C-2 phenyl replacements to obtain potent quinoline-based Staphylococcus aureus NorA inhibitors

Abstract

NorA is the most studied efflux pump of Staphylococcus aureus and is responsible for high level resistance towards fluoroquinolone drugs. Although along the years many NorA efflux pump inhibitors (EPIs) have been reported, poor information is available about structure-activity relationship (SAR) around their nuclei and reliability of data supported by robust assays proving NorA inhibition. In this regard, we focussed efforts on the 2-phenylquinoline as a promising chemotype to develop potent NorA EPIs. Herein, we report SAR studies about the introduction of different aryl moieties on the quinoline C-2 position. The new derivative 37a showed an improved EPI activity (16-fold) with respect to the starting hit 1. Moreover, compound 37a exhibited a high potential in time-kill curves when combined with ciprofloxacin against SA-1199B (norA+). Also, 37a exhibited poor non-specific effect on bacterial membrane polarisation and showed an improvement in terms of “selectivity index” in comparison to 1.     

Submitting articles to the BMJ

ObjectiveTo investigate how doctors engage with patients with psychotic illness in routine consultations.DesignConversation analysis of 32 consultations between psychiatrists and patients with schizophrenia or schizoaffective disorder.SettingTwo psychiatric outpatient clinics in east London and south west London.Participants7 psychiatrists and 32 patients with schizophrenia or schizoaffective disorder.ResultsPatients actively attempted to talk about the content of their psychotic symptoms in consultations by asking direct questions, repeating their questions and utterances, and producing these utterances in the concluding part of the consultation. In response, doctors hesitated, responded with a question rather than with an answer, and smiled or laughed (when informal carers were present), indicating that they were reluctant to engage with patients'' concerns about their psychotic symptoms.ConclusionsPatients repeatedly attempted to talk about the content of their psychotic symptoms, which was a source of noticeable interactional tension and difficulty. Addressing patients'' concerns about their illness may lead to a more satisfactory outcome of the consultation and improve engagement of such patients in the health services.

What is already known on this topic

Patients with psychotic illness are difficult to engage in the health servicesNo research has been published on how doctors engage with these patients in consultations

What this study adds

Patients actively attempt to talk about the content of their psychotic symptomsDoctors'' reluctance and discomfort in engaging with this topic is apparentAddressing patients'' concerns may lead to a more satisfactory outcome of the consultation and improve engagement with services     

Three new species,a new combination,and a neotypification in <Emphasis Type="Italic">Dahlstedtia</Emphasis> (Leguminosae,Millettieae, Papilionoideae) from South America

Three new species of Dahlstedtia, D. burkartii, D. dehiscens, and D. lewisiana, are described from South America, and their relationships with related species are discussed. Dahlstedtia burkartii, from Argentina, has pink flowers with standard straight, whereas D. dehiscens and D. lewisiana, both from Brazil, have purplish to lilac flowers with a reflexed standard petal. A new combination, Dahlstedtia peckoltii, is proposed based on Lonchocarpus peckoltii and a neotype is selected for the latter. Information about geographic distribution and phenology of the species is provided.     

我院远程医疗会诊情况分析与思考

目的 总结和回顾多年来远程会诊工作开展情况,探索提高远程医疗效率的方法。方法 对完成的139例远程会诊的相关资料统计分析。结果 目前远程会诊主要承担的是偏远地区、不方便外出就诊的患者,近90%是为病情急危患者组织的急诊会诊,60%是常见病、多发病中的复杂难治病例。结论 提高远程会诊质量和效率,有利于节约医疗资源,使更多基层患者得到救治,开展远程疑难病例、死亡病例讨论及远程查房等方式,开辟远程会诊的新领域。     

Regio- and enantio-selective glycosylation of tetrahydroprotoberberines by <Emphasis Type="Italic">Gliocladium deliquescens</Emphasis> NRRL1086 resulting in unique alkaloidal glycosides

