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.     

Applanation resonance tonometry for intraocular pressure in humans

Glaucoma is a group of diseases associated with optic nerve damage and loss of visual field. The aetiology is not completely understood, but one of the major risk factors is elevated intraocular pressure (IOP). Reliable methods for measuring the IOP are therefore important. The aim of the study was to investigate the ability of the applanation resonance tonometry (ART) system, based on continuous force and area recording, to measure IOP in humans. Both the phase of initial indentation (IOPIndentation) and the phase when the sensor was removed (IOPRemoval) from the cornea were analysed. The Goldmann applanation tonometry (GAT) was used as reference method. The study included 24 healthy volunteers with normal IOP and 24 patients with elevated IOP. The correlation and standard deviation (SD) between IOPIndentation and IOPGAT was R = 0.92 (p < 0.001), SD = 3.6 mmHg, n = 104, and between IOPRemoval and IOPGAT R = 0.94 (p < 0.001), SD = 3.1 mmHg, n = 104. In conclusion, resonance sensor technology has made it possible to introduce a new multi-point method for measuring IOP, and the method is relevant for measuring IOP in humans. The study indicates that with further development towards elimination of position dependence, the ART has the potential to become a useful clinical instrument for IOP measurement.     

Insulin-like growth factor II signaling through the insulin-like growth factor II/mannose-6-phosphate receptor promotes exocytosis in insulin-secreting cells

The insulin-like growth factor II (IGF-II)/mannose-6-phosphate (M-6-P) receptor is known to participate in endocytosis as well as sorting of lysosomal enzymes and is involved in membrane trafficking through rapid cycling between cytosolic membrane compartments and the plasma membrane. Here we demonstrate that IGF-II, acting through the IGF-II/M-6-P receptor, promotes exocytosis of insulin in the pancreatic β cell. The effect of IGF-II was evoked at nonstimulatory concentrations of glucose, was mediated by a pertussis toxin sensitive GTP-binding protein, was dependent on protein kinase C-induced phosphorylation, and was independent of changes in cytoplasmic free Ca²⁺ concentration. Since the applied concentration of IGF-II is within the range normally found free in circulation in humans, this novel signaling pathway for the IGF-II/M-6-P receptor is likely to be involved in modulation of insulin exocytosis under physiological conditions.     

Detection and quantification of beta cells by PET imaging: why clinical implementation has never been closer

In this issue of Diabetologia, Alavi and Werner ( https://doi.org/10.1007/s00125-018-4676-1) criticise the attempts to use positron emission tomography (PET) for in vivo imaging of pancreatic beta cells, which they consider as ‘futile’. In support of this strong statement, they point out the limitations of PET imaging, which they believe render beta cell mass impossible to estimate using this method. In our view, the Alavi and Werner presentation of the technical limitations of PET imaging does not reflect the current state of the art, which leads them to questionable conclusions towards the feasibility of beta cell imaging using this approach. Here, we put forward arguments in favour of continuing the development of innovative technologies enabling in vivo imaging of pancreatic beta cells and concisely present the current state of the art regarding putative technical limitations of PET imaging. Indeed, far from being a ‘futile’ effort, we demonstrate that beta cell imaging is now closer than ever to becoming a long-awaited clinical reality.     

