proton magnetic resonance spectroscopy in 12 patients with CRPS and 11 healthy controls. Interactions between peripheral metabolites in blood and central neurometabolites in the right and left thalamus were also investigated. RESULTS: The interactions between peripheral and central metabolites were different in the right and left hemispheres of healthy subjects, suggesting the presence of right hemisphere-dependent energy homeostasis and left hemisphere-dependent acid-base homeostasis that enables effective functioning. The interactions between central and peripheral metabolites in CRPS patients were distinct from those in healthy individuals, supporting the possibility of abnormal interactions and disrupted homeostasis between peripheral and central metabolites, which may result from neuroinflammation and immune system dysfunction. CONCLUSION: To the authors' knowledge, this is the first report describing abnormal metabolic dysfunction and disrupted homeostasis in interactions between metabolites of the peripheral and central nervous systems in CRPS. The approach used to uncover hidden pathophysiologies will improve understanding of how chronic pain can disrupt homeostasis in interactions between two systems and how alternative metabolites can be activated to recover and compensate for pathological dysfunctions in patients with CRPS.

Safety and efficacy of PG102P for the control of pruritus in patients undergoing hemodialysis (SNUG trial): study protocol for a randomized controlled trial.

BACKGROUND: Pruritus in patients undergoing hemodialysis is a highly prevalent complication that affects quality of life. Several medications are currently used for the treatment of uremic pruritus, but these are not satisfactory. PG102P, which is prepared from Actinidia arguta, has an immune-modulating effect on pruritus. This trial is designed to assess the antipruritic effect of PG102P compared with placebo. METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial will include 80 patients undergoing hemodialysis. The patients will be randomized in a 1:1 ratio to a treatment group (PG102P 1.5 g/day) or a control group (placebo). The treatment will last for 8 weeks, followed by a 2-week observational period. During the observational period, all of the patients will maintain the antipruritic treatment previously used. The primary endpoint will be measured as the difference in visual analog scale between the groups before and after treatment. Secondary outcomes include serum levels of total immunoglobulin E, eosinophil cationic protein, potassium, calcium, phosphorus, intact parathyroid hormone, and blood eosinophil count between weeks 0 and 8. Kidney Disease and Quality of Life and Beck's Depression Inventory questionnaires will be conducted. Safety assessments and any adverse events that occur will also be evaluated. DISCUSSION: The SNUG is a clinical study that aims to investigate the antipruritic effect of PG102P to ameliorate itching in patients undergoing hemodialysis. TRIAL REGISTRATION: Clinical Trials.gov, NCT03576235. Registered on 4 July 2018.

Discovery of Novel Biased Opioid Receptor Ligands through Structure-Based Pharmacophore Virtual Screening and Experiment.

Gi -protein-biased agonists with minimal ß-arrestin recruitment represent opportunities to overcome the serious adverse effects of human mu opioid receptor (µ-OR) agonists and developing alternative and safe treatments for pain. In order to discover novel non-morphinan opioid receptor agonists, we applied hierarchical virtual screening of our in-house database against a pharmacophore based on modeling the active conformations of opioid receptors. We discovered an initial hit compound, a novel µ-OR agonist with a pyrazoloisoquinoline scaffold. We applied computational R-group screening to this compound and synthesized 14 derivatives predicted to be the best. Of these, a new Gi -protein-biased compound, 1-{5-(3-chlorophenyl)-7,8-dimethoxy-3-[4-(methylsulfonyl)benzyl]-3H-pyrazolo[3,4-c]isoquinolin-1-yl}-N,N-dimethylmethanamine, showed an EC50 value of 179 nm against the µ-OR. This resulted in significant pain relief for mice in the phase II period of formalin response tests. This study provides a new strategy to identify diverse sets of promising compounds that might prove useful for the development of drugs that target other G-protein-coupled receptors.

Ciclopirox inhibits Hepatitis B Virus secretion by blocking capsid assembly.

