Motor equivalent control of the center of mass in response to support surface perturbations

To claim that the center of mass (CM) of the body is a controlled variable of the postural system is difficult to verify experimentally. In this report, a new variant of the method of the uncontrolled manifold (UCM) hypothesis was used to evaluate CM control in response to an abrupt surface perturbation during stance. Subjects stood upright on a support surface that was displaced in the posterior direction. Support surface translations between 0.03 and 0.12 m, each lasting for 275 ms, were presented randomly. The UCM corresponding to all possible combinations of joints that are equivalent with respect to producing the average pre-perturbation anterior–posterior position of the center of mass (CM_AP) were linearly estimated for each trial. At each point in time thereafter, the difference between the current joint configuration and the average pre-perturbation joint configuration was computed. This joint difference vector was then projected onto the pre-perturbation UCM as a measure of motor equivalence, and onto its complementary subspace, which represents joint combinations that lead to a different CM_AP position. A similar analysis was performed related to control of the trunk’s spatial orientation. The extent to which the joint velocity vector acted to stabilize the CM_AP position was also examined. Excursions of the hip and ankle joints both increased linearly with perturbation magnitude. The configuration of joints at each instance during the perturbation differed from the mean configuration prior to the perturbation, as evidenced by the joint difference vector. Most of this joint difference vector was consistent, however, with the average pre-perturbation CM_AP position rather than leading to a different CM_AP position. This was not the case, however, when performing this analysis with respect to the UCM corresponding to the control of the pre-perturbation trunk orientation. The projection of the instantaneous joint velocity vector also was found to lie primarily in the UCM corresponding to the pre-perturbation CM_AP position, indicating that joint motion was damped in directions leading to a change away from the pre-perturbation CM_AP position. These results provide quantitative support for the argument that the CM position is a planned variable of the postural system and that its control is achieved through selective, motor equivalent changes in the joint configuration in response to support surface perturbations. The results suggest that the nervous system accomplishes postural control by a control strategy that considers all DOFs. This strategy presumably resists combinations of DOFs that affect the stability of important task-relevant variables (CM_AP position) while, to a large extent, freeing from control combinations of those DOFs that have no effect on the task-relevant variables (Schöner in Ecol Psychol 8:291–314, 1995).     

New therapy from old drugs: synergistic bactericidal activity of sulfadiazine with colistin against colistin-resistant bacteria,including plasmid-mediated colistin-resistant mcr-1 isolates

The recent emergence of colistin (COL) resistance, particularly mcr-1 plasmid-mediated COL resistance in Gram-negative bacteria, has led to renewed interest in antibiotic combinations to overcome clinical therapeutic impasses. The aim of this study was to evaluate the potential of the synergistic and bactericidal activity of COL in combination with sulphonamide compounds, including sulfadiazine (SDI), sulfamethoxazole (SMX) and trimethoprim/sulfamethoxazole (SXT), as well as trimethoprim (TMP) against clinical COL-resistant bacterial strains, including strains with the plasmid-encoded mcr-1 gene. A collection of 55 COL-resistant and -susceptible strains from different origins (Laos, Thailand and France) was used in this study. Several in vitro methods were used to determine the potential of the synergistic activity of these combinations, including Etest on agar pre-treated plates, the Etest cross method and the chequerboard assay. A time–kill assay was performed to evaluate the potential bactericidal activity of combinations in addition to synergistic activity. Significant synergistic activity was observed with all combinations tested. The combination of COL?+?SDI presented the highest synergistic effect against the various species of COL-resistant strains (92.7%). For the other combinations, a synergistic effect was also observed but with lower frequency for COL?+?SMX (33.3%), COL?+?TMP (47.3%) and COL?+?SXT (31.5%). Synergy was observed independently of the COL resistance mechanism. These in vitro results suggest that the combination of COL?+?SDI would appear to be justifiable in patients with multidrug-resistant bacterial infections that cannot be treated with COL monotherapy.     

