New legal requirements for submission of product information to poisons centres in EU member states

Introduction: In the past eight years, the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) has been intensively involved in a European Commission led process to develop EU legislation on the information of hazardous products that companies have to notify to EU Poisons Centres (or equivalent “appointed bodies”). As a result of this process, the Commission adopted Regulation (EU) No 2017/542, amending the CLP Regulation by adding an Annex on harmonised product submission requirements.

Harmonised mixture information requirements: Detailed and consistent information on the composition of the hazardous product will become available to EU Poisons Centres (PC). The information will be submitted by companies to PCs (or equivalent “appointed bodies”) using a web-based software application or in-house software. Two new important features are introduced. Firstly, to be able to rapidly identify the product formula, a Unique Formula Identifier (UFI) on the product label links to the submitted information. Secondly, for better comparability of reports on poisonings between EU member states, a harmonised Product Categorisation System will specify the intended use of a product. Rapid product identification and availability of detailed composition information will lead to timely and adequate medical intervention. This may lead to considerable reduction in healthcare costs.

Additionally, for companies trading across the EU, costs of submission of this information will be reduced significantly.

Next steps: From 2017, an implementation period has started, consisting of a three-year period for stakeholders to implement the new requirements, followed by a gradual applicability for consumer products (2020), professional products (2021) and industrial use-only products (2024). Technical tools to generate the electronic format and the UFI together with guidance documents are expected to be made available by the end of 2017 by the European Chemicals Agency (ECHA). Guidance on interpretation of legal text and ECHA helpdesk support are planned to be ready at the end of 2018.     

High resolution sonography in the evaluation of the peripheral nervous system in polyneuropathy – a review of the literature

Clinical, laboratory and electrodiagnostic studies are the mainstay in the diagnosis of polyneuropathy. An accurate etiological diagnosis is of paramount importance to provide the appropriate treatment, prognosis and genetic counselling. High resolution sonography of the peripheral nervous system allows nerves to be readily visualized and to assess their morphology. Ultrasonography has brought pathophysiological insights and substantially added to diagnostic accuracy and treatment decisions amongst mononeuropathies. In this study the literature on its clinical application in polyneuropathy is reviewed. Several polyneuropathies have been studied by means of ultrasound: Charcot–Marie–Tooth, hereditary neuropathy with liability to pressure palsies, chronic inflammatory demyelinating polyneuropathy, Guillain‐Barré syndrome, multifocal motor neuropathy, paraneoplastic polyneuropathy, leprosy and diabetic neuropathy. The most prominent reported pathological changes were nerve enlargement, increased hypo‐echogenicity and increased intraneural vascularization. Sonography revealed intriguingly different patterns of nerve enlargement between inflammatory neuropathies and axonal and inherited polyneuropathies. However, many studies concerned case reports or case series and showed methodological shortcomings. Further prospective studies with standardized protocols for nerve sonography and clinical and electrodiagnostic testing are needed to determine the role of nerve sonography in inherited and acquired polyneuropathies.     

Increased nerve vascularization detected by color doppler sonography in patients with ulnar neuropathy at the elbow indicates axonal damage

Introduction: The aim of this study was to establish the prevalence of increased intraneural vascularization detected by ultrasonography (IVUS) in patients with ulnar neuropathy at the elbow (UNE) and to determine its relationship to clinical, ultrasonographic, and electrodiagnostic findings. Methods: High‐resolution ultrasonography and color Doppler imaging were performed in 137 patients with confirmed UNE, 24 patient controls, and 70 healthy controls (HCs). Results: IVUS was found in 21 (15%) of 137 patients with UNE, in 1 (4%) of 24 patient controls, and in 0 of 70 HCs (P = 0.001). Patients with IVUS were more likely to have severe weakness (P = 0.01), severe atrophy of ulnar‐innervated muscles (P = 0.008), axonal damage (P = 0.001), and more pronounced nerve enlargement (P = 0.03) than those without IVUS. Conclusions: IVUS in the ulnar nerve can be detected in patients with UNE and is associated with nerve enlargement and clinical and electrodiagnostic severity. In addition, IVUS is associated with axonal damage. Muscle Nerve, 2013     

Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers

AIMS: To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as a concentrated intranasal spray, compared with intravenous midazolam, in healthy adult subjects. METHODS: Subjects were administered single doses of 5 mg midazolam intranasally and intravenously in a cross-over design with washout period of 1 week. The total plasma concentrations of midazolam and the metabolite 1-hydroxymidazolam after both intranasal and intravenous administration were described with a single pharmacokinetic model. beta-band EEG activity was recorded and related to midazolam plasma concentrations using an exponential pharmacokinetic/pharmacodynamic model. RESULTS: Administration of the intranasal spray led to some degree of temporary irritation in all six subjects, who nevertheless found intranasal administration acceptable and not painful. The mean (+/-s.d.) peak plasma concentration of midazolam of 71 (+/-25 ng ml-1) was reached after 14 (+/-5 min). Mean bioavailability following intranasal administration was 0.83+/-0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11+/-0.25 l kg-1, mean systemic clearance 16.1+/-4.1 ml min-1 kg-1 and harmonic mean initial and terminal half lives 8.4+/-2.4 and 79+/-30 min, respectively. Formation of the 1-hydroxymetabolite after intranasal administration did not exceed that after intravenous administration. CONCLUSIONS: In this study in healthy volunteers a concentrated midazolam nasal spray was easily administered and well tolerated. No serious complications of the mode of administration or the drug itself were reported. Rapid uptake and high bioavailability were demonstrated. The potential of midazolam given via a nasal spray in the acute treatment of status epilepticus and other seizure disruptions should be evaluated.     