Chronic hepatitis B virus (HBV) infection can cause cirrhosis and hepatocellular carcinoma and is therefore a serious public health problem. Infected patients are currently treated with nucleoside/nucleotide analogs and interferon α, but this approach is not curative. Here, we screen 978 FDA-approved compounds for their ability to inhibit HBV replication in HBV-expressing HepG2.2.15 cells. We find that ciclopirox, a synthetic antifungal agent, strongly inhibits HBV replication in cells and in mice by blocking HBV capsid assembly. The crystal structure of the HBV core protein and ciclopirox complex reveals a unique binding mode at dimer-dimer interfaces. Ciclopirox synergizes with nucleoside/nucleotide analogs to prevent HBV replication in cells and in a humanized liver mouse model. Therefore, orally-administered ciclopirox may provide a novel opportunity to combat chronic HBV infection by blocking HBV capsid assembly.

Early dialysis initiation does not improve clinical outcomes in elderly end-stage renal disease patients: A multicenter prospective cohort study.

BACKGROUND: The optimal timing for initiating dialysis in end-stage renal disease (ESRD) is controversial, especially in the elderly. METHODS: 665 patients ≥65 years old who began dialysis from August 2008 to February 2015 were prospectively enrolled in the Clinical Research Center for End-Stage Renal Disease cohort study. Participants were divided into 2 groups based on the median estimated glomerular filtration rate at the initiation of dialysis. Propensity score matching (PSM) was used to compare the overall survival rate, cardiovascular events, Kidney Disease Quality of Life Short Form 36 (KDQOL-36) results, Karnofsky performance scale values, Beck's depression inventory values, and subjective global assessments. RESULTS: The mean patient age was 72.0 years, and 61.7% of the patients were male. Overall, the cumulative survival rates were lower in the early initiation group, although the difference was not significant after PSM. Additionally, the survival rates of the 2 groups did not differ after adjusting for age, sex, Charlson comorbidity index and hemoglobin, serum albumin, serum calcium and phosphorus levels. Although the early initiation group showed a lower physical component summary score on the KDQOL-36 3 months after dialysis, the difference in scores was not significant 12 months after dialysis. Furthermore, the difference was not significant after PSM. The Karnofsky performance scale, Beck's depression inventory, and subjective global assessments were not significantly different 3 and 12 months after dialysis initiation. CONCLUSIONS: The timing of dialysis initiation is not associated with clinical outcomes in elderly patients with ESRD.

The minimal effective dose of cis-9-cetylmyristoleate (CMO) in persons presenting with knee joint pain: A double-blind, randomized, placebo-controlled trial.

BACKGROUND: Nutraceuticals containing cis-9-cetylmyristoleate (CMO) are used to improve knee pain despite the lack of placebo-controlled studies in humans. The aim of the study was to explore the minimal effective dose of CMO for relieving knee joint pain. METHODS: Twenty-eight subjects with mild degree arthritic knee joint pain were randomized into 4 groups; groups A, B, and C that contained 100%, 80%, and 62.4% of fatty acid component with 12.5% of CMO, and control group D (starch 100%). The pain intensity, functional disability, and the Patient Global Impression of Change (PGIC) were assessed for a 12-week ingestion period. RESULTS: Compared to group D (n = 6), there were significant differences in pain score in group A (n = 7, P = 0.005) and group C (n = 7, P = 0.012), but not significant in group B (n = 6, P = 0.180). Western Ontario and McMaster Universities Arthritis (WOMAC) score decreased significantly in groups A and C. The PGIC was positive in the majority (>50%) in groups A, B, and C, whereas negative in 83.3% in group D (control). CONCLUSION: CMO is effective in alleviating knee pain in persons with mild degree arthritis of the knee joint, at an effective dose of 62.4%.

