Late-onset sepsis due to Salmonella Typhi in a preterm infant in a French neonatal unit.

We report a case of late-onset sepsis caused by Salmonella Typhi in a one-month old preterm infant hospitalised in our neonatal unit. An investigation of the index case was undertaken to identify the source of contamination. The patient made a complete recovery.

Wavelength-scale errors in optical localization due to spin-orbit coupling of light.

Far-field optical imaging techniques allow the determination of the position of point-like emitters and scatterers [1-3]. Although the optical wavelength sets a fundamental limit to the image resolution of unknown objects, the position of an individual emitter can in principle be estimated from the image with arbitrary precision. This is used for example in the determination of stars position [4] or in optical super-resolution microscopy [5]. Furthermore, precise position determination is an experimental prerequisite for the manipulation and measurement of individual quantum systems, such as atoms, ions, and solid-state-based quantum emitters [6-8]. Here we demonstrate that spin-orbit coupling of light in the emission of elliptically polarized emitters can lead to systematic, wavelength-scale errors in the estimation of the emitters position. Imaging a single trapped atom as well as a single sub-wavelength-diameter gold nanoparticle, we demonstrate a shift between the emitters measured and actual positions which is comparable to the optical wavelength. For certain settings, the expected shift can become arbitrarily large. Beyond optical imaging techniques, our findings could be relevant for the localization of objects using any type of wave that carries orbital angular momentum relative to the emitters position with a component orthogonal to the direction of observation.

Impact of the Council of Europe Resolution on quality and safety assurance requirements for medicinal products prepared in pharmacies for the special needs of patients.

INTRODUCTION AND OBJECTIVE: The regulation of pharmacy preparations, especially for standards for quality assurance and safety, is not harmonised across Europe and falls under the national competencies of individual states. There are concerns about quality control and safety for the medicinal products made in pharmacies, which is widespread in European countries. There are, however, good reasons to continue this practice, which is able to tailor preparations to the specific needs of a particular patient or patient group and to provide a supplementary source of supply when an industrially manufactured product, which is authorised for marketing is not available or when there are temporary shortages of licensed medicines. In seeking to provide guidelines for legislation and acting on the advice of an expert group dealing in pharmaceutical practices, the Committee of Ministers of the Council of Europe passed a resolution in 2011. The Council of Europe Resolution provides authorities and pharmacists with the means to reinforce safety measures for medicinal products prepared in pharmacies and to harmonise quality assurance and safety standards. It dealt with aspects of pharmacy preparation such as quality standards for preparation and distribution, marketing authorisation, product dossiers, labelling, reporting, and safety. In 2013 and 2014 the Committee of Experts carried out a survey to evaluate the impact of the resolution within a cross section of member states. The objectives of this study were both to monitor the extent to which the recommendations had been enshrined in national legislation and also to understand current differences in legislation and practice between the member states. METHODS: In the resolution of 2011 the member states were recommended to adapt their legislation in line with its provisions. The survey that was carried out in 2013 and 2014 followed the recommendations in the resolution. A questionnaire was made and sent to a cross section of member states. RESULTS: Among the member states involved, the results of this survey show a clear commitment to implement the recommendations of the resolution. CONCLUSIONS: This report presents the results of the survey with a discussion of outstanding issues.

Legislation on the preparation of medicinal products in European pharmacies and the Council of Europe Resolution.

