Characterization of N-glucuronidation of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in human liver: importance of UDP-glucuronosyltransferase 1A4.

The nicotine-derived tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is one of the most potent and abundant procarcinogens found in tobacco and tobacco smoke and is considered to be a causative agent for several tobacco-related cancers. Glucuronidation of the major metabolite of NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), has been implicated as an important mechanism for NNK detoxification. To characterize NNAL metabolism by N-glucuronidation in humans, high-pressure liquid chromatography was used to detect glucuronide conjugates of NNAL formed in human liver microsomes in vitro. In addition to peaks corresponding to the O-glucuronides of NNAL (NNAL-O-Gluc), a second series of peaks were observed in human liver microsomes that were identified by liquid chromatography-mass spectrometry to be NNAL N-glucuronides (NNAL-N-Gluc). Microsomes prepared from liver specimens from individual subjects (n = 42) exhibited substantial variability in the levels of NNAL-N-Gluc (49-fold variability) and NNAL-O-Gluc (49-fold variability) formed in vitro. This variability was likely not due to differences in tissue quality, as substantial variability (5-fold) was also observed in the ratio of NNAL-N-Gluc/NNAL-O-Gluc formation, with a mean ratio of 1.7 in the 42 specimens. Liver microsomes from smokers (n = 14) exhibited no significant difference in the levels of either NNAL-N-Gluc or NNAL-O-Gluc formation, or in the ratio of NNAL-N-Gluc/NNAL-O-Gluc formation, as compared with liver microsomes from never smokers (n = 28). Overexpressed UDP-glucuronosyltransferase (UGT) 1A4 exhibited significant levels of N-glucuronidating activity (V(max)/K(m) = 3.11 microl. min(-1). g(-1)) in vitro; no NNAL-N-glucuronide formation was detected for the 11 other overexpressed UGT enzymes tested in these studies. These results demonstrate the importance of N-glucuronidation in the metabolism of NNAL and the role of UGT1A4 in this pathway.     

Comparative evaluation of a heparin‐citrate anticoagulation for LDL‐apheresis in two primary apheresis systems

BACKGROUND: As COBE Spectra has been replaced in many parts of the world, we describe a new protocol for low‐density lipoprotein (LDL)‐apheresis performed on familial hypercholesterolemia patients for the Spectra Optia platform. METHODS: For all procedures, after administering a bolus of heparin of 2,500 U, 10,000 U of heparin added to a 600 ml ACD‐A bag was used as anticoagulant (AC). In a first phase (A), 16 apheresis procedures with COBE Spectra using an inlet:AC ratio of 25:1 were compared to 18 LDL‐apheresis treatments with Spectra Optia at split Inlet:AC ratios of 16:1/18:1 or 20:1/25:1. Platelet activation and coagulation markers were assessed. In a follow‐up phase (B), 20 procedures on Spectra Optia using an inlet:AC ratio of 20:1 were performed. RESULTS: Although coagulation markers and platelet activation analyzed were similar in both apheresis devices used, COBE Spectra procedures did not show any visual clumping in the sets. Visual analysis of clumping was highest in the Spectra Optia's 20:1/25:1 AC regimen (5/8 procedures). For the lowest Spectra Optia, AC regimen and during the follow‐up phase reversible clump formation in the disposable set was similar (1/10 procedures). Clumping was successfully reversed in all cases by temporarily lowering the inlet:AC ratio to 18:1. Blood cell counts (WBC, Plt, Hct) were similar for both COBE Spectra and Spectra Optia procedures. Spectra Optia had a significantly higher plasma removal efficiency versus COBE Spectra (84% vs.75%, P < .05). No serious adverse events were observed. CONCLUSION: Apheresis procedures on the Spectra Optia system with low‐dose heparin‐citrate anticoagulation are feasible and safe.     

Rapid and reliable detection of previous freezing of cerebral tissue by computed tomography and magnetic resonance imaging

Due to slowing or even inhibition of postmortem processes, freezing may make an estimation of the time-since-death very difficult. This is also true in previously frozen and subsequently thawed bodies. Knowledge of prior freezing is important, as it may lead to a different assessment of the time since death. Twelve pig heads were frozen at ?20 °C, and 6 heads were either kept at room temperature (approximately 20 °C) or in a cooling cell (approximately 5 °C). The frozen brains and cadavers were thawed at either room temperature or in a cooling cell. All specimens underwent repeated CT and MRI scanning until the brains were sampled for histological examination. Two radiologists assessed the images and two pathologists reviewed the histological slides with regard to thawing artifacts and putrefaction. All raters were blinded regarding whether the samples had been frozen, for how long and how they had been thawed. Imaging revealed distinct, tiny bubble-like artifacts only in previously frozen specimens. Histology also revealed artifacts only seen in such cases, namely very distinct, columnar bubbles in the cerebral cortex. All raters successfully identified previously unfrozen brains (100% specificity) and nearly all previously frozen brains. Our results suggest that initial post-mortem imaging can be of enormous importance in everyday forensic practice by identifying possible cases of previous freezing – cases that would therefore warrant closer scrutiny and thus raise caution regarding the time of death.     