Association of Serum Phosphorus Concentration with Mortality and Graft Failure among Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVES: Hyperphosphatemia in kidney transplant recipients has been shown to predict poorer graft and patient survival. However, studies examining hypophosphatemia are scarce. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: To evaluate the association of serum phosphorus level with patient and graft survival, we performed a retrospective multicenter cohort study. Between January of 1997 and August of 2012, 2786 kidney transplant recipients (41.7±11.4 years; 59.3% men; 73.5% living donors; 26.1% with diabetes; 3.8% with prior history of cardiovascular disease) were classified into seven groups according to serum phosphorus levels 1 year after transplantation, with intervals of 0.5 mg/dl (lowest group, <2.5 mg/dl; highest group, ≥5.0 mg/dl; reference group, 3.5-3.99 mg/dl). Survival analysis was performed by defining baseline time point as 1 year after transplantation. RESULTS: During median follow-up of 78.5 months, 60 patient deaths and 194 cases of graft loss occurred. In multivariate analysis, both lowest and highest serum phosphorus groups were associated with higher mortality, compared with the reference group (hazard ratio [HR], 4.82; 95% confidence interval [95% CI], 1.36 to 17.02; P=0.01; and HR, 4.24; 95% CI, 1.07 to 16.84; P=0.04, respectively). Higher death-censored graft loss was observed in the lowest and highest groups (HR, 3.32; 95% CI, 1.42 to 7.79; P=0.01; and HR, 2.93; 95% CI, 1.32 to 6.49; P=0.01, respectively), despite eGFR exhibiting no difference between the lowest group and reference group (65.4±19.3 versus 61.9±16.7 ml/min per 1.73 m2; P=0.33). Moreover, serum phosphorus showed a U-shape association with patient mortality and graft failure in restricted cubic spline curve analysis. CONCLUSIONS: Serum phosphorus level 1 year after transplantation exhibits a U-shape association with death-censored graft failure and patient mortality in kidney transplant patients characterized by relatively high rate of living donor transplant and low incidence of diabetes and prior cardiovascular disease compared with Western countries.

[11C]-(R)-PK11195 positron emission tomography in patients with complex regional pain syndrome: A pilot study.

Complex regional pain syndrome (CRPS) is characterized by severe and chronic pain, but the pathophysiology of this disease are not clearly understood. The primary aim of our case-control study was to explore neuroinflammation in patients with CRPS using positron emission tomography (PET), with an 18-kDa translocator protein specific radioligand [C]-(R)-PK11195. [C]-(R)-PK11195 PET scans were acquired for 11 patients with CRPS (30-55 years) and 12 control subjects (30-52 years). Parametric image of distribution volume ratio (DVR) for each participant was generated by applying a relative equilibrium-based graphical analysis. The DVR of [C]-(R)-PK11195 in the caudate nucleus (t(21) = -3.209, P = 0.004), putamen (t(21) = -2.492, P = 0.022), nucleus accumbens (t(21) = -2.218, P = 0.040), and thalamus (t(21) = -2.395, P = 0.026) were significantly higher in CRPS patients than in healthy controls. Those of globus pallidus (t(21) = -2.045, P = 0.054) tended to be higher in CRPS patients than in healthy controls. In patients with CRPS, there was a positive correlation between the DVR of [C]-(R)-PK11195 in the caudate nucleus and the pain score, the visual analog scale (r = 0.661, P = 0.026, R = 0.408) and affective subscales of McGill Pain Questionnaire (r = 0.604, P = 0.049, R = 0.364). We demonstrated that neuroinflammation of CRPS patients in basal ganglia. Our results suggest that microglial pathology can be an important pathophysiology of CRPS. Association between the level of caudate nucleus and pain severity indicated that neuroinflammation in this region might play a key role. These results may be essential for developing effective medical treatments.

Urinary Bladder-Relaxant Effect of Kurarinone Depending on Potentiation of Large-Conductance Ca2+-Activated K+ Channels.