Synergistic and bactericidal activities of mecillinam,amoxicillin and clavulanic acid combinations against extended-spectrum β-lactamase (ESBL)-producing Escherichia coli in 24-h time–kill experiments

This study aimed to evaluate the potential synergistic and bactericidal effects of mecillinam in combination with amoxicillin and clavulanic acid against extended-spectrum β-lactamase (ESBL)-producing Escherichia coli. Eight clinical E. coli isolates with varying susceptibility to mecillinam [minimum inhibitory concentrations (MICs) of 0.125 mg/L to >256 mg/L] and high-level resistance to amoxicillin (MICs > 256 mg/L) were used. Whole-genome sequencing was performed to determine the presence of β-lactamase genes and mutations in the cysB gene. The activities of single drugs and the combinations of two or three drugs were tested in 24-h time–kill experiments. Population analysis was performed for two strains before and after experiments. Only one strain had a mutation in the cysB gene resulting in an amino acid substitution. With the two-drug combinations, initial killing was observed both with mecillinam and amoxicillin when combined with clavulanic acid. Synergy was observed with mecillinam and clavulanic acid against one strain and with amoxicillin and clavulanic acid against three strains. However, following significant re-growth, a bactericidal effect was found only with amoxicillin and clavulanic acid against two strains. Pre-existing subpopulations with elevated mecillinam MICs were detected before experiments and were selected with mecillinam alone or in two-drug combinations. In contrast, the three-drug combination showed enhanced activity with synergy against six strains, a bactericidal effect against all eight strains, and suppression of resistance during 24-h antibiotic exposure. This combination may be of clinical interest in the treatment of urinary tract infections caused by ESBL-producing E. coli.     

Synergistic effect between nisin and polymyxin B against pandrug-resistant and extensively drug-resistant Acinetobacter baumannii

Acinetobacter baumannii is an opportunistic pathogen predominantly associated with nosocomial infections. The World Health Organization's data on antibiotic-resistant ‘priority pathogens’ reports carbapenem-resistant A. baumannii as a pathogen which is in critical need of research and development of new antimicrobials. Emerging resistance against polymyxins, last-resort drugs for carbapenem-resistant A. baumannii, increases the need for new therapeutic approaches such as synergistic combinations. Nisin, an antibacterial peptide produced by the Gram-positive bacteria L. lactis, is a US Food and Drug Administration approved food preservative with bactericidal action predominantly against other Gram-positive bacteria. A 2008 study reported that topical nisin was effective against staphylococcal mastitis in humans. Additionally, nisin has shown activity against Gram-negative bacteria in combination with antimicrobials such as polymyxin B. A recent in vitro study reported that nisin and polymyxin B exhibited synergistic activity against one isolate each of A. baumannii, Acinetobacter lwoffii and Acinetobacter calcoaceticus using time-kill assay and checkerboard technique. We evaluated the synergistic potential of nisin and polymyxin B against 15 unique clinical A. baumannii isolates using time-kill assay. Three of eight (38%) extensively drug-resistant and six of seven (86%) pandrug-resistant A. baumannii isolates showed synergy with one or more combinations of nisin and polymyxin B. The synergy seen with the use of lower concentrations of polymyxin B may help in reducing the dose-dependent side effects. Additional studies involving pharmacokinetics and pharmacodynamics of nisin are required to explore clinical possibilities.     

Ethanol and cocaine: Environmental place conditioning,stereotypy, and synergism in planarians

More than 90% of individuals who use cocaine also report concurrent ethanol use, but only a few studies, all conducted with vertebrates, have investigated pharmacodynamic interactions between ethanol and cocaine. Planaria, a type of flatworm often considered to have the simplest ‘brain,’ is an invertebrate species especially amenable to the quantification of drug-induced behavioral responses and identification of conserved responses. Here, we investigated stereotypical and environmental place conditioning (EPC) effects of ethanol administered alone and in combination with cocaine. Planarians displayed concentration-related increases in C-shaped movements following exposure to ethanol (0.01–1%) (maximal effect: 9.9 ± 1.1 C-shapes/5 min at 0.5%) or cocaine (0.1–5 mM) (maximal effect: 42.8 ± 4.1 C-shapes/5 min at 5 mM). For combined administration, cocaine (0.1–5 mM) was tested with submaximal ethanol concentrations (0.01, 0.1%); the observed effect for the combination was enhanced compared to its predicted effect, indicating synergism for the interaction. The synergy with ethanol was specific for cocaine, as related experiments revealed that combinations of ethanol and nicotine did not result in synergy. For EPC experiments, ethanol (0.0001–1%) concentration-dependently increased EPC, with significant environmental shifts detected at 0.01 and 1%. Cocaine (0.001–1 μM) produced an inverted U-shaped concentration–effect curve, with a significant environmental shift observed at 0.01 μM. For combined exposure, variable cocaine concentrations (0.001–1 μM) were administered with a statistically ineffective concentration of ethanol (0.0001%). For each concentration of cocaine, the environmental shift was enhanced by ethanol, with significance detected at 1 μM. Cocaethylene, a metabolite of cocaine and ethanol, also produced C-shapes and EPC. Lidocaine (0.001–10 μM), an anesthetic and analog of cocaine, did not produce EPC or C-shaped movements. Evidence from planarians that ethanol produces place-conditioning effects and motor dysfunction, and interacts synergistically with cocaine, suggests that aspects of ethanol neuropharmacology are conserved across species.     