Formation and emission of large furans and oxygenated hydrocarbons from flames

Many oxygenated hydrocarbon species formed during combustion, such as furans, are highly toxic and detrimental to human health and the environment. These species may also increase the hygroscopicity of soot and strongly influence the effects of soot on regional and global climate. However, large furans and associated oxygenated species have not previously been observed in flames, and their formation mechanism and interplay with polycyclic aromatic hydrocarbons (PAHs) are poorly understood. We report on a synergistic computational and experimental effort that elucidates the formation of oxygen-embedded compounds, such as furans and other oxygenated hydrocarbons, during the combustion of hydrocarbon fuels. We used ab initio and probabilistic computational techniques to identify low-barrier reaction mechanisms for the formation of large furans and other oxygenated hydrocarbons. We used vacuum-UV photoionization aerosol mass spectrometry and X-ray photoelectron spectroscopy to confirm these predictions. We show that furans are produced in the high-temperature regions of hydrocarbon flames, where they remarkably survive and become the main functional group of oxygenates that incorporate into incipient soot. In controlled flame studies, we discovered ∼100 oxygenated species previously unaccounted for. We found that large alcohols and enols act as precursors to furans, leading to incorporation of oxygen into the carbon skeletons of PAHs. Our results depart dramatically from the crude chemistry of carbon- and oxygen-containing molecules previously considered in hydrocarbon formation and oxidation models and spearhead the emerging understanding of the oxidation chemistry that is critical, for example, to control emissions of toxic and carcinogenic combustion by-products, which also greatly affect global warming.Oxygenated hydrocarbons produced during combustion can have a wide range of detrimental effects on human health, air quality, and regional and global climate. Furans, for example, are compounds that contain five-membered rings with four carbon atoms and one oxygen atom. They are frequently observed in the exhaust plumes and nearby environment of combustion sources. Many studies have shown that they are toxic, whether ingested or inhaled, and thus pose a considerable threat to human health (1–4). The simplest of these compounds (i.e., unsubstituted furan, C₄H₄O) is a cyclic, dienic ether with a low molecular weight, high volatility, and high lipophilicity. Studies on rats and mice have shown a dose-dependent increase in hepatocellular adenomas and carcinomas, indicating that furan is carcinogenic (4), and furan is marked as a high-priority substance and a carcinogenic risk by the World Health Organization (5).Combustion sources of furans include biomass burning (6–9), cigarette and pipe smoke (10, 11), waste incineration (12), electronic waste recycling (13, 14), and volcanic activity (15). The polychlorinated dibenzofurans (PCDFs) are among the most notorious environmental pollutants, and the main source of PCDFs is biomass burning (6–9, 16). Nonchlorinated furans and PCDFs have been shown to be kinetically linked (17, 18). Furans released during combustion are often partitioned into particles and are found in ash from peat (9) and wood (6) burning, in primary organic aerosols from meat cooking (19), and in secondary organic aerosols from hydrocarbon oxidation (20, 21). Wood burning for heating and cooking constitute a major human exposure to airborne particulate PCDFs in some parts of the world (22, 23).Previous work has suggested that oxygenated species can be attached to surfaces of soot particles of varying maturity emitted from flames and diesel engines, even before atmospheric processing (24–32). Functional groups that have been identified include alcohols/enols, carbonyls, peroxies, and ethers. Oxygen atoms bound to organic species on the particle surface have been shown to greatly affect soot hygroscopicity (28) and the ability of soot particles to adsorb atmospheric water vapor and act as cloud-condensation or ice nuclei. Soot particles emitted from combustors, such as diesel engines, are generally hydrophobic, and enhancements in hygroscopic particle emissions could have substantial indirect climate effects via their influence on cloud formation (33). The effect of soot emissions on cloud-nucleation properties is a major uncertainty in climate predictions (34–36).Despite the impact of large oxygenated hydrocarbons on combustion chemistry, the environment, and human health, very little is known about their formation mechanisms and emissions. In this paper we present evidence of the formation of oxygenated compounds, including furans, during the combustion of hydrocarbon fuels. Via a synergistic approach that includes ab initio methods and a stochastic model in conjunction with experimental measurements, we identify reaction pathways leading to formation of oxygenated compounds during the combustion of ethylene. We recorded aerosol mass spectra sampled from premixed and diffusion flames, using synchrotron-generated vacuum-UV (VUV) radiation for ionization, for comparison with masses of the predicted chemical compositions. The mass spectra show masses of oxygenated species that agree with the atomic compositions predicted by the simulations. Both experiments and simulations demonstrate that ∼50% of the mass peaks observed at some flame heights in the mass range 140–350 u (unified atomic mass units) contain signal from oxygenated species. We also recorded X-ray photoelectron spectroscopy (XPS) spectra of soot samples extracted from these flames for further validation of these mechanisms by comparison with functional groups of the predicted oxygenated species incorporated into particles. The XPS measurements confirm formation of furan precursors, hydroxyl groups, early in the soot-formation process and evolution of furan signatures, ether groups, as the combustion and particles evolve.The present study represents an important step toward the development of predictive models for the oxidation of hydrocarbons, which will require that the presence and reactivity of these oxygenated compounds are taken into account. Understanding the chemistry related to high-temperature hydrocarbon oxidation may provide a key to controlling emissions of harmful combustion byproducts, such as soot, nonchlorinated furans, and PCDFs, leading to multiple environmental and health benefits.     

Women's Perspectives on Female-Initiated Barrier Methods for the Prevention of HIV in the Context of Methamphetamine Use and Partner Violence