The large-conductance calcium-activated potassium channel (BKCa channel) plays critical roles in smooth muscle relaxation. In urinary bladder smooth muscle, BKCa channel activity underlies the maintenance of the resting membrane potential and repolarization of the spontaneous action potential triggering the phasic contraction. To identify novel BKCa channel activators, we screened a library of natural compounds using a cell-based fluorescence assay and a hyperactive mutant BKCa channel (Lee et al., 2013). From 794 natural compounds, kurarinone, a flavanone from Sophora flavescens, strongly potentiated BKCa channels. When treated from the extracellular side, this compound progressively shifted the conductance-voltage relationship of BKCa channels to more negative voltages and increased the maximum conductance in a dose-dependent manner. Whereas kurarinone strongly potentiated the homomeric BKCa channel composed of only the α subunit, its effects were much smaller on heteromeric channels coassembled with auxiliary ß subunits. Although the activation kinetics was not altered significantly, the deactivation of BKCa channels was dramatically slowed by kurarinone treatment. At the single-channel level, kurarinone increased the open probability of the BKCa channel without affecting its single-channel conductance. Kurarinone potently relaxed acetylcholine-induced contraction of rat bladder smooth muscle and thus decreased the micturition frequency of rats with overactive bladder symptoms. These results indicate that kurarinone can directly potentiate BKCa channels and demonstrate the therapeutic potentials of kurarinone and its derivatives for developing antioveractive bladder medications and supplements.

An exploratory study on the effectiveness of "Calmare therapy" in patients with cancer-related neuropathic pain: A pilot study.

PURPOSE: Calmare therapy (CT) has been suggested as a novel treatment for managing chronic pain. Recently, it was reported to show a positive therapeutic outcome for managing neuropathic pain condition. We performed an exploratory prospective study on the effectiveness of CT in patients with various types of cancer-related neuropathic pain (CNP). METHOD: We performed an open-labeled, single-arm, exploratory study on the effectiveness of CT in patients with various types of cancer-related neuropathic pain (CNP). The primary endpoint was a comparison of the 11-point Numerical Rating Scale (NRS) pain score at one month with the baseline score in each patient. Brief Pain Inventory (BPI) and consumption of opioid were also evaluated during follow-up period. RESULTS: CT significantly decreased NRS pain score at one month from baseline (p < 0.001) in 20 patients with chemotherapy-induced peripheral neuropathy (n = 6), metastatic bone pain (n = 7), and post-surgical neuropathic pain (n = 7). It also improved overall BPI scores, decreased consumption of rescue opioid (p = 0.050), and was found satisfactory by a half of patients (n = 10, 50.0%). CONCLUSIONS: Our preliminary results suggest that CT may be considered for cancer patients with various types of CNP. Large studies are necessary to confirm our findings and ascertain which additional CNP show positive response to CT.

5-diphenylacetamido-indirubin-3'-oxime as a novel mitochondria-targeting agent with anti-leukemic activities.

Current treatment for leukemia largely depends on chemotherapy. Despite the progress in treatment efficacy of chemotherapy, a poor outcome consequent upon chemoresistance against conventional anti-cancer drugs still remains to be solved. In this study, we report 5-diphenylacetamido-indirubin-3'-oxime (LDD398) as a novel mitochondria-targeting anti-leukemic agent, which is a derivative of indirubin used in traditional medicine. Treatment with LDD398 resulted in caspase activation, cell death, and growth arrest at G2/M phases in leukemia cells. Interestingly, LDD398 quickly collapsed mitochondrial membrane potential (MMP) within 1 h, accompanied by cytochrome c release into cytosol and severe depletion of cellular ATP. However, the LDD398-induced cellular events was significantly mitigated by blockage of mitochondrial permeability transition pore (MPTP) opening with chemical and genetic modifications, strongly supporting that LDD398 executes its anti-leukemic activity via an inappropriate opening of MPTP and a consequent depletion of ATP. The most meaningful finding was the prominent effectiveness of LDD398 on primary leukemia cells and also on malignant leukemia cells resistant to anticancer drugs. Our results demonstrate that, among a series of indirubin derivatives, LDD398 induces leukemia cell death via a different mode from indirubin or conventional chemotherapeutics, and can be employed as a potent anti-cancer agent in the treatment for newly diagnosed and relapsed leukemia.