The microbial transformation of a series of tetrahydroprotoberberines (THPBs, 1–5) by Gliocladium deliquescens NRRL1086 was investigated. In this research, the novel glycosylation of tetrahydroberberrubine (1) was observed with fast rate and high regio- and enantio-selectivity. One pair of unique enantiomorphic alkaloidal glycosides T-1 and T-2 was isolated and their structures were elucidated unambiguously by HR-MS, CD, 1D and 2D NMR spectrum. It is interesting that different amounts of glucose in the potato broth medium could influence the ratio of T-1 and T-2; in the 1.5% glucose medium, the ratio was about 15:1 and the yield of the S-form product T-1 may reach the theoretical maximum yield of about 50% which could provide one practical method to prepare the enantiomerically pure product and one alternative resolution method of tetrahydroberberrubine. The preliminary enzymatic research by using sodium dodecyl sulfate (SDS) and imidazole as glycosyltransferase and glycosidase inhibitors revealed that glycosyltransferase may contribute to glycosylation process. This is the first successful approach to glycosylation of tetrahydroprotoberberines.     

Changes in the House Sparrow Passer domesticus population in Valencia (Spain) from 1998 to 2008

Capsule The population of House Sparrow Passer domesticus has experienced a sharp decline in the municipality of Valencia.

Aims To investigate the population trends of House Sparrows.

Methods Between September 1998 and December 2008, House Sparrows were censused monthly in 22 urban parks covering a total of 118 ha. Additionally, birds in the wider urban landscape were censused in 24 plots of about 50 ha during the winter and spring of years 1998, 2003 and 2007.

Results The House Sparrow population experienced a significant decline of about 70% over 10 years in urban parks, with monthly peak values decreasing from about 2000 birds in 1998 to about 500 in 2008. Between 1998 and 2007, a significant decline was detected in the urban landscape mostly during the winter.

Conclusions Urban parks are a main feeding habitat for House Sparrows, and habitat structure of urban parks has remained similar throughout these years. Therefore, the decreasing number of sparrows recorded in parks probably reflects an overall population decline of the species in Valencia. This decline has coincided with high‐intensity urban development i.e. an increase in the building density and a reduction in the amount of wastelands and other feeding habitats. Thus, shortage of nest‐sites did not seem to be a limiting factor for the population, but a reduction of food availability may be partially responsible for the observed patterns.     

Qualitative interview study of communication between parents and children about maternal breast cancer

ObjectiveTo examine parents'' communication with their children about the diagnosis and initial treatment of breast cancer in the mother.DesignQualitative interview study within cross sectional cohort.SettingTwo breast cancer treatment centres.Participants32 women with stage I or stage II breast cancer with a total of 56 school aged children.ResultsWomen were most likely to begin talking to their children after their diagnosis had been confirmed by biopsy, but a minority waited until after surgery or said nothing at all. Family discussion did not necessarily include mention of cancer. There was considerable consistency in the reasons given for either discussing or not discussing the diagnosis. The most common reason for not communicating was avoidance of children''s questions and particularly those about death. While most mothers experienced helpful discussion with a doctor concerning their illness, few were offered help with talking to children; many would have liked help, particularly the opportunity for both parents to talk to a health professional with experience in understanding and talking to children.ConclusionsParents diagnosed with cancer or other serious illnesses should be offered help to think about whether, what, and how to tell their children and about what children can understand, especially as they may well be struggling themselves to come to terms with their illness.     

华东某省三级公立医院员工薪酬现状调查

目的 分析华东某省三级公立医院薪酬结构和薪酬水平并提出合理化建议,为公立医院薪酬制度改革和补偿机制改革提供决策依据。方法 以某省58家三级公立医院为研究对象,运用描述性分析、t检验和方差分析等方法,对薪酬结构和薪酬水平进行统计分析。结果 财政补助收入仅占总收入的4%;薪酬支出占总支出的26.6%,无地域差异;医务员工年人均收入9.47万元,存在地域差异;医务员工薪酬水平是非私营单位在岗职工的1.76倍。结论 政府应加大对公立医院的财政补助力度,放宽对医疗行业薪酬总量管控,提升医务员工薪酬水平和社会薪酬地位;公立医院迫切需要建立一套科学、合理的薪酬分配体系。     

Molecular and epidemiological characterization of recurrent Mycobacterium ulcerans infections in Benin

BackgroundBuruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans, an environmental mycobacterium. Although transmission of M. ulcerans remains poorly understood, the main identified risk factor for acquiring Buruli ulcer is living in proximity of potentially contaminated water sources. Knowledge about the clinical features of Buruli ulcer and its physiopathology is increasing, but little is known about recurrence due to reinfection.Methodology/Principal findingsWe describe two patients with Buruli ulcer recurrence due to reinfection with M. ulcerans, as demonstrated by comparisons of DNA from the strains isolated at the time of the first diagnosis and at recurrence. Based on the spatial distribution of M. ulcerans genotypes in this region and a detailed study of the behavior of these two patients with respect to sources of water as well as water bodies and streams, we formulated hypotheses concerning the sites at which they may have been contaminated.Conclusions/SignificanceSecond episodes of Buruli ulcer may occur through reinfection, relapse or a paradoxical reaction. We formally demonstrated that the recurrence in these two patients was due to reinfection. Based on the sites at which the patients reported engaging in activities relating to water, we were able to identify possible sites of contamination. Our findings indicate that the non-random distribution of M. ulcerans genotypes in this region may provide useful information about activities at risk.     

15例Dieulafoy病的内镜下诊断及治疗

目的:探讨消化道内窥镜对于胃Dieulafoy病的诊断和治疗作用。方法:对山东省立医院近3年收治的15例Dieulafoy病的临床资料进行回顾性分析。结果:13例内镜下止血治疗成功,无再出血(随访时间为12个月到36个月);1例内镜下治疗后再次出血,给予第二次内镜治疗后,随访18个月未再出血;1例因患者家属商议后坚持行外科手术治疗(近端胃切除术)。结论:内镜下治疗可作为处理胃Dieulafoy病的首选方案,仔细而谨慎的内镜下操作有助于提高胃Dieulafoy病的诊断。     

Antioxidant and α-Amylase Inhibitory Compounds from Aerial Parts of Varthemia iphionoides Boiss

Various extracts of aerial parts of Varthemia (Varthemia iphionoides Boiss) were investigated for radical-scavenging activity, antioxidative activity, and porcine pancreas α-amylase inhibitory activity. The ethanol and water extracts showed a pronounced 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity, with inhibition of about 90% at a concentration of 100 μg/ml, and α-amylase inhibitory activity of about 70% at a concentration of 200 μg/ml by the 2-chloro-4-nitrophenyl α-maltotrioside (CNP-G₃) degradation method. The ethanol extract was purified by column chromatography to give seven 3-methoxyflavones (1–7) and eudesmane sesquiterpene, selina-4,11(13)-dien-3-on-12-oic acid (8). The structures of these compounds were established by NMR, MS, and UV spectroscopy. Of 3-methoxyflavones, 5,7,4′-trihydroxy-3,6-dimethoxyflavone (1), 5,7,4′-trihydroxy-3,3′-dimethoxyflavone (2), and 5,4′-dihydroxy-3,7,3′-trimethoxyflavone (3,7,3′-tri-O-methyl-quercetin) (7) exhibited pronounced radical-scavenging activity. The antioxidative activity in the linoleic acid system was considerable in compounds 1, 2, and 5,4′-dihydroxy-3,6,7-trimethoxyflavone (4). Compounds 1, 2, 4, 5 (5,7,4′-trihydroxy-3-methoxyflavone), and 6 (5,4′-dihydroxy-3,7-dimethoxyflavone) showed markedly high inhibitory activity against porcine pancreas α-amylase. Eudesmane sesquiterpene did not show any activity.     

Qualitative study of views of health professionals and patients on guided self management plans for asthma

ObjectivesTo explore the views held by general practitioners, practice nurses, and patients about the role of guided self management plans in asthma care.DesignQualitative study using nine focus groups that each met on two occasions.SettingSouth Wales.Subjects13 asthma nurses, 11 general practitioners (six with an interest in asthma), and 32 patients (13 adults compliant with treatment, 12 non-compliant adults, and seven teenagers).ResultsNeither health professionals nor patients were enthusiastic about guided self management plans, and, although for different reasons, almost all participants were ambivalent about their usefulness or relevance. Most professionals opposed their use. Few patients reported sustained use, and most felt that plans were largely irrelevant to them. The attitudes associated with these views reflect the gulf between the professionals'' concept of the “responsible asthma patient” and the patients'' view.ConclusionsAttempts to introduce self guided management plans in primary care are unlikely to be successful. A more patient centred, patient negotiated plan is needed for asthma care in the community.     