Reproducibly emitting reference materials for volatile and semi-volatile organic compounds—using finite element modeling for emission predictions

Recent research into emissions of (semi-)volatile organic compounds [(S)VOC] from solid materials has focused on the development of suitable reference materials for quality assurance/quality control of emission test chamber measurements, which fulfill requirements such as homogenous and reproducible (S)VOC release. The approach of this study was to find a method for preparation of a material with predictable (S)VOC emission rates. A VOC (styrene) and an SVOC (2,6-diisopropylnaphthalene, DIPN), loaded into either vacuum grease or a 1:1 mixture of paraffin/squalane, have been tested. For the prediction of the emission rates, a model using the finite element method (FEM) was created to simulate the (S)VOC emission profiles. Theoretical and experimental results obtained in a Micro-Chamber/Thermal Extractor (μ-CTE?) and in 24 L emission test chamber measurements were in good agreement. Further properties were investigated concerning the material applicability, such as shelf life and inter-laboratory comparability. The maximum relative standard deviation in the inter-laboratory study was found to be 20%.     

Primary acute angle closure: long-term clinical outcomes over a 10-year period in the Chinese population

To investigate long-term clinical outcomes after acute angle closure in the Chinese population. A 10-year retrospective review of primary acute angle closure in Hong Kong Chinese to document patient demographics, treatment, and pre- and post-acute angle closure intraocular pressure (IOP) and visual acuity (VA). The year of attack was correlated with the timing of laser, last VA and IOP, and the number of anti-glaucoma eye drops. In 210 eyes (200 patients), 10 % had a simultaneous bilateral acute angle closure. VA improvement was noted in 68.6 % of eyes whilst 11.4 % were blinded. At 3.7 ± 2.4 years of follow-up, 49.5 % had IOP <21 mmHg with medication or surgery, 41.9 % needed anti-glaucoma eye drops, and 13.8 % had undergone trabeculectomy. The older the year of attack, the poorer the VA (r = 0.2, p = 0.03) and the longer the laser wait time (r = 0.3, p < 0.0001). VA outcome and laser promptness in acute angle closure has improved over the years. At 4 years after the attack, 50 % had normal IOP, 69 % had improved VA but 11 % were blinded.     

The international migration of dentists: directions for research and policy

In 2010, the World Health Organization Global Code of Practice for International Recruitment of Health Personnel (the WHO Code) was adopted by the 193 Member States of the WHO. The WHO Code is a tool for global diplomacy, providing a policy framework to address the challenges involved in managing dentist migration, as well as improving the retention of dental personnel in source countries. The WHO Code recognizes the importance of migrant dentist data to support migration polices; minimum data on the inflows, outflows and stock of dentists are vital. Data on reasons for dentist migration, job satisfaction, cultural adaptation issues, geographic distribution and practice patterns in the destination country are important for any policy analysis on dentist migration. Key challenges in the implementation of the WHO Code include the necessity to coordinate with multiple stakeholders and the lack of integrated data on dentist migration and the lack of shared understanding of the interrelatedness of workforce migration, needs and planning. The profession of dentistry also requires coordination with a number of private and nongovernmental organizations. Many migrant dentist source countries, in African and the South‐Asian WHO Regions, are in the early stages of building capacity in dentist migration data collection and research systems. Due to these shortcomings, it is prudent that developed countries take the initiative to pursue further research into the migration issue and respond to this global challenge.     

Identification of early vascular calcification with 18F-sodium fluoride: potential clinical application

Vascular calcification plays a prominent role in cardiovascular disease. Once considered to be a passive consequence of aging, this pathological process is now accepted to be dynamic and tightly regulated, its onset triggered by inflammation and necrosis and its progression bearing key similarities to osteogenesis. A major potential advance in our ability to understand the natural history and clinical implications of vascular calcification is the detection of its early and dynamic stages through the use of the positron-emitting radiotracer, ¹⁸F-sodium fluoride. Alongside anatomical information gained from computed tomography, hybrid positron emission and computed tomography (PET/CT) imaging with ¹⁸F-sodium fluoride has, for the first time, enabled the non-invasive detection of microcalcification within the aortic valve, great vessels, and vulnerable coronary plaque. This has raised promise that exploring this process may allow improved risk prediction, better application of current therapies and ultimately the development of novel treatments to target this widespread pathology.