N4-Substituted Piperazinyl Norfloxacin Derivatives with Broad-Spectrum Activity and Multiple Mechanisms on Gyrase, Topoisomerase IV, and Bacterial Cell Wall Synthesis

Fluoroquinolones are an important class of antibiotics with broad-spectrum antibacterial and antitubercular activity. Here, we describe the design and synthesis of a series of 38 N4-substituted piperazinyl norfloxacin derivatives. Their activity and mechanism of action were characterized using in silico, in vitro, and in vivo approaches. Several compounds displayed interesting activities against both Gram-negative and Gram-positive bacteria, and few displayed antimycobacterial activity, whereby some were as potent as norfloxacin and ciprofloxacin. Molecular docking experiments suggested that the new derivatives inhibit both DNA gyrase and DNA topoisomerase IV in a similar manner as norfloxacin. Selecting the most promising candidates for experimental mode of action analysis, we confirmed DNA gyrase and topoisomerase IV as targets of all tested compounds using enzymatic in vitro assays. Phenotypic analysis of both Escherichia coli and Bacillus subtilis confirmed a typical gyrase inhibition phenotype for all of the tested compounds. Assessment of possible additional targets revealed three compounds with unique effects on the B. subtilis cell wall synthesis machinery, suggesting that they may have an additional target in this pathway. Comparison with known cell wall synthesis inhibitors showed that the new compounds elicit a distinct and, so far, unique phenotype, suggesting that they act differently from known cell wall synthesis inhibitors. Interestingly, our phenotypic analysis revealed that both norfloxacin and ciprofloxacin displayed additional cellular effects as well, which may be indicative of the so far unknown additional mechanisms of fluoroquinolones

An increased response to experimental muscle pain is related to psychological status in women with chronic non-traumatic neck-shoulder pain

<p>Abstract</p> <p>Background</p> <p>Neck-shoulder pain conditions, e.g., chronic trapezius myalgia, have been associated with sensory disturbances such as increased sensitivity to experimentally induced pain. This study investigated pain sensitivity in terms of bilateral pressure pain thresholds over the trapezius and tibialis anterior muscles and pain responses after a unilateral hypertonic saline infusion into the right legs tibialis anterior muscle and related those parameters to intensity and area size of the clinical pain and to psychological factors (sleeping problems, depression, anxiety, catastrophizing and fear-avoidance).</p> <p>Methods</p> <p>Nineteen women with chronic non-traumatic neck-shoulder pain but without simultaneous anatomically widespread clinical pain (NSP) and 30 age-matched pain-free female control subjects (CON) participated in the study.</p> <p>Results</p> <p>NSP had lower pressure pain thresholds over the trapezius and over the tibialis anterior muscles and experienced hypertonic saline-evoked pain in the tibialis anterior muscle to be significantly more intense and locally more widespread than CON. More intense symptoms of anxiety and depression together with a higher disability level were associated with increased pain responses to experimental pain induction and a larger area size of the clinical neck-shoulder pain at its worst.</p> <p>Conclusion</p> <p>These results indicate that central mechanisms e.g., central sensitization and altered descending control, are involved in chronic neck-shoulder pain since sensory hypersensitivity was found in areas distant to the site of clinical pain. Psychological status was found to interact with the perception, intensity, duration and distribution of induced pain (hypertonic saline) together with the spreading of clinical pain. The duration and intensity of pain correlated negatively with pressure pain thresholds.</p

Three Clusters of Different Properties Characterize Women with Chronic Trapezius Myalgia

Objectives: A correlative study on data from 14 women with unilateral chronic shoulder pain was undertaken. Methods: Data were obtained on evoked pain and pressure pain thresholds [PPTs] changes upon muscle exertion and biopsy findings on capillary density and Muscular pathology. The PPTs were measured in the trapezius muscle, before and after a static abduction endurance test of the shoulder [electronic algometer]. Holding time and pain intensity was registered. Capillarization and ragged red fibers, cytochrome-c-oxidase negative fibers, and moth-eaten muscle fibers were analyzed in the same trapezius muscles. Results: Principal component analysis was used for multivariate analysis, showing a model with three statistically significant components. The first component explained 33 percent of the variation. Pressure pain threshold changes were positively correlated with capillarization, and negatively correlated with prevalence of moth-eaten fibers and cytochrome-c-oxidase negative fibers. The second component explained 23 percent of the variation, and reflected the correlations between holding time, differences in pain and PPTs, i.e., between various aspects of perceived pain after exertion. The third component explained 19 percent of the variation. The pain difference correlated positively with the prevalence of cytochrome-c-oxidase negative fibers and raggedred fibers; subjects with high prevalence of these two fiber types presented increased pain. In summary, Our results suggest that not only capillarization and histopathological findings of the trapezius muscle, but also centrally modulated pain intensity and PPT changes after muscle exertion are associated. Conclusions: Three clusters of different properties were revealed in women with trapezius myalgia, highlighting the multifactorial mechanisms responsible. These components may have prognostic value.Original Publication:Ann L Persson, Bengt H Sjolund and Britt Larsson, Three Clusters of Different Properties Characterize Women with Chronic Trapezius Myalgia, 2008, JOURNAL OF MUSCULOSKELETAL PAIN, (16), 4, 287-297.http://dx.doi.org/10.1080/10582450802479768Copyright: New York; Haworth Medical Presshttp://www.haworthpressinc.com