No brood parasitism by the Great Spotted Cuckoo Clamator glandarius on the Azure-winged Magpie Cyanopica cyanus

Capsule No case of parasitic interaction was found after 12 years of intensive monitoring of a marked population in Spain where both species are sympatric.

Aims To evaluate whether the Azure-winged Magpie is parasitized, and suggest possible causes that affect its relationship with the Great Spotted Cuckoo.

Methods Data from a long-term field study of marked individuals in a population of Azure-winged Magpie in Spain, were collected from about 60 nests per year over 12 years.

Results Although common in the area, no eggs or young of the Great Spotted Cuckoo were found in an Azure-winged Magpie nest.

Conclusion The Great Spotted Cuckoo does not appear to parasitize the Azure-winged Magpie, and we suggest that elevated predation rates on nests may be an important, overlooked factor potentially affecting the choice of host species by this brood parasite.     

Tribulus terrestris and female reproductive system health: A comprehensive review

BackgroundTribulus terrestris L. (T. terrestris) positive performance on the male sexual system has been confirmed, but little is known about its effects on the female reproductive system.PurposeThis review discussed in detail the beneficial impact of T. terrestris and its secondary metabolites on the female reproductive system.Study design and methodsIn this review, the scientific Databases of Science direct, Pubmed, Web of Science, Google, Google Scholar, Researchgate, EMBASE, Scientific Information (SID), and Elsevier were searched profoundly. Studies about the pharmacological activities of T. terrestris on the female reproductive system in each aspect of investigations: human, in vivo, and in vitro studies, in the period from 1998 to 2020 were admitted. Our study was not limited by the language of publications.Results23 articles about the effects of T. terrestris on the female reproductive system were found. These studies approved the T. terrestris efficacy on improvements in histological features of the ovary and uterus of polycystic ovary syndrome patients as well as the well-working of normal ovaries, enhancements in the sexual desire of postmenopausal syndrome, improve ovarian and breast cancers.ConclusionThese studies showed that the positive effect of T. terrestris on the female reproductive system was due to the presence of a secondary metabolite called protodioscin; a steroidal saponin compound, as the dominant active component of this plant.     

Endpiece: Three different talks

ObjectivesTo characterise the information needs of family doctors by collecting the questions they asked about patient care during consultations and to classify these in ways that would be useful to developers of knowledge bases.DesignObservational study in which investigators visited doctors for two half days and collected their questions. Taxonomies were developed to characterise the clinical topic and generic type of information sought for each question.SettingEastern Iowa.ParticipantsRandom sample of 103 family doctors.ResultsParticipants asked a total of 1101 questions. Questions about drug prescribing, obstetrics and gynaecology, and adult infectious disease were most common and comprised 36% of all questions. The taxonomy of generic questions included 69 categories; the three most common types, comprising 24% of all questions, were “What is the cause of symptom X?” “What is the dose of drug X?” and “How should I manage disease or finding X?” Answers to most questions (702, 64%) were not immediately pursued, but, of those pursued, most (318, 80%) were answered. Doctors spent an average of less than 2 minutes pursuing an answer, and they used readily available print and human resources. Only two questions led to a formal literature search.ConclusionsFamily doctors in this study did not pursue answers to most of their questions. Questions about patient care can be organised into a limited number of generic types, which could help guide the efforts of knowledge base developers.

Key messages

• Questions that doctors have about the care of their patients could help guide the content of medical information sources and medical training
• In this study of US family doctors, participants frequently had questions about patient care but did not pursue answers to most questions (64%)
• On average, participants spent less than 2 minutes seeking an answer to a question
• The most common resources used to answer questions included textbooks and colleagues; formal literature searches were rarely performed
• The most common generic questions were “What is the cause of symptom X?” “What is the dose of drug X?” and “How should I manage disease or finding X?”