心外膜脂肪厚度、CT值及Syntax评分与冠心病的关系

目的探讨心外膜脂肪厚度、CT值及心脏外科与介入治疗狭窄冠脉研究(Syntax)评分与冠心病的关系。 方法选取2017年2月至2018年10月就诊于临沂市兰陵县人民医院心血管内科,经冠状动脉造影检查确诊的冠心病患者,共69例作为研究组,另选同期正常健康体检者60例作为对照组。两组均行冠状动脉CT血管成像(CTA)检查,比较心外膜脂肪厚度及CT值。分析冠心病患者造影结果,计算Syntax评分,比较不同水平Syntax评分冠心病患者心外膜脂肪厚度及CT值差异。 结果研究组患者甘油三酯[(1.62±0.68)mmol/L]、总胆固醇[(5.12±1.83)mmol/L]水平明显高于对照组[(1.50±0.53)mmol/L,(4.90±1.20)mmol/L](t＝4.60,3.82;均P<0.05);研究组高密度脂蛋白胆固醇[(1.49±0.43)mmol/L]和低密度脂蛋白胆固醇[(2.45±0.63)mmol/L]水平与对照组[(1.50±0.55)mmol/L,(2.50±0.55)mmol/L]比较,均差异无统计学意义(t＝0.55,0.34;均P>0.05)。研究组心外膜脂肪厚度[(12.30±2.66)mm]高于对照组[(9.50±1.85)mm](t＝8.60,P<0.01);研究组心外膜脂肪CT值[(-98.60±15.66)HU]高于对照组[(-70.55±9.82)HU](t＝19.36,P<0.01);低积分组冠心病患者心外膜脂肪厚度[(11.30 ± 2.20)mm]、心外膜脂肪CT值[(-90.60±9.55)HU]、平均Syntax评分[(-17.32±8.42)分]低于高积分组冠心病患者[(14.50±2.76)mm、(-115.30±13.36)HU、(-30.44±9.19)分],均差异有统计学意义(t＝6.42,9.58,21.15;均P<0.01)。 结论心外膜脂肪厚度、CT值可能影响冠心病患者Syntax评分结果,可作为患者病情评估的参考指标,有推广价值。     

中药炮制增效原理探讨

目的:改进中药炮制方法,提高炮制品质量。方法:探讨能使中药炮制后增效的原理。结果:发现能使药物增效的方法和原理很多。结论:选择适当的炮制方法,能更好地发挥药物的药理作用。     

Relative location of epitopes involved in synergistic antibody binding using human chorionic gonadotropin as a model

We systematically screened a large panel of well-characterized monoclonal antibodies (mAb) directed towards various epitopes on human chorionic gonadotropin (hCG) for synergistic binding of ¹²⁵I-hCG when they were adsorbed to a solid phase. The epitope locations involved in synergy were then related to the crystal structure of hCG and discussed in accordance with available data on the hCG epitopes. Enhanced binding of hCG was specific for certain pairs of mAb and was reflected in a 3–50-fold increased apparent functional affinity constant for hCG. Surface plasmon resonance revealed that when the mAb were captured by a polyclonal anti-IgG1 coupled to the Biacore chip, the off rates for hCG were significantly slower with synergistic mAb combinations than for the corresponding single mAb or nonsynergistic pairs of mAb, whereas the on rates did not differ appreciably. Each of the two antibodies involved in synergistic binding of hCG (more than 3-fold compared to additive binding of the two mAb) always belonged to a different epitope cluster in a separate antigenic domain on hCG. Synergistic epitope combinations on holo-hCG were located in similar structural planes. Combinations of mAb directed towards the epitope clusters α₂/β_3/5, α₂/hCGβ_CTP (C-terminal peptide) and β_3/5/hCGβ_CTP showed the strongest enhancement, with binding more than 10-fold greater than the sum of ¹²⁵I-hCG bound to the individual mAb, followed by pairs of mAb directed towards the epitope groups β₁/β_3/5, c_1/2/β_3/5, β₁/α₂, and α₂/α_3/5 (3–9-fold). The greater frequency of synergy obtained with the linear epitopes of the hCGβ_CTP can be ascribed to their greater molecular flexibility relative to the constrained discontinuous epitopes on hCGα and core-hCGβ (residues 1–112). In general, these studies provide a method for rapid screening of synergistic antibody pairs which also helps to identify non-overlapping epitopes that are accessible in similar structural planes. In turn, this facilitates the design of high-affinity bispecific antibodies targetted to a single antigen molecule.     