RESEARCH ARTICLE Open Access

An increased response to experimental muscle pain is related to psychological status in women with chronic non-traumatic neck-shoulder pai

Elderly patients with COPD require more health care than elderly heart failure patients do in a hospital-based home care setting

Background: Elderly patients with advanced stages of COPD or chronic heart failure (CHF) often require hospitalization due to exacerbations. We hypothesized that telemonitoring supported by hospital-based home care (HBHC) would detect exacerbations early, thus, reducing the number of hospitalization. We also speculated that patients with advanced COPD or CHF would present differences regarding exacerbation frequency and the need of HBHC. Methods: The Health Diary system, based on digital pen technology, was employed. Patients aged amp;gt;= 65 years with amp;gt;= 2 hospitalizations the previous year were included. Exacerbations were categorized and treated as either COPD or CHF exacerbation by an experienced physician. All HBHC contacts (home visits or telephone consultations) were registered. Results: Ninety-four patients with advanced diseases were enrolled (36 COPD and 58 CHF subjects) of which 53 subjects (19 COPD and 34 CHF subjects) completed the 1-year study period. Death was the major reason for not finalizing the study. Compared to the 1-year prior inclusion, the intervention significantly reduced hospitalization. Although COPD subjects were younger with less comorbidity, exacerbations and HBHC contacts were significantly greater in this group. Conclusions: COPD subjects exhibit exacerbations more frequently, mainly due to disease characteristics, thus, demanding much more HBHC.Funding Agencies|county council of Ostergotland (Region Ostergotland); European Regional Development Fund through the NovaMedTech venture; RISE Research Institutes of Sweden AB</p

Patient expectations for a multimodal pain rehabilitation programme: active participation and coping skills. A qualitative study.

To describe what patients with chronic pain expect from a multimodal pain rehabilitation programme

Can a telemonitoring system lead to decreased hospitalization in elderly patients?

Introduction Growing populations of elderly patients with chronic obstructive pulmonary disease (COPD) or heart failure (HF) require more healthcare. A four-year telehealth intervention - the Health Diary system based on digital pen technology - was implemented. We hypothesized that study patients with advanced COPD or HF would have lower rates of hospitalization when using the Health Diary. The aim was to investigate the effects of the intervention on healthcare costs and the number of hospitalizations, as well as other care required in COPD and HF patients. Methods Patients were introduced to the telemonitoring system which was supervised by a specialized hospital-based home care (HBHC) unit. Staff associated with this unit were responsible for the healthcare provided. The study included patients with COPD or HF, aged amp;gt;= 65 years who were frequently hospitalized due to exacerbations - at least two inpatient episodes within the last 12 months. Observed number of hospitalizations and total healthcare costs were compared with the expected values, which were calculated using the generalized estimating equations (GEE) method. Results A total of 36 COPD and 58 HF patients with advanced stages of disease were included. The number of hospitalizations was significantly reduced for both HF and COPD patients participating in telemonitoring. Accordingly, hospitalization costs were significantly reduced for both groups, but the total healthcare cost was not significantly different from the expected costs. Conclusion A telemonitoring system, the Health Diary, combined with a specialized HBHC unit significantly decreases the need for hospital care in elderly patients with advanced HF or COPD without increasing total healthcare costs

Removal of organic micropollutants in the biological units of a Swedish wastewater treatment plant

The present study investigates the presence and removal of target organic micropollutants in a large Swedish wastewater treatment plant designed for nutrient removal including activated sludge, trickling filters, nitrifying moving bed biofilm reactors (MBBRs) and post-denitrifying MBBRs. A total of 28 organic micropollutants were analysed, at concentrations ranging from few ng/L to \ub5g/L, in the influent and effluent of the different biological reactors in two sampling campaigns. The observed micropollutant removal efficiencies of the wastewater treatment plant varied from insignificant (&lt; 20%) to high (&gt; 90%) between compounds. The activated sludge reactor, being the first in line, contributed to most of the removal from the water phase. Additional removal of a few compounds was observed in the biofilm units, but most of the persistent compounds remained stable through all biological treatments