     

Emerging tobacco hazards in China: 2. Early mortality results from a prospective study

ObjectiveTo monitor the evolving epidemic of mortality from tobacco in China following the large increase in male cigarette use in recent decades.DesignProspective study of smoking and mortality starting with 224 500 interviewees who should eventually be followed for some decades.Setting45 nationally representative small urban or rural areas distributed across China.SubjectsMale population aged 40 or over in 1991, of whom about 80% were interviewed about smoking, drinking, and medical history.Results74% were smokers (73% current, only 1% former), but few of this generation would have smoked substantial numbers of cigarettes since early adult life. Overall mortality is increased among smokers (risk ratio 1.19; 95% confidence interval 1.13 to 1.25, P<0.0001). Almost all the increased mortality involved neoplastic, respiratory, or vascular disease. The overall risk ratios currently associated with smoking are less extreme in rural areas (1.26, 1.12, or 1.02 respectively for smokers who started before age 20, at 20-24, or at older ages) than in urban areas (1.73, 1.40, or 1.16 respectively).ConclusionThis prospective study and the accompanying retrospective study show that by 1990 smoking was already causing about 12% of Chinese male mortality in middle age. This proportion is predicted to rise to about 33% by 2030. Long term continuation of the prospective study (with periodic resurveys) can monitor the evolution of this epidemic.

Key messages

• In recent years most young men in China have become persistent cigarette smokers, starting at about age 20; this will cause high mortality in middle age and old age
• Currently, however, most middle aged and older smokers (particularly in rural areas) have not persistently used substantial daily numbers of cigarettes ever since they were young adults, so their current tobacco attributed mortality is more limited
• Nationally representative retrospective and prospective studies now show that in about 1990 “only” about 12% of adult male deaths in middle age were caused by smoking
• Continuation of the present prospective study will monitor the growth of the epidemic of tobacco related deaths in China over the next few decades

     

Evaluating Clinical Trial Designs for Investigational Treatments of Ebola Virus Disease

BackgroundExperimental treatments for Ebola virus disease (EVD) might reduce EVD mortality. There is uncertainty about the ability of different clinical trial designs to identify effective treatments, and about the feasibility of implementing individually randomised controlled trials during an Ebola epidemic.ConclusionsThe MSA discards ineffective treatments quickly, while reliably providing evidence concerning effective treatments. The MSA is appropriate for the clinical evaluation of EVD treatments.     

A method for human health impact assessment in social LCA: lessons from three case studies

Purpose

Improving human health is a long-lasting endeavour of mankind. In the field of social life cycle assessment (SLCA), the importance of human health is often highlighted, and further development of impact assessment methods has been recommended. The purpose of this article is to present a method for assessing human health impacts within SLCA.

Methods

By using a systematic combining approach, knowledge and experience about assessing human health impacts were obtained from three previously conducted case studies. The first case study was about an airbag system, the second about a catalytic converter and the third about gold jewellery. The disability-adjusted life years (DALY) indicator was used for impact assessment in all three case studies.

Results and discussion

Both positive and negative human health impacts associated with the products were identified and assessed in the three case studies. For the airbag system, avoided health impacts in the use phase outweighed health impacts during production. For the catalytic converter, whether health impacts avoided exceeded health impacts caused or not depended on which time perspective regarding impacts was employed. Gold jewellery does not help avoiding any health impacts but caused considerable health impacts when produced at a certain location. Based on experience from these case studies, a generic human health impact assessment method was developed, and a life cycle human health typology for products was developed based on the method. The method provides a basis for analysis and interpretation of health impacts along product life cycles, and it is therefore important to report both positive and negative health impacts separately for different actors.

Conclusions

The developed human health impact assessment method involves the assessment and comparison of both positive and negative human health impacts along product life cycles. In addition to the products assessed in the three case studies, we suggest additional products that could be particularly interesting to assess with the developed method, including medicines, seat belts, other conflict minerals, alcoholic beverages and products with a high chemical impact.