A BRCA1/2 mutation,high breast density and prominent pushing margins of a tumor independently contribute to a frequent false-negative mammography

Female BRCA1/2 mutation carriers develop in up to 50% breast cancer (BC) before age 50 years. We investigated whether the specific histologic features of BRCA1/2-associated breast cancer influence imaging. We correlated the mammographic results with the histology of 34 BC in BRCA1/2 mutation carriers and 34 sporadic cancers in patients, matched for age and year of diagnosis. Mammography was significantly more frequently false-negative in carriers than controls (62% vs. 29% p = 0.01), despite comparable tumor size (mean solidus in circle 1.51 vs. 1.75) and breast density (high 41% vs. 53%). The image in carriers was significantly less as spiculated mass (6 vs. 18 p = 0.01). Cancers of BRCA1/2 mutation carriers had frequently higher mitotic counts (p < 0.0001) and prominent pushing margins around the tumor (p = 0.08) (p = 0.05 for 32 BRCA1). We also observed that prominent "pushing margins" correlated significantly with a false-negative mammography (p = 0.005) and with a mammographic image of a smooth, not a spiculated, mass (p = 0.01). False-negative mammography correlated independently with: BRCA1/2 mutation (p = 0.02), prominent pushing margins (p = 0.03) and high breast density (p = 0.01). MRI was carried out in 12 carriers, had 100% sensitivity and detected 5 cancers, still occult at physical examination and mammography. A BRCA1/2 mutation and high breast density at mammography contribute independently to false-negative mammography results. In mutation carriers any mammographic mass must be regarded with suspicion. Pushing margins of the tumor partly explain these results. For early BC detection in mutation carriers additional methods like MRI may be needed. This may not be necessary in other young women with breast symptoms.     

Unipolarity of fibroblasts in rodent periodontal ligament

In order to investigate whether fibroblasts in rodent periodontal ligament have a structural polarity, the position of the Golgi apparatus or the centriolar region in the cells was studied using light and electron microscopy. It appeared that, in the periodontal ligament of continuously erupting mouse and rat incisors, centrioles in fibroblasts on the tooth side of the ligament are preferably located in the anterior (occlusally directed) part of the cytoplasm. Polarity of fibroblasts in a single direction was less pronounced or absent on the bone side of the tissue. In the mouse, fibroblasts in the connective tissue adjacent to the incisor also contained an extensive system of cytoplasmic microtubules, whereas in the fibroblasts on the bone side of the ligament microtubules were less frequent. Unipolarity of fibroblasts was also observed in the periodontal ligament of the rat maxillary first molar, which is characterized by a limited eruption. Here, the Golgi region was usually situated in that pole of the cells that was directed towards the alveolar wall and the occlusal plane. It is suggested that structural polarity of fibroblasts in the periodontal ligament of rodent teeth is associated with orientation of functional activities of the cells, such as unidirectional movement or unidirectional deposition or phagocytosis of collagen.     

MRI screening for breast cancer in women with familial or genetic predisposition: design of the Dutch National Study (MRISC)

Mammography screening of women aged 50–70 years for breast cancer has proven to be effective in reducing breast cancer mortality. There is no consensus about the value of breast cancer screening in women aged 40–49 years. Five to ten per cent of all breast cancers are hereditary. One of the options to reduce the risk of breast cancer mortality for women with a familial or genetic predisposition is intensive surveillance. However, the effectiveness of mammography screening for breast cancer in these women, who are mainly younger than 50 years, is unproven. MRI might increase the effectiveness of screening in women with a familial or genetic predisposition. This paper describes the design of the Dutch national study for Magnetic Resonance Imaging (MRI) screening in women with a familial or genetic predisposition. The aims of this study are to investigate: the value of regular surveillance in women with a familial or genetic predisposition for breast cancer, the efficacy of MRI as compared to mammography, cost-effectiveness of regular screening and quality of life during surveillance. Included are women with a lifetime risk of familial breast cancer of 15% or more or BRCA1/2 mutation carriers, who visit one of the Dutch family cancer clinics. The aim is to include 2,500 women. The study started on 1 November 1999. On 1 January 2002, more than 1700 women, including 210 proven carriers of a BRCA1 or BRCA2 mutation, were included in the study.