INTRODUCTION: The rights of patients should be sufficiently protected even when an appropriate authorised medicine does not exist or is unavailable on the market. The Resolution, which was adopted by the Committee of Ministers of the Council of Europe in 2011, aims at harmonising quality and safety standards for pharmacy preparation of medicinal products in Europe. TWO PILLARS OF EU REGULATION AND THE EXCEPTIONS TO THEM: The system of regulation of medicinal products is built upon two pillars: the marketing authorisation of the medicinal product and the licence for manufacturing and wholesale. This article provides insight into the recent interpretation of the European Court of Justice concerning the scope of European Union (EU) regulation of medicinal products and the circumstances in which the EU regulation does not apply: pharmacy preparations, specialties and the compassionate use of medicines, including manufacturing licence. EU REGULATION AND THE RESOLUTION CONCERNING PHARMACY PREPARATION: Pharmacy preparations are allowed under certain strict conditions according to EU regulations. However, pharmacies specialised in preparation and distributing medicinal products to local pharmacies do not fulfil these strict conditions in EU regulation. Apart from the legal context, relevant standards for safety and quality assurance are needed in Europe in order to protect patients' rights and to avoid risks from pharmacy preparations. DISCUSSION AND CONCLUSIONS: The Council of Europe Resolution provides a means of establishing standards for safety and quality assurance for pharmacy preparations through Good Manufacturing Practice Guidelines. The Resolution is available to authorities and pharmacists in order to prevent incidents with medicines prepared in pharmacies which may threaten patients' safety. The authors conclude that pharmacy practices have changed over time in Europe and this may imply a reason for a reform of EU regulation on medicinal products.

Aseptic preparation of parenteral medicinal products in healthcare establishments in Europe.

In many cases, parenteral medicines with a marketing authorisation cannot be administered directly to patients, that is, they are not presented in ready-to-administer form. Before administration to patients, these medicines have to be reconstituted. Reconstitution has a special position; it can neither be seen as industrial manufacture nor as 'regular' pharmacy preparation. There are other processes in healthcare establishments (eg, parenteral nutrition), related to the reconstitution process, where the requirements of national quality assurance standards for the safe preparation of sterile products are equally important and have to be fulfilled. In European healthcare establishments, aseptic preparation of parenteral medicinal products is considered to be a process of crucial importance for patient safety because errors in the preparation of these medicines may lead to a product that can cause immediate damage to patients. Aseptic preparation of medicinal products is carried out in hospital pharmacies as well as in clinical areas in healthcare establishments. The Committee of Experts on Quality and Safety Standards for Pharmaceutical Practices and Pharmaceutical Care (Council of Europe; hereafter: Committee of Experts), supported by the European Directorate for the Quality of Medicines & Healthcare, is undertaking work on the topic of aseptic preparation of medicines. The work is carried out in cooperation with the European Association of Hospital Pharmacists on the basis of a Resolution CM/Res AP(2011)1 on Quality and Safety Assurance requirements for Medicinal Products prepared in Pharmacies for the Special Needs of Patients, which was adopted by the Committee of Ministers on 19 January 2011. The Resolution includes some recommendations and an outlook to further work on reconstitution of parenteral medicines. A survey that was sent to the different European countries demonstrated that there is no or just limited regulation concerning reconstitution in Europe. This article describes the risks associated with poor reconstitution practices and the previous work as well as the ongoing activities concerning reconstitution at the European level. The article emphasises the need for regulation in this area, which is missing at present. It is expected that consensus can be reached on a guidance document for reconstitution at the European level.

Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior.

Hypersecretion of central corticotropin-releasing hormone (CRH) has been implicated in the pathophysiology of affective disorders. Both, basic and clinical studies suggested that disrupting CRH signaling through CRH type 1 receptors (CRH-R1) can ameliorate stress-related clinical conditions. To study the effects of CRH-R1 blockade upon CRH-elicited behavioral and neurochemical changes we created different mouse lines overexpressing CRH in distinct spatially restricted patterns. CRH overexpression in the entire central nervous system, but not when overexpressed in specific forebrain regions, resulted in stress-induced hypersecretion of stress hormones and increased active stress-coping behavior reflected by reduced immobility in the forced swim test and tail suspension test. These changes were related to acute effects of overexpressed CRH as they were normalized by CRH-R1 antagonist treatment and recapitulated the effect of stress-induced activation of the endogenous CRH system. Moreover, we identified enhanced noradrenergic activity as potential molecular mechanism underlying increased active stress-coping behavior observed in these animals. Thus, these transgenic mouse lines may serve as animal models for stress-elicited pathologies and treatments that target the central CRH system.

[Botulism: prevention, clinical diagnostics, therapy and possible threat]. / Botulismus: Prävention, Diagnostik, Therapie und mögliche Bedrohungslagen.