Comparative Biochemical and Proteomic Analyses of Soybean Seed Cultivars Differing in Protein and Oil Content.

This study develops differential protein profiles of soybean (Glycine max) seeds (cv. Saedanbaek and Daewon) varying in protein (47.9 and 39.2%) and oil (16.3 and 19.7%) content using protamine sulfate (PS) precipitation method coupled with a 2D gel electrophoresis (2DGE) approach. Of 71 detected differential spots between Daewon and Saedanbaek, 48 were successfully identified by MALDI-TOF/TOF. Gene ontology analysis revealed that up-regulated proteins in Saedanbaek were largely associated with nutrient reservoir activity (42.6%), which included mainly seed-storage proteins (SSPs; subunits of glycinin and ß-conglycinin). Similar results were also obtained in two cultivars of wild soybean (G. soja cv. WS22 and WS15) differing in protein content. Western blots confirmed higher accumulation of SSPs in protein-rich Saedanbaek. Findings presented and discussed in this study highlight a possible involvement of the urea cycle for increased accumulation of SSPs and hence the higher protein content in soybean seeds.

Discovery of novel purine-based heterocyclic P2X7 receptor antagonists.

The pyridine core skeleton of the previously reported dichloropyridine-based potent hP2X7 receptor antagonist 5 (IC50 = 13 nM in hP2X7-expressing HEK293 cells) was modified with various heterocyclic scaffolds. Among the derivatives with quinoline, quinazoline, acridine, and purine scaffolds, the chloropurine-based analog 9o exhibited the most potent antagonistic activity, with an IC50 value of 176 ± 37 nM in an ethidium bromide uptake assay. In addition, 9o significantly inhibited IL-1ß release in THP-1 cells stimulated with LPS/IFN-γ/BzATP (IC50 = 120 ± 15 nM). Although 9o was less active than the previous antagonist 5, 9o exhibited greatly improved metabolic stability in the in vitro evaluation (71.4% in human, 72.3% in mouse).

An alternative distal approach for the lumbar medial branch radiofrequency denervation: a prospective randomized comparative study.

BACKGROUND: An alternative technique involving a "distal approach" can be used for lumbar medial branch radiofrequency denervation (LMBRFD). We described and assessed this technique by comparing it with a conventional tunnel vision approach in a prospective randomized trial. METHODS: Eighty-two patients underwent LMBRFD by a distal (n = 41) or a tunnel vision approach (n = 41). The primary end point was a comparison of the mean difference in the change of 11-point numeric rating scale (NRS) scores of low back pain from entry to the scores at 1 month (NRS at baseline--NRS at 1 month) and at 6 months (NRS at baseline--NRS at 6 months) between the distal approach group and the tunnel vision approach group. The secondary end points were a change of NRS and the Oswestry disability index over time. RESULTS: Thirty-four patients in each group had complete time courses. There were no statistically significant differences in the change of NRS scores between the groups at 1 month (corrected P = 0.19; 97.5% 2-sided confidence interval [CI], -1.37 to 0.37) and 6 months (corrected P = 0.53; 97.5% CI, -1.36 to 0.77). Patients in both groups showed a statistically significant reduction in NRS and Oswestry disability index scores from baseline to that of the scores at 1 and 6 months (all P < 0.0001, Bonferroni corrected). The procedure-related pain score was significantly lower in the distal approach group (P = 0.001; 99% CI, -2.00 to -0.23). CONCLUSIONS: Patients who underwent LMBRFD by the tunnel vision or distal approaches showed significant pain relief at the 6-month follow-up. Less periprocedural pain was reported in the distal approach group. We consider that the distal approach provides an improved option for LMBRFD.