Psychotropic drug use in non-psychiatric departments of three European university hospitals

The use of psychotropic drugs in the university hospitals in Tartu, Estonia; Huddinge, Sweden; and Badajoz, Spain, were studied, using the defined daily doses per 100 bed-days (DDD/100 bed-days) method. The total amount of drugs used in the surgical and medical departments was 50 DDD/100 bed-days in Huddinge, versus 33 and 14 DDD/100 bed-days in Tartu and Badajoz, respectively. Barbiturates accounted for 35% of all psychotropics in Tartu but were practically not used in Huddinge. In contrast, antidepressants were practically not used in Tartu. The use of psychotropic drugs in the intensive care units was highest in Huddinge (320 DDD/100 bed-days), compared with Tartu and Badajoz (177 and 96 DDD/100 bed-days, respectively). The frequency of psychotropic drug use were strikingly different in the three hospitals studied.     

Automated GMP production and long-term experience in radiosynthesis of CB1 tracer [18F]FMPEP-d2

Here, we describe the development of an in-house-built device for the fully automated multistep synthesis of the cannabinoid CB₁ receptor imaging tracer (3R,5R)-5-(3-([¹⁸F]fluoromethoxy-d₂)phenyl)-3-(((R)-1-phenylethyl)amino)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one ([¹⁸F]FMPEP-d₂), following good manufacturing practices. The device is interfaced to a HPLC and a sterile filtration unit in a clean room hot cell. The synthesis involves the nucleophilic ¹⁸F-fluorination of an alkylating agent and its GC purification, the subsequent ¹⁸F-fluoroalkylation of a precursor molecule, the semipreparative HPLC purification of the ¹⁸F-fluoroalkylated product, and its formulation for injection. We have optimized the duration and temperature of the ¹⁸F-fluoroalkylation reaction and addressed the radiochemical stability of the formulated product. During the past 5 years (2013–2018), we have performed a total of 149 syntheses for clinical use with a 90% success rate. The activity yield of the formulated product has been 1.0 ± 0.4 GBq starting from 11 ± 2 GBq and the molar activity 600 ± 300 GBq/μmol at the end of synthesis.     

High-resolution CT by diffraction-enhanced x-ray imaging: mapping of breast tissue samples and comparison with their histo-pathology

The aim of this study was to introduce high-resolution computed tomography (CT) of breast tumours using the diffraction-enhanced x-ray imaging (DEI) technique and to compare results with radiological and histo-pathological examinations. X-ray CT images of tumour-bearing breast tissue samples were acquired by monochromatic synchrotron radiation (SR). Due to the narrow beam and a large sample-to-detector distance scattering is rejected in the absorption contrast images (SR-CT). Large contrast enhancement is achieved by the use of the DEI-CT method, where the effects of refraction and scatter rejection are analysed by crystal optics. Clinical mammograms and CT images were recorded as reference material for a radiological examination. Three malignant and benign samples were studied in detail. Their radiographs were compared with optical images of stained histological sections. The DEI-CT images map accurately the morphology of the samples, including collagen strands and micro-calcifications of dimensions less than 0.1 mm. Histo-pathological examination and reading of the radiographs were done independently, and the conclusions were in general agreement. High-resolution DEI-CT images show strong contrast and permit visualization of details invisible in clinical radiographs. The radiation dose may be reduced by an order of magnitude without compromising image quality, which would make possible clinical in vivo DEI-CT with future compact SR sources.     

Automated production of [18F]FTHA according to GMP

14‐(R,S)‐[¹⁸F]fluoro‐6‐thia‐heptadecanoic acid is a tracer for fatty acid imaging by positron emission tomography. High demand for this tracer required us to replace semiautomatic synthesis with a fully automated procedure. An automated synthesis device was constructed in‐house for multistep nucleophilic ¹⁸F‐fluorination and a control system was developed. The synthesis device was combined with a sterile filtration unit and both were qualified. 14‐(R,S)‐[¹⁸F]fluoro‐6‐thia‐heptadecanoic acid was produced according to good manufacturing practice guidelines set by the European Union. The synthesis includes an initial nucleophilic labelling reaction, deprotection, preparative HPLC separation, purification of the final product, and formulation for injection. The duration and temperature of the reaction and hydrolysis were optimized, and the radiochemical stability of the formulated product was determined. The rotary evaporator used to evaporate the solvent after HPLC purification was replaced with solid phase extraction purification. We also replaced the human serum albumin used in the earlier procedure with a phosphate buffer‐ascorbic acid mixture in the final formulation solution. From 2011 to 2016, we performed 219 synthesis procedures, 94% of which were successful. The radiochemical yield of 14‐(R,S)‐[¹⁸F]fluoro‐6‐thia‐heptadecanoic acid, decay‐corrected to the end of bombardment, was 13% ± 6.3%. The total amount of formulated end product was 1.7 ± 0.8 GBq at end of synthesis.     