In times of increased terrorist threat health professionals need to be prepared for bioterrorist events. The goal must be to give doctors an overview over the current state of knowledge and risk assessment of botulinum toxin. This review is based on Information gathered by a systematic analysis of the literature and by contacting experts. The toxicity of botulinum toxin exceeds any other known natural toxin. Clinical features of botulism consist of an acute, afebrile symmetrical and descending paralysis, regardless of the route of exposure, with normal mental status, sensory functions and electrolyte values. The initial diagnosis is often wrong in individual cases of botulism, but clusters with typical symptoms and two or more cases usually provide the diagnosis. Current treatment is primarily supportive care, respiratory support and antitoxin administration. Early application of antitoxin can limit the extent of the paralysis, but will not reverse it. Antitoxin for adult patients is of equine origin, while children in the USA can be treated with a recently developed human antitoxin. A pentavalent toxoid vaccine is available for persons at high risk of exposure. Botulinum toxin is easily extracted and ubiquitously available. These two features, together with the high toxicity, makes misuse easy. Misuse will continue to occur. Although a rare disease in Western Europe, botulism should be included in the differential diagnosis in patients with specific symptoms of paralysis. There is the potential threat of deliberate release of botulinum toxin. For this reason every outbreak of botulism must be assessed for any possible links to terrorism.

Comparison of long-term monitoring methods for bipolar affective disorder.

Long-term monitoring is a clinical necessity in bipolar affective disorder. The most important requirements are usability and value for clinical decisions. Four methods of long-term monitoring - (1) the Adjective Mood Scale by von Zerssen, (2) Kraepelin's early life charts, (3) the NIMH Life Chart Method by Leverich and Post and (4) the Social Rhythm Metric by Monk - were compared regarding the acceptance by patients, the time commitment needed for documentation and training as well as the usability for the clinician regarding psychotherapy and decision support in pharmacotherapy. The Adjective Mood Scale is easiest to learn, Kraepelin's life chart offers the best graphical presentation, the NIMH life charts offer the best clinical decision support and the Social Rhythm Metric integrates a psychotherapeutic approach.

The Stanley Foundation Bipolar Network: results of the naturalistic follow-up study after 2.5 years of follow-up in the German centres.

The Stanley Foundation Bipolar Network (SFBN) is an international, multisite network investigating the characteristics and course of bipolar disorder. Methods (history, ratings and longitudinal follow-up) are standardized and equally applied in all 7 centres. This article describes demographics and illness characteristics of the first 152 German patients enrolled in the SFBN as well as the results of 2.5 years of follow-up. Patients in Germany were usually enrolled after hospitalisation. More than 72% of the study population suffered from bipolar I disorder and 25% from bipolar II disorder. The mean +/- SD age of the study participants was 42.08 +/- 13.5 years, and the mean +/- SD age of onset 24.44 +/- 10.9 years. More than 40% of the sample reported a rapid-cycling course in history, and even more a cycle acceleration over time. 37% attempted suicide at least once. 36% had an additional Axis I disorder, with alcohol abuse being the most common one, followed by anxiety disorders. During the follow-up period, only 27% remained stable, 56% had a recurrence, 12.8% perceived subsyndromal symptoms despite treatment and regular visits. 27% suffered from a rapid-cycling course during the follow-up period. Recurrences were significantly associated with bipolar I disorder, an additional comorbid Axis I disorder, rapid cycling in history, a higher number of mood stabilizers and the long-term use of typical antipsychotics. Rapid cycling during follow-up was only associated with a rapid-cycling course in history, a higher number of mood stabilizers and at least one suicide attempt in history.

Electronic diary for bipolar patients.

Long-term monitoring methods providing an overview of the course of bipolar disorder of individual patients are a clinical necessity at least for patients who require a combination therapy with drugs that have only proven their efficacy for monotherapy. The Life Chart Method (LCM) of the NIMH is an adequate method for this purpose. Unfortunately, due to data entry and management requirements, it is too expensive for everyday clinical use. The 'electronic diary for patients with bipolar disorder' is meant to provide a method to minimize the effort for detailed long-term monitoring of patients with bipolar affective disorder and thus make it available for the everyday clinical use for every bipolar patient.