喹硫平、阿立哌唑联合文拉法辛治疗难治性抑郁症的对照研究

目的探讨非典型抗精神病药喹硫平、阿立哌唑合并抗抑郁药文拉法辛治疗难治性抑郁症的疗效和不良反应。方法将78例难治性抑郁症患者随机分为喹硫平组(n=27)、阿立哌唑组(n=26)和对照组(n=25),在均使用文拉法辛治疗的同时喹硫平组和阿立哌唑组,分别合并小剂量喹硫平和阿立哌唑治疗8周。采用汉密尔顿抑郁量表(HAMD)、汉米尔顿焦虑量表(HAMA),在治疗前及治疗1、2、4、8周各测定1次;并在治疗前及治疗8周测血常规、肝功能、体重及副反应评定量表(TESS)。结果喹硫平组和阿立哌唑组在治疗第2周末开始HAMD(F=6.918,P0.01)、HAMA(F=4.782,P0.05)评分显著低于对照组。经过8周治疗,喹硫平组(78%)和阿立哌唑组(73%)的显效率显著好于对照组(χ2=9.416,P0.01)。3组患者治疗过程中出现的不良反应均为轻度可控。结论喹硫平和阿立哌唑合并文拉法新治疗难治性抑郁症有增效作用,疗效好、见效快、安全性高。     

Spectrum of activity,mutation rates,synergistic interactions,and the effects of pH and serum proteins for fusidic acid (CEM-102)

Fusidic acid (CEM-102) is a steroidal antimicrobial agent with focused Gram-positive activity that acts by preventing bacterial protein synthesis via interacting with elongation factor G. A collection of 114 wild-type isolates (>80 species) was used to define the contemporary limits of fusidic acid spectrum against Gram-positive and Gram-negative species. Reference broth microdilution and anaerobic agar dilution methods were performed. Modifications of standardized test methods included adding 10% human serum and adjusting the medium pH to 5, 6, and 8. Synergy was assessed by the checkerboard method and time-kill studies. Mutational rates to resistance were determined at 4×, 8×, and 16× MIC. Against Gram-positive pathogens, fusidic acid MIC values ranged from 0.06 to 32 μg/mL with the greatest potency against Staphylococcus aureus, Corynebacterium spp., and Micrococcus luteus (MIC results, 0.25, ≤0.12, and ≤0.5 μg/mL, respectively). Enterococci and streptococci were less susceptible (MIC ranges, 2–8 and 16–32 μg/mL, respectively). Fusidic acid activity against Gram-negative species was more limited (all MIC values, ≥2 μg/mL) except for Empedobacter brevis, Moraxella catarrhalis and Neisseria meningitidis. A 4-fold increase in fusidic acid MIC results was observed when 10% serum was added to the broth. Decreasing medium pH to 5.0 to 6.0 negated the protein binding effects. Among the 8 antimicrobial combinations tested, gentamicin and rifampin enhanced the activity when combined with fusidic acid (no antagonism). Fusidic acid in vitro activity was most improved when combined with rifampin. Single-step mutational rates ranged from 1.2 × 10⁻⁶ for 4× MIC to 9.8 × 10⁻⁸ for 16× MIC. In conclusion, these in vitro results for fusidic acid tested against contemporary strains confirm a persisting antimicrobial spectrum, especially against staphylococci and some other Gram-positive species.