Canonical transient receptor potential channel subtype 3‐mediated hair cell Ca2+ entry regulates sound transduction and auditory neurotransmission

The physiological significance of canonical transient receptor potential (TRPC) ion channels in sensory systems is rapidly emerging. Heterologous expression studies show that TRPC3 is a significant Ca²⁺ entry pathway, with dual activation via G protein‐coupled receptor (GPCR)–phospholipase C–diacylglycerol second messenger signaling, and through negative feedback, whereby a fall in cytosolic Ca²⁺ releases Ca²⁺–calmodulin channel block. We hypothesised that the latter process contributes to cochlear hair cell cytosolic Ca²⁺ homeostasis. Confocal microfluorimetry with the Ca²⁺ indicator Fluo‐4 acetoxymethylester showed that, when cytosolic Ca²⁺ was depleted, Ca²⁺ re‐entry was significantly impaired in mature TRPC3^?/? inner and outer hair cells. The impact of this disrupted Ca²⁺ homeostasis on sound transduction was assessed with the use of distortion product otoacoustic emissions (DPOAEs), which constitute a direct measure of the outer hair cell transduction that underlies hearing sensitivity and frequency selectivity. TRPC3^?/? mice showed significantly stronger DPOAE (2f₁ ? f₂) growth functions than wild‐type (WT) littermates within the frequency range of best hearing acuity. This translated to hyperacusis (decreased threshold) measured by the auditory brainstem response (ABR). TRPC3^?/? and WT mice did not differ in the levels of temporary and permanent threshold shift arising from noise exposure, indicating that potential GPCR signaling via TRPC3 is not pronounced. Overall, these data suggest that the Ca²⁺ set‐point in the hair cell, and hence membrane conductance, is modulated by TRPC3s through their function as a negative feedback‐regulated Ca²⁺ entry pathway. This TPRC3‐regulated Ca²⁺ homeostasis shapes the sound transduction input–output function and auditory neurotransmission.     

Incidence of Chronic Radiodermatitis after Fluoroscopically Guided Interventions: A Retrospective Study

PurposeTo assess the incidence and risk factors for chronic radiodermatitis after fluoroscopically guided interventions (FGIs) in high-risk patients.Materials and MethodsBetween 2010 and 2016, of 55,782 patients who underwent FGIs, 359 had a risk procedure for skin injury (maximal skin dose > 3 Gy, air kerma > 5 Gy, dose area product [DAP] > 500 Gy.cm², or fluoroscopy time > 60 minutes). Ninety-one of these patients were examined by a dermatologist for radiodermatitis (median time after procedure, 31.2 months [95% confidence interval, 14.2–50.7]). In each case, the clinical features and topography of the skin lesions were recorded and their incidence calculated. The characteristics of the patients and of the FGIs were tested as risk factors.ResultsEight patients (8.8%) had chronic radiodermatitis; 19 (20.9%) had acute radiodermatitis. Body mass index, DAP value, and air kerma were the only risk factors identified.ConclusionsThis study shows that chronic radiodermatitis may be considered a frequent side effect in an at-risk population. The lesions are commonly benign, but extensive sclerosis can occur. Patients should be better informed about the side effects and offered a skin exam periodically.     

EMA对草药产品申请上市许可或注册的非临床资料的要求

EMA于2017年8月发布了"公认和传统草药产品申请上市许可或注册的非临床文件的指导原则（草案）"。该指导原则指出传统和公认的草药物质或制剂,在获得人体充分而详实经验的情况下,单次给药和重复给药毒性、毒代动力学研究、免疫毒性以及局部耐受性试验是不必要的;而其生殖毒性、遗传毒性和致癌性,如果发表的文献不能用或不足,附加非临床试验是必要的。详细介绍该指导原则主要内容,以期对拟在欧盟上市的中草药产品有所帮助,也对我国草药监管有所启发。     

Kinetic Modeling of Contrast-Enhanced MRI: An Automated Technique for Assessing Inflammation in the Rheumatoid Arthritis Wrist

In recent years, development of rheumatoid arthritis (RA) drug therapy has been more directly targeted to counteract specific mechanisms of inflammation, and it is now believed that early aggressive treatment with disease modifying drugs is important to inhibit future structural joint damage. The development of these new treatments has increased the need for methodologies to assess disease activity in RA and monitor the effectiveness of drug therapy. Unlike X-ray, which shows only structural bone damage, magnetic resonance imaging (MRI) can depict soft tissue damage and synovitis, the primary pathology of RA. Recent studies have also indicated that MRI is sensitive to pathophysiologic changes that may predate radiographic erosions and may predict future joint damage. In this study, we have developed a computer automated analysis technique for MR wrist images that provides an objective measure of RA synovitis. This method applies a two-compartment pharmacokinetic model to every voxel of a dynamic contrast-enhanced MRI (DCE-MRI) dataset and outputs resulting parametric images. The aim of this technique is to not only objectively quantify the severity of rheumatoid synovitis, but to also locally determine where areas of serious disease activity are situated through kinetic modeling of blood-tissue exchange. Preliminary results show good correlation to early enhancement rate, which has previously been shown to be a useful clinical marker of RA activity. However, the use of tracer kinetic modeling methods potentially provides more specific information regarding underlying RA physiology. This approach could provide a useful new tool in RA patient management and could substantially improve RA therapeutic studies by calculating objective biomarkers of the disease state.     