Preliminary toxicokinetic study with different crystal forms of S (+)-ibuprofen (dexibuprofen) and R,S-ibuprofen in rats.

The aim of the study was to gain information on the plasma concentration-time profiles of both ibuprofen (CAS 15687-27-1) enantiomers in the rat after single oral application of two different crystal forms of S (+)-ibuprofen (dexibrufen, CAS 51146-56-6) and racemic ibuprofen in order to optimize blood-sampling times in a subsequent subchronic toxicity study. The application of either commercial racemic ibuprofen or recrystallised S (+)-ibuprofen (60 mg/kg) to two groups of 4 rats per blood sampling term was carried out in order to define Cmax and tmax and AUC of the plasma-concentrations of the ibuprofen enantiomers. The crystals of commercial (manufactured according to an usual manufacturing procedure) and recrystallised (S(+)- and racemic ibuprofen were different in respect to their shape and size. The recrystallised crystal species of S (+)- and racemic ibuprofen has better galenic (tabletting-) properties and tablets containing the modified S (+)-ibuprofen species showed favorable clinical results. The toxicokinetic behaviour of the recrystallised species was investigated in comparison to the commercial crystal species because of its slightly but significantly slower dissolution rate in simulated gastric and enteric juice. As the AUC0-24 h S-(+)-ibuprofen and the AUC0-24 h, R-(-)-ibuprofen after application of commercial and recrystallised crystal species were not different, the crystal form apparently did not exert an influence on the extent of absorption of S-(+)-ibuprofen and racemic ibuprofen in the rat. The rat has a high inversion capacity and the inversion of R-(-)-ibuprofen after application of commercial and recrystallised racemic ibuprofen was nearly complete in this study. The effects of crystallinity on solubility in simulated media in vitro did not correlate to the findings on the extent of absorption in the rat in vivo.

The release of endogenous histamine in distinct brain areas is modified by electrical stimulation.

In anaesthetized cats, mamillary bodies, hypothalamic areas and medial amygdaloid nuclei were bilaterally superfused through push-pull cannulae and the effects of the electrical stimulation on the release of endogenous histamine were investigated. Electrical stimulation of the mamillary body increased the release of histamine in the stimulated area, as well as in the contralateral mamillary body. Electrical stimulation of the lateral hypothalamic area enhanced the histamine release in the contralateral hypothalamic area. Stimulation of the posterior hypothalamic area led to a delayed increase in the histamine release in the stimulated area. Stimulation of the medial amygdaloid nucleus reduced the release if histamine in the ipsilateral posterior hypothalamic area, while the histamine release in the contralateral lateral hypothalamic area was enhanced. The results demonstrate that electrical stimulation of distinct brain areas rich in histaminergic neurons may either increase, or decrease the release rate of histamine in the stimulated area and/or in remote brain areas.

Histamine, histidine decarboxylase and histamine-N-methyltransferase in brain areas of spontaneously hypertensive rats.

Histamine levels, histidine decarboxylase and histamine-N-methyltransferase activities were determined in various brain areas of young (9-week old) and adult (18-week old) normotensive rats (WKY) and hypertensive rats (SHR). When compared with WKY, histamine levels were increased in the anterior and posterior hypothalamus of young and adult SHR, as well as in the brainstem of young SHR. Histidine decarboxylase activity was unchanged in the posterior hypothalamus and in the medulla oblongata of young and adult SHR as well as in the anterior hypothalamus of young SHR, but it was slightly decreased in the anterior hypothalamus of adult SHR. Histidine decarboxylase activity was enhanced in the cortex-midbrain of young, as well as adult SHR, histamine-N-methyltransferase in the cortex-midbrain of young SHR. The following differences were found between young and adult rats: histamine levels were elevated in the cortex-midbrain of adult WKY and SHR. In the cortex-midbrain and brainstem of adult WKY and SHR histidine decarboxylase activity was also increased, while histamine-N-methyltransferase activity was elevated in the cortex-midbrain of adult WKY. The findings show changes in histamine levels, histidine decarboxylase and histamine-N-methyltransferase activities in SHR and suggest involvement of histaminergic neurons in hypertension. The activity of histaminergic neurons of adult rats seems to be higher than that of young animals.