Quantitative comparison between two phase contrast techniques: diffraction enhanced imaging and phase propagation imaging

Two x-ray phase contrast imaging techniques are compared in a quantitative way for future mammographic applications: diffraction enhanced imaging (DEI) and phase propagation imaging (PPI). DEI involves, downstream of the sample, an analyser crystal acting as an angular filter for x-rays refracted by the sample. PPI simply uses the propagation (Fresnel diffraction) of the monochromatic and partially coherent x-ray beam over large distances. The information given by the two techniques is assessed by theoretical simulations and compared at the level of the experimental results for different kinds of samples (phantoms and real tissues). The imaging parameters such as the energy, the angular position of the analyser crystal in the DEI case or the sample to detector distance in the PPI case were varied in order to optimize the image quality in terms of contrast, visibility and figure of merit.     

Effects of exercise intensity and duration on nocturnal heart rate variability and sleep quality

Acute physical exercise may affect cardiac autonomic modulation hours or even days during the recovery phase. Although sleep is an essential recovery period, the information on nocturnal autonomic modulation indicated by heart rate variability (HRV) after different exercises is mostly lacking. Therefore, this study investigated the effects of exercise intensity and duration on nocturnal HR, HRV, HR, and HRV-based relaxation, as well as on actigraphic and subjective sleep quality. Fourteen healthy male subjects (age 36 ± 4 years, maximal oxygen uptake 49 ± 4 ml/kg/min) performed five different running exercises on separate occasions starting at 6 p.m. with HR guidance at home. The effect of intensity was studied with 30 min of exercises at intensities corresponding to HR level at 45% (easy), 60% (moderate) and 75% (vigorous) of their maximal oxygen uptake. The effect of duration was studied with 30, 60, and 90 min of moderate exercises. Increased exercise intensity elevated nocturnal HR compared to control day (p < 0.001), but it did not affect nocturnal HRV. Nocturnal HR was greater after the day with 90- than 30- or 60-min exercises (p < 0.01) or control day (p < 0.001). Nocturnal HRV was lower after the 90-min exercise day compared to control day (p < 0.01). Neither exercise intensity nor duration had any impact on actigraphic or subjective sleep quality. The results suggest that increased exercise intensity and/or duration cause delayed recovery of nocturnal cardiac autonomic modulation, although long exercise duration was needed to induce changes in nocturnal HRV. Increased exercise intensity or duration does not seem to disrupt sleep quality.     

The human GIMAP5 gene has a common polyadenylation polymorphism increasing risk to systemic lupus erythematosus

Background

Several members of the GIMAP gene family have been suggested as being involved in different aspects of the immune system in different species. Recently, a mutation in the GIMAP5 gene was shown to cause lymphopenia in a rat model of autoimmune insulin‐dependent diabetes. Thus it was hypothesised that genetic variation in GIMAP5 may be involved in susceptibility to other autoimmune disorders where lymphopenia is a key feature, such as systemic lupus erythematosus (SLE).

Material and methods

To investigate this, seven single nucleotide polymorphisms in GIMAP5 were analysed in five independent sets of family‐based SLE collections, containing more than 2000 samples.

Result

A significant increase in SLE risk associated with the most common GIMAP5 haplotype was found (OR 1.26, 95% CI 1.02 to 1.54, p = 0.0033). In families with probands diagnosed with trombocytopenia, the risk was increased (OR 2.11, 95% CI 1.09 to 4.09, p = 0.0153). The risk haplotype bears a polymorphic polyadenylation signal which alters the 3′ part of GIMAP5 mRNA by producing an inefficient polyadenylation signal. This results in higher proportion of non‐terminated mRNA for homozygous individuals (p<0.005), a mechanism shown to be causal in thalassaemias. To further assess the functional effect of the polymorphic polyadenylation signal in the risk haplotype, monocytes were treated with several cytokines affecting apoptosis. All the apoptotic cytokines induced GIMAP5 expression in two monocyte cell lines (1.5–6 times, p<0.0001 for all tests).

Conclusion

Taken together, the data suggest the role of GIMAP5 in the pathogenesis of SLE.     

Gene Therapy for Fabry Disease: A Review of the Literature

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme, α-galactosidase A. The lack of adequate enzymatic activity results in a systemic accumulation of neutral glycosphingolipids, predominantly globotriaosylceramide, in the lysosomes of, especially, endothelial and smooth muscle cells of blood vessels. Enzyme replacement therapy is at present the only available specific treatment for Fabry disease; however, this therapy has important drawbacks. Gene-mediated enzyme replacement is a reasonable and highly promising approach for the treatment of Fabry disease. It corresponds to a single gene disorder in which moderately low levels of enzyme activity should be sufficient for clinical efficacy and, thanks to cross-correction mechanisms, the transfection of a small number of cells will potentially correct distant cells too. This article summarizes the studies that have been carried out concerning gene therapy for the treatment of Fabry disease. We briefly review the literature from earlier studies in the 1990s to the current achievements.     

CT-guided needle localization for intraoperative biopsy of the head and neck

Needle-localized intraoperative biopsy was first described for the nonpalpable breast mass using mammography for needle placement. This technique can be adapted by substituting CT (or MRI) for mammography. It can be a valuable tool in localizing the nonpalpable areas of concern in the head and neck, especially when the location is obscure or the patient has undergone previous radiation and/or surgical therapy.