BackgroundFemale-initiated barrier methods for the prevention of HIV may be an effective alternative for drug-using women who are unable to negotiate safe sex, often as a result of physical and/or sexual partner violence.MethodsUtilizing a SAVA (substance abuse, violence, and AIDS) syndemic framework, we qualitatively examined perspectives on female condoms and vaginal microbicides among 18 women with histories of methamphetamine abuse and partner violence in San Diego, California.FindingsMost women were not interested in female condoms owing to perceived discomfort, difficulty of insertion, time-intensive effort, and unappealing appearance. Alternatively, most women viewed vaginal microbicides as a useful method. Positive aspects included convenience, ability to disguise as a lubricant, and a sense of control and empowerment. Concerns included possible side effects, timing of application, and unfavorable characteristics of the gel. Acceptability of female-initiated barrier methods was context dependent (i.e., partner type, level of drug use and violence that characterized the sexual relationship).ConclusionsFindings indicate that efforts are needed to address barriers identified for vaginal microbicides to increase its uptake in future HIV prevention trials and marketing of future Food and Drug Administration-approved products. Strategies should address gender-based inequalities (e.g., partner violence) experienced by drug-using women and promote female empowerment. Education on female-initiated barrier methods is also needed for women who use drugs, as well as health care providers and other professionals providing sexual health care and contraception to women with histories of drug use and partner violence.     

Potential Barriers to Healthcare in Malawi for Under-five Children with Cough and Fever: A National Household Survey

Failure to access healthcare is an important contributor to child mortality in many developing countries. In a national household survey in Malawi, we explored demographic and socioeconomic barriers to healthcare for childhood illnesses and assessed the direct and indirect costs of seeking care. Using a cluster-sample design, we selected 2,697 households and interviewed 1,669 caretakers. The main reason for households not being surveyed was the absence of a primary caretaker in the household. Among 2,077 children aged less than five years, 504 episodes of cough and fever during the previous two weeks were reported. A trained healthcare provider was visited for 48.0% of illness episodes. A multivariate regression model showed that children from the poorest households (p=0.02) and children aged >12 months (p=0.02) were less likely to seek care when ill compared to those living in wealthier households and children of higher age-group respectively. Families from rural households spent more time travelling compared to urban households (68.9 vs 14.1 minutes; p<0.001). In addition, visiting a trained healthcare provider was associated with longer travel time (p<0.001) and higher direct costs (p<0.001) compared to visiting an untrained provider. Thus, several barriers to accessing healthcare in Malawi for childhood illnesses exist. Continued efforts to reduce these barriers are needed to narrow the gap in the health and healthcare equity in Malawi.Key words: Healthcare surveys, Health expenditure, Health services accessibility, Malaria, Pneumonia, Malawi     

Measurement of the migration of a focal knee resurfacing implant with radiostereometry: An experimental study

Background and purpose

Articular resurfacing metal implants have been developed to treat full-thickness localized articular cartilage defects. Evaluation of the fixation of these devices is mandatory. Standard radiostereometry (RSA) is a validated method for evaluation of prosthetic migration, but it requires that tantalum beads are inserted into the implant. For technical reasons, this is not possible for focal articular resurfacing components. In this study, we therefore modified the tip of an articular knee implant and used it as a marker for RSA, and then validated the method.

Material and methods

We modified the tip of a resurfacing component into a hemisphere with a radius of 3 mm, marked it with a 1.0-mm tantalum marker, and implanted it into a sawbone marked with 6 tantalum beads. Point-motion RSA of the “hemisphere bead” using standard automated RSA as the gold standard was compared to manual measurement of the tip hemisphere. 20 repeated stereograms with gradual shifts of position of the specimen between each double exposure were used for the analysis. The tip motion was compared to the point motion of the hemisphere bead to determine the accuracy and precision.

Results

The accuracy of the manual tip hemisphere method was 0.08–0.19 mm and the precision ranged from 0.12 mm to 0.33 mm.

Interpretation

The accuracy and precision for translations is acceptable when using a small hemisphere at the tip of a focal articular knee resurfacing implant instead of tantalum marker beads. Rotations of the implant cannot be evaluated. The method is accurate and precise enough to allow detection of relevant migration, and it will be used for future clinical trials with the new implant.We have developed a double-coated monobloc articular resurfacing metal implant, with a small peg for primary fixation, to treat localized, full-thickness articular cartilage defects (Manda et al. 2011, Martinez-Carranza et al. 2013). The osseointegration of this implant after 6 and 12 months has been evaluated in animal models by several authors, with promising but varied results (Kirker-Head et al. 2006, Custers et al. 2009, Custers 2010). However, it has not yet been studied in humans. With radiostereometric analysis (RSA), it is possible to obtain highly accurate 3D measurements from calibrated stereoradiographs. By performing repeated measurements over time, implant migration can be quantified and loosening predicted with high sensitivity (Kärrholm et al. 1994, Ryd et al. 1995). The method requires the insertion of tantalum markers into the skeleton and the implant. Marking of an implant requires modification of the implant design, but it is not feasible for custom-made articular focal knee implants. To our knowledge, no other RSA study has been published on these types of components. The aim of this study was to validate point-motion RSA when applied to a new articular resurfacing metal implant used for focal cartilage knee injuries.