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.     

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.     

Regional vulnerability of hippocampal subfields to aging measured by structural and diffusion MRI

In the past few years, there has been an increasing awareness of the regional vulnerability of the hippocampus to age‐related processes. However, to date, no studies have assessed the effects of age on different structural magnetic resonance parameters in the specific hippocampal subfields. In this study, we measured volume, mean diffusivity (MD) and fractional anisotropy (FA) in the presubiculum, subiculum, fimbria, cornu ammonis (CA) 1,2‐3,4‐DG and the whole hippocampus in fifty cognitively intact elder adults between 50 and 75 years of age (20 men, 30 women). Segmentation of hippocampal subfields was performed using FreeSurfer. Individual MD and FA images were coregistered to T1‐weighted volumes using FLIRT of FSL. Linear regression analyses were performed to assess the effects of age on the anatomical measures of each subfield. In addition, multiple regression analyses were also carried out to assess which of the anatomical measures that showed a correlation with age in the previous analyses, were the best age predictors in the hippocampus. In agreement with previous studies, our results showed a significant association between age and volume (P < 0.001) as well as MD (P < 0.001) in the whole hippocampus. Regarding the specific hippocampal subfields, we found that age had a significant negative effect on volume in CA2‐3 (P < 0.001) and CA4‐DG (P < 0.001). Importantly, we found a positive effect of age on MD in CA2‐3 (P < 0.001) and fimbria (P < 0.001) as well as a negative age effect on FA in the subiculum (P < 0.001). Multiple regression analyses revealed that the best overall predictors of age in the hippocampus were MD in the fimbria and volume of CA2‐3, which explained 73.8% of the age variance. These results indicate that age has an effect both on volume and diffusion tensor imaging measures in different subfields, suggesting they provide complementary information on age‐related processes in the hippocampus. © 2013 Wiley Periodicals, Inc.     

Effect of Dapagliflozin in DAPA-HF According to Background Glucose-Lowering Therapy

OBJECTIVETo determine whether the benefits of dapagliflozin in patients with heart failure and reduced ejection fraction (HFrEF) and type 2 diabetes in the Dapagliflozin And Prevention of Adverse-Outcomes in Heart Failure trial (DAPA-HF) varied by background glucose-lowering therapy (GLT).RESEARCH DESIGN AND METHODSWe examined the effect of study treatment by the use or not of GLT and by GLT classes and combinations. The primary outcome was a composite of worsening heart failure (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death.RESULTSIn the 2,139 type 2 diabetes patients, the effect of dapagliflozin on the primary outcome was consistent by GLT use or no use (hazard ratio 0.72 [95% CI 0.58–0.88] vs. 0.86 [0.60–1.23]; interaction P = 0.39) and across GLT classes.CONCLUSIONSIn DAPA-HF, dapagliflozin improved outcomes irrespective of use or no use of GLT or by GLT type used in patients with type 2 diabetes and HFrEF.     

A prospective study of smoking and risk of prostate cancer

We evaluated the hypothesis that smoking increases the incidence of and mortality from prostate cancer. High-quality smoking information was collected in 1971–1975 in a nationwide cohort of 135,006 male construction workers in Sweden. We achieved virtually complete follow-up through record linkages and ascertained as of December 1991 2,368 incident cases of prostate cancer and 709 deaths due to this disease. Rate ratios (RR) of prostate cancer incidence and mortality, with 95% confidence intervals (CI), were estimated in Poisson-based age-adjusted models, with amount and duration of smoking as independent variables. We found no convincing association between current smoking status, number of cigarettes smoked or years since onset and risk of prostatic cancer. The age-adjusted incidence RR among previous smokers was 1.09 and among current smokers 1.11 compared with non-smokers. Weak and inconsistent trends were seen with increasing number of cigarettes smoked per day and increasing duration among current smokers. Smokers of 15 or more cigarettes daily for at least 30 years experienced an incidence RR of 1.30. Mortality in ex-smokers was similar to that in never-smokers; it was, however, slightly increased among current smokers without any trend with amount smoked or duration. The weak and inconsistent associations between smoking and prostate cancer could easily have arisen due to bias or confounding. We therefore conclude that smoking is most likely not causally linked to the occurrence of prostate cancer. © 1996 Wiley-Liss, Inc.