The framing of alcohol in (non-)sponsored movies: A comparative content analysis of alcohol advertising and portrayals in sponsored and non-sponsored Dutch movies

Aims: Alcohol advertising, in the form of product placement, has been shown to influence the viewer’s alcohol consumption. However, it is not just the portrayal itself that affects behavioural outcomes; the particular message that is conveyed in an alcohol portrayal may actually influence consumer behaviour in a manner known as “framing”. Therefore, the prevalence and framing of alcohol portrayals in movies was investigated by focussing on product placement strategies, several portrayal characteristics and compliance with relevant guidelines/laws. Furthermore, a comparison is made between movies sponsored by an alcohol brand and non-sponsored movies.

Methods: Sixteen Dutch movies (of which 50% were sponsored) underwent content analysis using a four-category, 21-item coding scheme. Alcohol was present in every movie and a total of 937 alcohol portrayals were analysed.

Findings: The results show that the alcohol portrayals were predominantly positive. In the sponsored movies, more liquor was consumed and alcohol portrayals had a lower plot connection.

Conclusions: In general, the differences between alcohol portrayals in movies sponsored by an alcohol brand compared with non-sponsored movies were rather small. However, the portrayals sometimes offend the legislation regarding regular alcohol commercials, and given the effects of alcohol portrayals on young viewers, this needs attention.     

Medical service provider networks

In many countries, health insurers or health plans choose to contract either with any willing providers or with preferred providers. We compare these mechanisms when two medical services are imperfect substitutes in demand and are supplied by two different firms. In both cases, the reimbursement is higher when patients select the in‐network provider(s). We show that these mechanisms yield lower prices, lower providers' and insurer's profits, and lower expense than in the uniform‐reimbursement case. Whatever the degree of product differentiation, a not‐for‐profit insurer should prefer selective contracting and select a reimbursement such that the out‐of‐pocket expense is null. Although all providers join the network under any‐willing‐provider contracting in the absence of third‐party payment, an asymmetric equilibrium may exist when this billing arrangement is implemented.     

The cost-effectiveness of trivalent and quadrivalent influenza vaccination in communities in South Africa,Vietnam and Australia

BackgroundTo inform national healthcare authorities whether quadrivalent influenza vaccines (QIVs) provide better value for money than trivalent influenza vaccines (TIVs), we assessed the cost-effectiveness of TIV and QIV in low-and-middle income communities based in South Africa and Vietnam and contrasted these findings with those from a high-income community in Australia.MethodsIndividual based dynamic simulation models were interfaced with a health economic analysis model to estimate the cost-effectiveness of vaccinating 15% of the population with QIV or TIV in each community over the period 2003–2013. Vaccination was prioritized for HIV-infected individuals, before elderly aged 65+ years and young children. Country or region-specific data on influenza-strain circulation, clinical outcomes and costs were obtained from published sources. The societal perspective was used and outcomes were expressed in International$ (I$) per quality-adjusted life-year (QALY) gained.ResultsWhen compared with TIV, we found that QIV would provide a greater reduction in influenza-related morbidity in communities in South Africa and Vietnam as compared with Australia. The incremental cost-effectiveness ratio of QIV versus TIV was estimated at I$4183/QALY in South Africa, I$1505/QALY in Vietnam and I$80,966/QALY in Australia.ConclusionsThe cost-effectiveness of QIV varied between communities due to differences in influenza epidemiology, comorbidities, and unit costs. Whether TIV or QIV is the most cost-effective alternative heavily depends on influenza B burden among subpopulations targeted for vaccination in addition to country-specific willingness-to-pay thresholds and budgetary impact.     

艾叶的化学成分、药理作用及产品开发研究进展

艾叶为我国传统中药材,主要含有挥发油、黄酮、多糖、鞣酸、萜类及微量元素等多种化学成分。其药理作用较为广泛,包括抗菌、抗病毒、抗氧化、保肝利胆、止血及抗凝血、抗过敏、免疫调节、抗癌等。目前其应用集药品、食品、保健品等于一体,具有广阔的开发前景。对艾叶的化学成分、药理作用及产品的开发研究进展做一概述,为更合理有效地利用艾叶药材、开发艾叶产品提供参考。     

FDA对皮肤外用药活性成分人体最大用量试验的要求

美国食品药品管理局（FDA）于2018年5月发布了“考虑列入OTC专论的外用药活性成分的最大用量试验：研究要点和考虑的因素供企业用的指导原则”。最大用量试验（MUsT）是评估外用药体内生物利用度的标准方法,该指导原则对MUsT许多研究要点提出了具体的建议。详细介绍该指导原则的主要内容,期待对我国这方面的研究和监管有益。